The antero-posterior heterogeneity of the ventral tegmental area.

Neuroscience 282 (2014) 198–216

REVIEW THE ANTERO-POSTERIOR HETEROGENEITY OF THE VENTRAL TEGMENTAL AREA M. J. SANCHEZ-CATALAN, a,b J. KAUFLING, c,d F. GEORGES, c,d P. VEINANTE a,b AND M. BARROT a,b*

functions. This review highlights the need for a more comprehensive analysis of VTA heterogeneity. This article is part of a Special Issue entitled: Ventral Tegmentum & Dopamine. Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

a Institut des Neurosciences Cellulaires et Inte´gratives, Centre National de la Recherche Scientifique, Strasbourg, France b

Universite´ de Strasbourg, Strasbourg, France

c

Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France d

Key words: dopamine, ventral behavior, drugs of abuse.

Universite´ de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France

tegmental

Contents Introduction VTA antero-posterior functional heterogeneity GABA transmission Ethanol, acetaldehyde and salsolinol Ethanol behavioral studies From ethanol to acetaldehyde and salsolinol Neurochemical studies Electrophysiological studies Opioids Cholinergic system Cocaine Other drugs Affect and pain Neuroanatomy of the VTA Definition of the VTA The VTA and the A10 dopamine cell group Cytoarchitectonic subdivisions of the VTA BASES for the aVTA/pVTA differences The tVTA Detecting the tVTA tVTA control of dopamine cells tVTA and behavior Conclusion Acknowledgments References

Abstract—The ventral tegmental area (VTA) is a brain region processing salient sensory and emotional information, controlling motivated behaviors, natural or drug-related reward, reward-related learning, mood, and participating in their associated psychopathologies. Mostly studied for its dopamine neurons, the VTA also includes functionally important GABA and glutamate cell populations. Behavioral evidence supports the presence of functional differences between the anterior VTA (aVTA) and the posterior VTA (pVTA), which is the topic of this review. This antero-posterior heterogeneity concerns locomotor activity, conditioned place preference and intracranial self-administration, and can be seen in response to ethanol, acetaldehyde, salsolinol, opioids including morphine, cholinergic agonists including nicotine, cocaine, cannabinoids and after local manipulation of GABA and serotonin receptors. It has also been observed after viralmediated manipulation of GluR1, phospholipase Cc (PLCc) and cAMP response element binding protein (CREB) expression, with impact on reward and aversion-related responses, on anxiety and depression-related behaviors and on pain sensitivity. In this review, the substrates potentially underlying these aVTA/pVTA differences are discussed, including the VTA sub-nuclei and the heterogeneity in connectivity, cell types and molecular characteristics. We also review the role of the tail of the VTA (tVTA), or rostromedial tegmental nucleus (RMTg), which may also participate to the observed antero-posterior heterogeneity of the VTA. This region, partly located within the pVTA, is an inhibitory control center for dopamine activity. It controls VTA and substantia nigra dopamine cells, thus exerting a major influence on basal ganglia

area,

tVTA,

198 199 199 199 199 201 202 202 203 204 204 205 205 205 205 206 206 207 209 209 210 210 211 211 211

INTRODUCTION The ventral tegmental area (VTA) is studied for its implication in a wide range of functions including the processing of salient sensory and emotional information, the control of motivated behavior, natural or drug-related reward, reward-related learning, mood, and their associated psychopathologies (Nestler and Carlezon, 2006; Fields et al., 2007; Grace et al., 2007; BrombergMartin et al., 2010; Hong, 2013; Creed et al., 2014; Gillies et al., 2014; Ikemoto and Bonci, 2014; Meye and

*Correspondence to: M. Barrot, Institut des Neurosciences Cellulaires et Inte´gratives, CNRS UPR3212, 5 rue Blaise Pascal, 67084 Strasbourg, France. Tel: +33-388-456-633. E-mail address: [email protected] (M. Barrot). Abbreviations: aVTA, anterior VTA; CNQX, 6-cyano-7nitroquinoxaline-2,3-dione; CREB, cAMP response element binding protein; EM-1, endomorphin-1; NMDA, N-methyl-D-aspartate; PLCc, phospholipase Cc; pVTA, posterior VTA; RMTg, rostromedial tegmental nucleus; tVTA, tail of the VTA; VTA, ventral tegmental area. http://dx.doi.org/10.1016/j.neuroscience.2014.09.025 0306-4522/Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved. 198

M. J. Sanchez-Catalan et al. / Neuroscience 282 (2014) 198–216

Adan, 2014; Nikulina et al., 2014; Overton et al., 2014; Walsh and Han, 2014). While most work related to the dopamine cells of the VTA, recent attention has also been given to the GABA and glutamate cell populations (Roeper, 2013; Creed et al., 2014; Morales and Root, 2014). Beyond this cellular heterogeneity, behavioral evidence has accumulated since the late nineties supporting the presence of a major antero-posterior heterogeneity within the VTA (Ikemoto, 2007). The functional difference between the anterior VTA (aVTA) and the posterior VTA (pVTA) is particularly supported by studies of the locomotor, rewarding and reinforcing properties of various drugs of abuse. However, the substrate underlying such aVTA/ pVTA differences remains elusive, with hypotheses based on neuroanatomy, connectivity and cellular and molecular heterogeneity. Moreover, in the past decade, an inhibitory control center for midbrain dopamine cells was identified and named the tail of the VTA (tVTA) or rostromedial tegmental nucleus (RMTg). The tVTA is partly located within the pVTA and thus should also be considered when studying the antero-posterior heterogeneity of the VTA. In this review, we will first describe the behavioral and physiological evidence supporting the antero-posterior heterogeneity of the VTA. Indeed, historically, the first data highlighting the importance of the VTA anteroposterior functional heterogeneity came from experiments of behavioral pharmacology. Most of these studies did a direct side-by-side comparison of intra aVTA and pVTA drug injections. We will then provide information on the possible bases for such heterogeneity, including the presence of subnuclei within the VTA and the presence of potential differences in connectivity, in cell types and in molecular cell characteristics. It is indeed important to also consider the available information on VTA anatomical heterogeneity, even though no direct link has been established yet between the antero-posterior functional heterogeneity and the precise VTA subnuclei. Last, we will summarize the present knowledge on the tVTA, a structure with its most rostral portion within the pVTA and extending caudally beyond the VTA, that exerts a major control over the activity of mesencephalic dopamine cells. The tVTA may have a critical role in basal ganglia functions. While published work has not directly compared the aVTA, pVTA and tVTA, some evidence suggests that the latter structure might be mediating some of the functions that were previously attributed to the pVTA.

VTA ANTERO-POSTERIOR FUNCTIONAL HETEROGENEITY GABA transmission A third of a century ago, it was observed that injections of GABA modulators in the VTA had different effects on locomotor activity depending on the injection site (Arnt and Scheel-Kruger, 1979) (Table 1). Agonists of GABAA receptors increased locomotor activity when delivered in the pVTA but not in the aVTA, while GABAA antagonists increased activity when delivered in the aVTA but not the pVTA. In the late nineties, Ikemoto et al. observed that

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Wistar rats self-administered antagonists of the GABAA receptor, such as picrotoxin and bicuculline, into the aVTA but not into the pVTA (Ikemoto et al., 1997b; Ikemoto, 2005), whereas they self-administered the GABAA agonist muscimol into the pVTA but not into the aVTA (Ikemoto et al., 1998). These data (Table 1) highlighted the presence of a prominent functional heterogeneity at the level of the GABAergic transmission along the antero-posterior axis of the VTA. However, it may be challenging to control for the anatomical selectivity of local injections, due to the diffusion of injected compounds. Thus, the rewarding effects of GABAA antagonist in the aVTA were later proposed to be associated with the supramammillary nucleus, a hypothalamic area anterior to the VTA and that plays also a role in reward (Ikemoto, 2005, 2010). Nevertheless, differences in the consequences of pVTA and aVTA manipulations remained valid, and these first functional data on the antero-posterior heterogeneity of the VTA opened the path to other studies, in particular in the field of ethanol action and alcoholism (Table 1). It should be noted that, for a long time, the ‘‘aVTA’’ and the ‘‘pVTA’’ were functionally compared without the frontier between them being anatomically defined. A study on the response to cocaine showed that the aVTA/pVTA limit in rats was around 5.5 mm from the bregma, which neuroanatomically corresponds to the position of the interpeduncular nucleus below the VTA ((Olson et al., 2005), see cocaine section below). Ethanol, acetaldehyde and salsolinol Ethanol behavioral studies. Manipulations of the VTA can modify the ethanol intake in rats (Hodge et al., 1993; Katner et al., 1997). While rats directly self-administer ethanol into the VTA, this reinforcing property displays a neuroanatomical selectivity (Fig. 1, Table 1). Indeed, rats self-administer ethanol into the pVTA but not into the aVTA (Rodd-Henricks et al., 2000, 2003; Rodd et al., 2004b, 2005d; Ding et al., 2014), and the infusion of ethanol into the pVTA also increases the rat locomotor activity (Sanchez-Catalan et al., 2009). Considering data obtained in a strain of alcohol-preferring rats, the preferential sensitivity of the pVTA may be relevant to the vulnerability to alcohol. Alcohol-preferring rats self-infuse lower doses of ethanol into the pVTA than Wistar rats (Rodd et al., 2004a), and the dose of ethanol eliciting self-infusion in the pVTA is even lower after chronic ethanol drinking (Rodd et al., 2005b,c). Ethanol can act through several ion channels and neurotransmitter systems (Morikawa and Morrisett, 2010), a major mediator of its action being the GABAergic system. In this context, the alcohol intake (Melon and Boehm, 2011) and the conditioned place preference to ethanol (Bechtholt and Cunningham, 2005) may be decreased by a manipulation of GABAA or GABAB receptors in the pVTA respectively. However another study was also supportive of an influence of aVTA GABAA receptors on ethanol intake (Nowak et al., 1998). Despite the pVTA selectivity for ethanol self-administration, it should be noted that the oral ethanol intake and the locomotor effects

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Table 1. Selected behavioral data on the aVTA, the pVTA and the tVTA. Abbreviations: aVTA, anterior VTA; CPA, conditioned place aversion; CPP, conditioned place preference; FST, forced swim test; ICSA, intracranial self-administration; pVTA, posterior VTA; tVTA, tail of the VTA; VTA, ventral tegmental area In the aVTA Ethanol

Rat

Does not support ICSA

In the pVTA

References

Supports ICSA

Rodd et al., 2000, 2004b (2005d), Ding et al. (2014) Rodd et al. (2003, 2004a, 2005b,c), Ding et al. (2009c, 2012c) Sanchez-Catalan et al. (2009), Marti-Prats et al. (2010, 2013) Rodd et al. (2002, 2005d) Sanchez-Catalan et al. (2009) Rodd et al. (2008) Hipolito et al. (2010)

Supports ICSA

Increases locomotor activity Acetaldehyde

Rat


Salsolinol

Rat


Opioid

Rat

Supports weak ICSA, not CPP, & weakly increases locomotor activity

Cholinergic agonists

Cocaine

Mouse Rat

D9THC

Rat Mouse Rat

AMPA GABAA

Rat Rat

5-HT3 GluR1 PLC!

Rat Rat Rat

Carbachol supports weak ICSA & does not support CPP Nicotine does not support ICSA

Does not support ICSA Does not support ICSA & CPP Doesn’t increase locomotor activity Supports CPA Antagonists support ICSA Agonists do not support ICSA Antagonists but not agonists increase locomotor activity Agonists do not support ICSA Favors morphine CPP Favors morphine CPP Increases sucrose preference Increases anxiety-like behavior No effect on FST No effect on foot-shock response Increases morphine sensitization

CREB mCREB

Supports ICSA Increases locomotor activity Supports ICSA Increases locomotor activity & sensitization Supports CPP Supports ICSA, CPP & increases locomotor activity Supports CPP Carbachol & neostigmine support ICSA, carbachol supports CPP Nicotine supports ICSA Nicotine & carbachol supports ICSA Carbachol increases locomotor activity Supports ICSA Supports ICSA Supports ICSA, CPP & increases locomotor activity Doesn’t support CPA Antagonists do not support ICSA Agonists support ICSA Agonists but not antagonists increase locomotor activity Agonists support ICSA Favors morphine CPA Favors morphine CPA Decreases sucrose preference No effect on anxiety-like behavior Decreases immobility latency in FST Increases foot-shock sensitivity Does not affect morphine sensitization Favors morphine & cocaine CPA Favors morphine & cocaine CPP

Rat

Favors morphine & cocaine CPP Favors morphine & cocaine CPA

Rat Mouse

Supports ICSA & CPP Supports active, passive and conditioned avoidance

Rat Rat

Supports CPA Suppresses cocaine-induced avoidance behavior in runway test (I, L) Supports ICSA (I) Inhibits fear-conditioned freezing, passive response to predator odor & anxietylike behavior (L) Increases motor coordination & motor skill learning (L)

Hipolito et al. (2011) Zangen et al. (2002) Terashvili et al. (2004) Ikemoto and Wise (2002) Ikemoto et al. (2006) Farquhar et al. (2012) Ikemoto et al. (2003) Rodd et al. (2005a) David et al. (2004) Zangen et al. (2006) Ikemoto et al. (2004) Ikemoto et al. (1997b), Ikemoto (2005) Ikemoto et al. (1998) Arnt and Scheel-Kruger (1979) Rodd et al. (2007) Carlezon et al. (2000) Bolanos et al. (2003)

Bolanos et al. (2005) Olson et al. (2005)

tVTA & behavior Opioid Activation

Inhibition (I) or lesion (L)

of ethanol may be modified by microinjections of GABA agonists or antagonists into the aVTA (Nowak et al., 1998; Boehm et al., 2002; Moore and Boehm, 2009).

Jhou et al. (2012) Stamatakis and Stuber (2012), Lammel et al. (2012) Jhou et al. (2013) Jhou et al. (2012) Jhou et al. (2009a) Bourdy et al. (2014)

The reinforcing properties of ethanol in the pVTA depend on the dopaminergic system. Indeed, the co-infusion of the D2 agonist quinpirole into the pVTA,


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Fig. 1. Schematic of the behavioral action of ethanol, acetaldehyde and salsolinol in the aVTA and the pVTA. The aVTA/pVTA limit in rats is around 5.5 mm from the bregma, which neuroanatomically corresponds to the presence of the interpeduncular nucleus below the VTA. Various receptors can influence the behavioral consequences of the pVTA microinjections. Abbreviations: 5-HT, 5-hydroxytryptamine; aVTA, anterior ventral tegmental area; CPP, conditioned place preference; ICSA, intracranial self-administration; IP, interpeduncular nucleus; pVTA, posterior ventral tegmental area.

which would inhibit the dopamine system by stimulating local autoreceptors (Ford, 2014), prevents the local selfadministration of ethanol (Rodd et al., 2004b, 2005d). The self-administration can then be reinstated by the co-infusion into the pVTA of the D2 antagonist sulpiride (Rodd et al., 2004b). Moreover, at terminal fields, the blockade of D1 and D2 dopamine receptors in the nucleus accumbens shell, the ventral pallidum or the medial prefrontal cortex, but not in the nucleus accumbens core, reduces the pVTA ethanol self-administration (Ding et al., 2014). This role of the dopaminergic system is not limited to the self-administration of ethanol into the pVTA. Indeed, the oral intake of ethanol and ethanol seeking behavior are both reduced by the pVTA microinjection of a D2 agonist (Nowak et al., 2000; Hauser et al., 2011). Pre-treatment with the D1 antagonist SCH23390 in the pVTA also decreases ethanol intake, but does not alter ethanol-seeking (Czachowski et al., 2012). Interestingly, while ethanol is not directly self-administered in the aVTA, the local manipulation of the dopaminergic system can influence some ethanol-related behaviors. Thus, the aVTA microinjection of D2 agonists reduces ethanol intake but not ethanol-seeking behavior (Nowak et al., 2000; Hauser et al., 2011). The pVTA self-administration of ethanol is also locally influenced by other transmitter systems, including the opioid, the 5-HT, the cholinergic (nicotinic), the glutamatergic and the cannabinoid systems, reflecting the complex regulation of VTA activity. The endogenous opioid system is intimately associated with ethanol addiction (Gianoulakis, 2009), and opioid antagonists are even used as a treatment for alcoholism (Spanagel and Kiefer, 2008). The intra-pVTA administration of an opioid antagonist prevents the locomotor-activating effects of intra-pVTA ethanol in rats (Sanchez-Catalan et al., 2009), and decreases ethanol-induced conditioned place preference in mice (Bechtholt and Cunningham, 2005). Various intra-pVTA 5-HT3 antagonists can also reduce the pVTA ethanol self-administration (Rodd-Henricks et al., 2003; Rodd et al., 2005d), the pVTA self-administration of a mixture of ethanol and cocaine (Ding et al., 2012c) and the oral self-administration of ethanol (Rodd et al., 2010), while the 5-HT3 antagonists had no effect on oral

ethanol self-administration when delivered into the aVTA (Rodd et al., 2010). In fact, rats will even self-administer a 5-HT3 agonist in the pVTA but not in the aVTA (Rodd et al., 2007). The pVTA ethanol self-administration is also attenuated by the co-infusion of a 5HT2A antagonist (R96544), but not by a 5HT1B antagonist (GR55562) (Ding et al., 2009c). An intra-pVTA microinjection of nicotine can favor ethanol seeking, which is prevented by a nicotinic (mecamylamine) or 5-HT3 receptor antagonist (zacopride) (Hauser et al., 2014). An intra-pVTA administration of the glutamate antagonist CNQX (6-cyano-7nitroquinoxaline-2,3-dione) also reduces ethanol-seeking, but without affecting ethanol intake (Czachowski et al., 2012). Last, the local cannabinoid system also influences ethanol action, since the administration of a CB1 agonist (WIN 55–212) into the pVTA, but not into the aVTA, alters the time-course of binge-like ethanol intake in mice (Linsenbardt and Boehm, 2009). These various interactions may also participate in a cross-vulnerability between alcohol and other drugs of abuse. In addition, the hyperpolarization-activated cyclic nucleotide–gated (HCN) ion channels have also been proposed as a molecular target of ethanol (Brodie and Appel, 1998; Okamoto et al., 2006), and their overexpression in the pVTA increases voluntary ethanol intake in rats (Rivera-Meza et al., 2014). From ethanol to acetaldehyde and salsolinol. Significant evidence implicates the first metabolite of ethanol, acetaldehyde, in the mechanisms underlying the psychopharmacological effects of ethanol (Correa et al., 2012). In fact, it has been demonstrated that acetaldehyde has rewarding properties per se (Correa et al., 2012). The relevance of the role of acetaldehyde in the VTA is further supported by the local presence of the enzymatic machinery necessary to metabolize ethanol (Moreno et al., 1995; Sanchez-Catalan et al., 2008). Rats self-administer acetaldehyde into the pVTA (Fig. 1) but not the aVTA, and the co-administration of the D2/3 agonist quinpirole is able to block this intrapVTA acetaldehyde self-administration (Rodd-Henricks et al., 2002; Rodd et al., 2005d). Acetaldehyde microinjection into the pVTA also increases locomotor activity

202


in rats, which is prevented by an intra-pVTA pre-treatment with a l-opioid receptor antagonist (Sanchez-Catalan et al., 2009). The critical role of acetaldehyde in pVTA ethanol action is demonstrated by the pharmacological use of an acetaldehyde sequestering agent, D-penicillamine. Indeed, the locomotor activity induced by an intra-pVTA ethanol administration can be reduced by D-penicillamine (Marti-Prats et al., 2010). Moreover, a low dose of intrapVTA ethanol can even induce motor depressant action after pre-treatment with D-penicillamine or with sodium azide, a catalase inhibitor blocking the transformation of ethanol into acetaldehyde. Interestingly, this depressant effect can be prevented by the local microinjection of the GABAA antagonist bicuculline (Marti-Prats et al., 2013). Similarly, pre-treatment with the aldehyde dehydrogenase inhibitor cyanamide, which reduces the acetaldehyde degradation, stimulates motor activity in response to the intra-pVTA administration of a normally noneffective dose of ethanol (Marti-Prats et al., 2013). These studies suggest that acetaldehyde is involved in the activating effects of ethanol in the pVTA, while the nonmetabolized ethanol would display a motor depressant action through GABAA receptors (Marti-Prats et al., 2013). The use of sequestering-agents of acetaldehyde proves to be a useful pharmacological tool to assess the role of this metabolite in ethanol effects. The recent demonstration that the intra-pVTA administration of D-penicillamine can block relapse in a preclinical model of alcohol deprivation (Orrico et al., 2013) also suggests a therapeutic potential for these compounds. The acetaldehyde is also a highly reactive compound. In the presence of dopamine, a condensation reaction leads to the production of salsolinol (1-methyl-6,7dihidroxy-1,2,3,4-tetrahydroisoquinoline) (Fig. 1), which has been implicated in some of the neurobiological effects of ethanol (Hipolito et al., 2012). Thus, a salsolinol microinjection into the pVTA is sufficient to increase the locomotor activity of rats in a dose-dependent manner, this action being blocked by an intra-pVTA pre-treatment with the opioid antagonist naltrexone or with the selective l-opioid antagonist b-funaltrexamine (Hipolito et al., 2010). When repeated, the intra-pVTA administration of salsolinol leads to locomotor sensitization (Hipolito et al., 2010) and induces conditioned place preference (Hipolito et al., 2011). Furthermore, rats self-administer salsolinol directly into the pVTA, but not into the aVTA, this self-administration being impaired by pre-treatment with the D2 agonist quinpirole or the 5-HT3 antagonist ICS205–930 (Rodd et al., 2008). The reinforcing properties of salsolinol are thus similar to those of acetaldehyde and of ethanol itself but they can be seen at much lower doses (Rodd-Henricks et al., 2000, 2002, 2003; Rodd et al., 2004b, 2005d; Sanchez-Catalan et al., 2009), highlighting salsolinol as an important and likely candidate to mediate the neurobiological effects of ethanol. (Table 1) Neurochemical studies. While there is agreement that ethanol administration into the aVTA does not influence dopamine levels in the nucleus accumbens (Ericson et al., 2008) (more specifically in the nucleus accumbens shell (Ding et al., 2009b)), there are discrepancies

concerning the consequences of pVTA administration, some authors observing increased dopamine levels in the nucleus accumbens shell (Melis et al., 2007; Ding et al., 2009b), whereas others did not observe changes when sampling the transition zone between the core and the shell (Ericson et al., 2008). The ethanol injection into the pVTA but not the aVTA was also proposed to increase extracellular dopamine levels in the ventral pallidum and in the medial prefrontal cortex (Ding et al., 2011). When repeated, the infusion of ethanol into the pVTA sensitizes the dopaminergic response, further increasing extracellular dopamine levels in the nucleus accumbens shell (Ding et al., 2009b); and cross-sensitization between drugs of abuse can also be observed, as repeated pVTA administration of nicotine increases the effect of a pVTA ethanol administration on the nucleus accumbens shell dopamine levels (Ding et al., 2012b). In line with an interaction between ethanol action and the cholinergic system, the antagonism of nicotinic receptors by mecamylamine in the aVTA blocks the dopamine level increase in the nucleus accumbens after intraaccumbens ethanol perfusion (Ericson et al., 2008). Interestingly, acetaldehyde and salsolinol administered into the pVTA increase the extracellular dopamine levels in the nucleus accumbens shell (Melis et al., 2007; Hipolito et al., 2011; Deehan et al., 2013), supporting the idea that the properties of these compounds are similar to the ones of ethanol. The stimulation of the dopaminergic transmission by an intra-pVTA salsolinol administration can be blocked by the pVTA pre-treatment with the l-opioid antagonist b-funaltrexamine, which parallels the behavioral action of salsolinol (Hipolito et al., 2011). The pVTA dopamine levels are also associated with spontaneous preference for alcohol. Indeed, the basal pVTA dopamine levels are lower in a strain of alcoholpreferring rats compared to their Wistar controls (Liu et al., 2006). However, when exposed to alcohol drinking, the alcohol preferring rats display increased basal pVTA dopamine levels (Engleman et al., 2011). This could suggest that the alcohol intake in these rats may be driven by compensatory mechanisms in order to reach a higher steady-state of dopaminergic activity. Such a hypothesis is attractive and would be in agreement with a ‘‘self-medication’’ hypothesis, suggesting that alcohol helps these animals reach an optimized ‘‘hedonic set-point’’. Exploring this hypothesis will require further research. Finally, ethanol may not only recruit the dopamine system. Acute and repeated systemic ethanol administration as well as chronic ethanol drinking increases the extracellular levels of glutamate in the pVTA (Ding et al., 2012a, 2013). Electrophysiological studies. Despite behavioral evidence, electrophysiological studies do not usually differentiate between the anterior and the pVTA dopamine neurons. Some recent studies, however, assessed the effects of ethanol and its derivates on dopamine neurons of the aVTA and the pVTA. These dopamine neurons have similar electrophysiological features, although different responses to ethanol (Guan et al., 2012). In ex vivo brain slices, ethanol inhibits the


dopamine neurons of the aVTA whereas it stimulates the ones of the pVTA (Melis et al., 2007, 2013; Guan et al., 2012). This latter effect is due to a reduction of the GABAergic influence on pVTA dopamine neurons (Guan et al., 2012), which thus favors the disinhibition of dopamine cells (Johnson and North, 1992). Likewise, voluntary ethanol intake increases the number of active dopamine neurons in the pVTA of alcohol-preferring rats (Morzorati et al., 2010). As this action of alcohol is associated with a reduced pVTA sensitivity of N-methyl-D-aspartate (NMDA) receptors in the pVTA, it is more likely due to a disinhibitory mechanism rather than to the recruitment of excitatory inputs (Fitzgerald et al., 2012). Behavioral and neurochemical studies have shown that acetaldehyde and salsolinol have stimulating properties into the pVTA (Rodd-Henricks et al., 2002; Rodd et al., 2008; Sanchez-Catalan et al., 2009; Hipolito et al., 2010, 2011). Accordingly, it has been observed that they enhance the activity of the pVTA dopamine neurons (Melis et al., 2007; Xie et al., 2012; Xie and Ye, 2012). Moreover, the acetaldehyde derived from ethanol has been proposed to be responsible for the activating effect of ethanol on dopamine cells (Melis et al., 2013). Salsolinol was proposed to enhance dopamine activity through an opioid-dependent mechanism (Xie et al., 2012), however an action on VTA glutamate inputs was also suggested (Xie and Ye, 2012). Opioids Opioids have both dopamine-dependent and dopamineindependent activating and rewarding properties. In the

203

VTA, the opioids can recruit dopamine cells through a disinhibitory mechanism (Johnson and North, 1992; Jalabert et al., 2011). While some authors observed no significant correlation between the VTA antero-posterior placement of morphine injection and the resulting place conditioning (De Jaeger et al., 2013), data from other groups support the idea that opioids can have different behavioral consequences depending on the anteroposterior level within the VTA (Zangen et al., 2002; Jhou et al., 2012). Indeed, endomorphin-1 (EM-1) induces intracranial self-administration, conditioned place preference and increases locomotor activity when administered into the pVTA (Zangen et al., 2002; Terashvili et al., 2004) (Fig. 2, Table 1), whereas it displays weaker intracranial self-administration and stimulating effects and fails to induce conditioned place preference when delivered into the aVTA (Zangen et al., 2002). Similar to ethanol studies, this aVTA/pVTA dichotomy associated with local microinjections does not mean that the aVTA cannot influence systemic drug response. Indeed the reversible inactivation of the aVTA by lidocaine decreases morphine-induced conditioned place preference (Moaddab et al., 2009). Moreover, the inactivation of the aVTA, but not of the pVTA, by GABA agonists impairs heroin-conditioned immunomodulation (Hutson et al., 2014). Last, the inactivation of AMPA receptors by CNQX delivery into the aVTA blocks the morphine-induced place conditioning and the heroin self-administration, although it does not modulate those behaviors (but it modulates the motor-activating effects) when the AMPA antagonist is administered into the pVTA (Shabat-Simon et al., 2008).

Fig. 2. Schematic of the manipulations of the aVTA and the pVTA sustaining intracranial self-administration (ICSA), inducing conditioned place preference (CPP) and stimulating locomotor activity (activity), local electrophysiological response of dopamine cells (DA), and behavioral consequences of viral-mediated local expression of GluR1, PLCc, CREB and mCREB. The aVTA/pVTA limit in rats is around 5.5 mm from the bregma, which neuroanatomically corresponds to the presence of the interpeduncular nucleus below the VTA. Abbreviations: 5-HT, 5hydroxytryptamine; aVTA, anterior ventral tegmental area; CPA, conditioned place aversion; D9THC, D9tetrahydrocannabinol; FST, forced swim test; IP, interpeduncular nucleus; pVTA, posterior ventral tegmental area.

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A set of studies using viral vector-mediated expression of various proteins in the aVTA or in the pVTA are important to mention here. Thus, the overexpression of the GluR1 subunit of the AMPA receptor (Carlezon et al., 2000), of the phospholipase Cc (PLCc) which is implicated in the intracellular cascade activated by neurotrophic factors (Bolanos et al., 2003) or of the transcription factor cAMP response element binding protein (CREB) (Olson et al., 2005) modulates in opposite ways the rewarding properties of a low dose of morphine depending whether this overexpression is performed in the aVTA or in the pVTA. When GluR1, PLCc or CREB are overexpressed in the aVTA, the rewarding properties of morphine as evaluated by place conditioning are enhanced, while the same dose of morphine becomes aversive if these proteins are overexpressed in the pVTA (Carlezon et al., 2000; Bolanos et al., 2003; Olson et al., 2005). These data are further reinforced by the fact that the aVTA or the pVTA overexpression of mCREB, a dominant negative form of CREB acting as an antagonist, leads to consequences that are opposite to the ones of CREB overexpression (Olson et al., 2005), i.e. an aversion to a low dose of morphine if overexpressed in aVTA and an enhancement of morphine reward if overexpressed in the pVTA. The opposite action of the aVTA and the pVTA manipulations on morphine place conditioning was particularly striking after the PLCc overexpression (Bolanos et al., 2003); furthermore, the PLCc overexpression in the aVTA, but not in the pVTA, also enhanced morphine-induced locomotor sensitization (Bolanos et al., 2005). As neurotrophic factors in the VTA have been related to the effects of drug of abuse (Nikulina et al., 2014), the PLCc data suggest that the action of neurotrophic factors might also depend on the considered anteroposterior level within the VTA. Cholinergic system The cholinergic system is a key modulator of the VTA dopamine cells (Faure et al., 2014), but the behavioral effect of cholinergic agents may vary depending on the VTA subregions. Thus, nicotine, the cholinergic agonist carbachol and the acetylcholinesterase inhibitor neostigmine support intracranial self-administration in the pVTA of rats (Ikemoto and Wise, 2002; Ikemoto et al., 2003, 2006; Farquhar et al., 2012) (Fig. 2, Table 1), whereas the intracranial self-administration of carbachol is weaker (Ikemoto and Wise, 2002) and the intracranial self-administration of nicotine does not occur (Ikemoto et al., 2006) into the aVTA. The pVTA self-administration of carbachol is prevented by a muscarinic (scopolamine), a nicotinic (dihydro-b-erythroidine) or a D1 receptor (SCH23390) antagonist (Ikemoto and Wise, 2002), and the pVTA self-administration of nicotine by a nicotinic antagonist (mecamylamine) and a D2 agonist (quinpirole) (Ikemoto et al., 2006). Furthermore, the administration of carbachol into the pVTA also induces locomotor activity, conditioned place preference and c-Fos expression in several brain regions (Ikemoto and Wise, 2002; Ikemoto et al., 2003; Schifirnet et al., 2014). Some discrepancies are however present concerning the ability of carbachol to induce conditioned place preference into the aVTA (Ikemoto and

Wise, 2002; Schifirnet et al., 2014), which may be related to the definition of ‘‘aVTA’’. Indeed, a recent study proposed the presence of an aVTA (supporting carbachol conditioned place preference), a mid-VTA (lacking such conditioned response) and a pVTA (supporting carbachol conditioned place preference) along the VTA antero-posterior axis (Schifirnet et al., 2014). However, it may be difficult to discriminate aVTA from lateral hypothalamus effects with very rostral injection sites. The microinjection of a mGlu2/3 receptor agonist (LY379268) or mGlu5 receptor antagonist (2-methyl-6(phenylethynyl)pyridine, MPEP) into the pVTA decreases nicotine intravenous self-administration in Wistar rats (Liechti et al., 2007; D’Souza and Markou, 2011), further highlighting the role of the pVTA in the reinforcing properties of nicotine. Ex vivo electrophysiological studies have also suggested that nicotine preferentially activates dopamine neurons of the pVTA, whereas nicotine effect is weaker on neurons from the aVTA, which is likely due to a different expression of nicotinic receptors (Li et al., 2011; Zhao-Shea et al., 2011). Overall, these studies provide evidence of an activating effect of cholinergic agonists in the VTA, and most importantly within the pVTA. Cocaine Rodents self-administer cocaine into the pVTA (David et al., 2004; Rodd et al., 2005a) (Fig. 2, Table 1), but not in the aVTA (Rodd et al., 2005a). This pVTA selfadministration of cocaine can be blocked by systemic pre-treatment with a D1 (SCH23390) or a 5HT1B (GR127935) antagonist, by the co-infusion of a 5HT3 (ICS205–930) antagonist, or by the co-infusion of the D2/3 agonist quinpirole (David et al., 2004; Rodd et al., 2005a). While the pVTA preferentially supports intracranial cocaine self-administration, both the aVTA and the pVTA can influence systemic cocaine effects. For example, the inhibition of the aVTA (but not of the pVTA) by muscimol increases the motivation for cocaine intake (as shown by higher breaking-point in selfadministration), and also decreases the number of cocaine self-infusions under a FR1 fixed ratio, suggesting an enhanced rewarding effect of cocaine (Lee et al., 2007). Moreover, cocaine place conditioning can also be suppressed by the microinjection of a l-opioid agonist into the aVTA, but not into the pVTA, while microinjections into the pVTA, but not the aVTA, suppress cocaine-induced locomotor activity (Soderman and Unterwald, 2008). These data could suggest a possible dissociation between the pathways underlying the rewarding and the locomotor effects of cocaine. However, the dopaminergic lesion of the medial pVTA (sparing the parabrachial pigmented nucleus of the VTA) (Ouachikh et al., 2013), but not of the aVTA (Ouachikh et al., 2014), impairs cocaine-induced conditioned place preference. The respective roles of the aVTA and the pVTA in cocaine responses are thus complex, which may also reflect the complexity of the feed-forward and feed-back circuitry of the ventral tegmentum and basal ganglia.


Similarly to morphine place conditioning, the aVTA and the pVTA manipulations of the transcription factor CREB have opposite actions on cocaine place conditioning (Olson et al., 2005). A viral-mediated overexpression of CREB in the rat aVTA favors place preference for a threshold dose of cocaine, while the same dose becomes aversive if CREB is overexpressed in the pVTA; and these effects are mirrored after the expression of the dominant negative mCREB (Olson et al., 2005). This study was particularly important as it also searched for the limit between the aVTA and the pVTA in rats. For this, the viral vectors for CREB or mCREB expression were injected at different antero-posterior levels within the VTA, and the response to cocaine was tested in the place conditioning paradigm. An inflexion point was observed between the rewarding and aversive effects of cocaine, around 5.5 mm from the bregma, which neuroanatomically correspond to the location of the interpeduncular nucleus below the VTA. This transition point is similar to the one that was more recently observed between the lack or presence of conditioned place preference after intra-VTA carbachol administration (Schifirnet et al., 2014).

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preference, while the overexpression in the pVTA blunted it. These findings should also be considered in the context of VTA neurotrophic factors and mood disorders (Nikulina et al., 2014; Walsh and Han, 2014), as PLCc participates to the intracellular signaling cascade activated by these factors. Last, some data also report differences in the control of pain-related responses along the antero-posterior extent of the VTA. Thus, pVTA PLCc overexpression in rats lowered the foot-shock thresholds inducing a jump response, while an aVTA overexpression did not affect it (Bolanos et al., 2003). Experiments on tail shocks’ thresholds inducing vocalizations also showed aVTA/pVTA differences in the control of such responses. The microinjection of the cholinergic agonist carbachol into the pVTA strongly increased the shock intensity necessary to elicit a vocalization (Schifirnet et al., 2014), which was prevented by either nicotinic (mecamylamine) or muscarinic (atropine) antagonists. No influence was observed at more anterior levels (designed in this article as ‘‘midVTA’’), and an increase in the shock intensity eliciting vocalization was again observed more rostrally (designed in this article as ‘‘aVTA’’) but in this case only mecamylamine prevented it.

Other drugs An opposite modulation of brain stimulation reward has been observed after blocking NMDA and AMPA receptors in the VTA. The changes in reward threshold positively correlated with the VTA antero-posterior position of a NMDA antagonist injection, while it negatively correlated with the antero-posterior position of an AMPA antagonist injection (Ducrot et al., 2013). The influence of AMPA antagonism was thus stronger in the aVTA. Interestingly, intra-aVTA infusions of AMPA itself were also reported to induce conditioned place avoidance, while intra-pVTA AMPA infusions had no effect (Ikemoto et al., 2004). D9tetrahydrocannabinol can induce locomotor activity and conditioned place preference and can support intracranial self-administration when delivered into the pVTA but not into the aVTA (Zangen et al., 2006) (Table 1). Affect and pain Recent attention has been given to the heterogeneity of the VTA cells (Roeper, 2013; Morales and Root, 2014) and of the projection pathways originating from the VTA (Lammel et al., 2014; Walsh and Han, 2014), particularly concerning reward, aversion and depression. Similarly, the aVTA/pVTA differences are not limited to the effect of rewarding or locomotor activating substances (Figs. 1 and 2, Table 1). For example, the overexpression of PLCc in the aVTA, but not in the pVTA, increased the anxiety-like behavior in an elevated plus-maze, while the pVTA overexpression, but not the aVTA one, decreased the latency to immobility in the forced swim test (Bolanos et al., 2003). These data partially dissociated the influence on anxiety and depression-related behaviors, which may be further supported by the fact that the aVTA overexpression of PLCc increased sucrose

NEUROANATOMY OF THE VTA All the behavioral findings reported above provide convincing evidences for the functional antero-posterior heterogeneity of the VTA. This raises the question of the morphofunctional substrate of such heterogeneity. Among the parameters to consider, the neuroanatomy of the VTA (for review: (Yetnikoff et al., 2014)) is a critical one. Definition of the VTA The first occurrence of the VTA in the literature is due to Tsai in 1925 (Tsai, 1925). In its description of the opossum brain, he identified with Nissl and Golgi staining a region lateral to the interpeduncular nucleus as the trigonum interpeduncular. This region included the mamillary peduncle, the medial lemniscus and the nucleus tegmenti ventralis (presently VTA). This latter nucleus constituted the medial part of the trigonum interpeduncular and it spanned from the cerebral peduncle to the ventral tip of the substantia nigra. Before Tsai’s study, the fusiform aspect of the cells of the nucleus tegmenti ventralis had led it to be considered as a part of the substantia nigra (Kosaka and Hiraiwa, 1915; Castaldi, 1923). Accordingly, it has also been designated as the nucleus niger suboculomotorius (Hassler, 1937). However, the small size of the cells as well as the close proximity to the mamillo- and the olfactotegmentalis tracti suggested specific anatomical and functional features for the nucleus tegmenti ventralis; but whether the nucleus tegmentis ventralis belonged or not to the substantia nigra remained an issue that was long discussed. This debate was also due to the cytoarchitectonic heterogeneity of the region, and to the difficulty to clearly differentiate it from the substantia nigra compact part in primates as compared to rodents. In the

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fifties, Nauta’s work confirmed Tsai conclusions, by showing that some brain structures, such as the lateral hypothalamus, project to the VTA but not to the substantia nigra. The ‘‘ventral tegmental area of Tsai’’ was then mentioned for the first time by Nauta in 1958 (Nauta, 1958) (For historical review see: (Oades and Halliday, 1987)).

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The VTA and the A10 dopamine cell group Dopamine was detected in the central nervous system at the end of the fifties (Montagu, 1957; Wei-Malherbe and Bone, 1957), then in neurons in 1962 (Carlsson et al., 1962). This led to the classification, on a neurochemical basis, of 12 catecholaminergic cell groups in the brain (Dahlstrom and Fuxe, 1964). However, the cytoarchitectonic frontiers of brain structures do not always fit with neurochemically identified cell groups. In Dahlstro¨m and Fuxe definition (Dahlstrom and Fuxe, 1964), areas A1–A7 correspond to noradrenergic regions and areas A8–A12 to dopaminergic regions, with five additional dopaminergic regions later identified (A13–A17). Even though dopamine cells form an uninterrupted continuum through the midbrain, three groups were locally defined: A8 associated with the retrorubral field, A9 with the substantia nigra compact part, and A10 with the VTA. The A10 group was distinguished from the two others based on specific inputs, notably described by Nauta (for review: (Ikemoto, 2007)). The connectivity thus influenced the definition of mesencephalic cell groups, and the terms VTA and A10 were often synonymous in the literature; even though the A10 group stricto sensu is only composed of the dopamine cells of the VTA. In the eighties, it was proposed to extend the definition of the A10 group (Hokfelt et al., 1984), by including in it the dopamine neurons of the retrorubral nucleus, of the lateral hypothalamus, of the dorsal raphe and of the periaqueductal gray. While some continuity may be observed between these cell groups, this distinction which further separated the notion of VTA from the A10 group was not followed and is not presently used. Cytoarchitectonic subdivisions of the VTA The subdivisions of the VTA were defined on neuroanatomical and functional basis. Historically, the first subdivisions were cytoarchitectonic, based on the heterogeneity of the morphology and orientation of cells bodies of the VTA and of their neuritis. Functional distinctions were observed more recently. Three studies published in 1979 divided the VTA of Tsai in five nuclei (Phillipson, 1979a,b,c) (Fig. 3). Using Golgi staining, two lateral nuclei were identified: the paranigral nucleus and the parabrachial pigmentosus nucleus (presently parabrachial pigmented nucleus), which are rich in dopamine cells. These nuclei are present over a large part of the rostrocaudal extent of the VTA. The paranigral nucleus is in a zone just above the anterolateral part of the interpeduncular nucleus, and it is mostly composed of fusiform, medium-sized cell bodies and of smaller cells with few spiny dendrites. The limits of the parabrachial pigmented nucleus are more difficult to define as this

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Fig. 3. Schematic of the organization of the rat VTA. The five subdivisions of the VTA, as firstly described by Phillipson (1979a,b,c), are shown on frontal plates of the rat brainstem modified from rat brain atlases, from the aVTA (top) to the pVTA (bottom). The recently defined tVTA is also presented. The anteroposterior distance from the Bregma is indicated above each plate. The aVTA/pVTA limit in rats is around 5.5 mm from the bregma, which neuroanatomically corresponds to the presence of the interpeduncular nucleus below the VTA. Abbreviations: aopt, accessory optic tract; aVTA, anterior VTA; CLi, caudal linear nucleus; cp: cerebral peduncle; fr, fasciculus retroflexus; IF, interfascicular nucleus; IP, interpeduncular nucleus; ml, medial lemniscus; MM, medial mammillary nucleus; mp, mammillary peduncle; PBP, parabrachial pigmented nucleus; pn, pontine nuclei; PN, paranigral nucleus; PPTg: pedunculopontine tegmental nucleus; pVTA, posterior VTA; R, red nucleus; RLi, rostral linear nucleus; RRF, retrorubral field; scp, superior cerebellar peduncle; SNC, substantia nigra, compact part; SNL, substantia nigra, lateral part; SNR, substantia nigra, reticular part; SuMM, supramammillary nucleus, medial part; tth, trigeminothalamic tract; tVTA, tail of the VTA; xscp, decussation of the scp; VTA, ventral tegmental area.


subregion of the VTA is found dorsally and/or dorsolaterally to the paranigral nucleus depending on the anteroposterior level. It also constitutes the lateral limit between the VTA and the substantia nigra. One of the types of cell bodies is in fact similar to the fusiform neurons found on the dorsal tiers of the substantia nigra compact part. Other neurons of the parabrachial pigmented nucleus have a medium-sized globular cell body with numerous radial dendrites. Three median nuclei have been proposed in the VTA: the interfascicular, the rostral linear and the caudal linear nuclei. The interfascicular nucleus extends over the whole antero-posterior extent of the VTA and it is composed of round and densely packed cells, smaller than in the rest of the VTA. Overlying it in its anterior part is the rostral linear nucleus, containing the largest cells of the VTA, and in its posterior part, the caudal linear nucleus. This architectonic parcellation of the VTA into five subregions still remains valid, but other subdivisions have also been proposed (for review of VTA subdivisions, see: (Halliday and Tork, 1986; Oades and Halliday, 1987; Fallon and Loughlin, 1995; Ikemoto, 2007)). In this context, the recent work from Ikemoto is particularly significant. Based solely on the cytoarchitectonic dimension of the VTA, four lateral nuclei were proposed (Ikemoto, 2007). These include the classical paranigral nucleus and parabrachial pigmented nucleus, rich in dopamine cells (Phillipson, 1979a,b,c; Halliday and Tork, 1986; Oades and Halliday, 1987), as well as two additional nuclei: the parafascicular retroflexus area, and the tVTA (Perrotti et al., 2005; Kaufling et al., 2009; Jhou et al., 2009b). In this latter case, only the rostral third of what is now known as the tVTA/RMTg was really described. The parafascicular retroflexus area is the most anterior part of the VTA, with a low density of dopamine cells, continuous with those of the lateral hypothalamus and of the supramamillary nucleus. This area is thus composed of the most anterior part of the paranigral nucleus and of the parabrachial pigmented nucleus. These two nuclei are indeed difficult to differentiate at this anterior level, while they are clearly distinguished in the mid third of the VTA. Then, in the posterior part of the VTA, another group of cells localized dorsolaterally to the interpeduncular nucleus can be seen, based on a Nissl staining. This region was previously included in the paranigral nucleus, but data from the last decade converge to designate it as a distinct region: the tVTA or RMTg (Perrotti et al., 2005; Kaufling et al., 2009; Jhou et al., 2009a,b; Bourdy and Barrot, 2012). This recent analysis of VTA subregions (Ikemoto, 2007) also highlights a classical problem in the definition of the VTA: do the median nuclei (the interfascicular, the rostral linear and the caudal linear nuclei) really belong to the VTA or should they be associated with other structures such as the raphe nuclei? Different authors (Swanson, 1982; Kalivas, 1993; Ikemoto, 2007) would consider that these three median nuclei are not part of the VTA. Thus, while the VTA and the A10 dopamine group are often used as synonyms, the VTA would only include the lateral nuclei (the paranigral nucleus and the parabrachial pigmented nucleus), while the A10 group of

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cell would also include the three median nuclei (Kalivas, 1993). Ikemoto also designated the rostral linear nucleus and the caudal linear nucleus as raphe nuclei, which is also the case since the 4th edition (1998) of the Paxinos and Watson atlas of the rat brain (Paxinos and Watson, 1998, 2007). Last, it is to be noted that in the recent versions of the rat and of the mouse brain atlases (Paxinos and Watson, 2007; Franklin and Paxinos, 2008) a parainterfascicular nucleus has also been identified in the mid to posterior third of the VTA. The parainterfascicular nucleus is wedged between the paranigral nucleus and the parabrachial pigmented nucleus. This name has then been reused by different groups (over 35 references can be presently retrieved under Google Scholar) in rats (Colussi-Mas and Schenk, 2008; Nair-Roberts et al., 2008; Wang and Morales, 2008; Brischoux et al., 2009; Zhang et al., 2014) and in other species (Reyes et al., 2012; Cavalcanti et al., 2014; Schweimer et al., 2014). Accordingly, a recent cytoarchitectonic and chemoarchitectonic reanalysis of the mouse midbrain dopamine cell groups has been done (Fu et al., 2012). Despite the obvious existence of different anatomical subdivisions within the VTA, the question and the study of their respective functions has not yet really been addressed. This is likely due to the difficulty in selectively manipulating these groups of cells, due to their relatively small size, proximity and mostly shared neurochemistry. Recent progress has allowed the study of selected VTA cell populations based on their neurochemistry and/or connectivity (for example mesolimbic vs. mesocortical) (Roeper, 2013; Lammel et al., 2014; Walsh and Han, 2014), leading to major scientific advances. However, these studies did not differentiate yet between VTA subnuclei. The search for specific molecular markers of these sub-regions would allow major progress in the field, by making possible to perform promoter-driven selective targeting of VTA subregions.

BASES FOR THE aVTA/pVTA DIFFERENCES The aVTA and the pVTA cannot be considered as separate brain structures per se. The functional differences that exist between them are thus likely to be based on the preferential targeting of different VTA subnuclei (see above), on differences in connectivity, on differences in the proportion of the various cell types (dopamine, GABA, glutamate, neuropeptides. . .), and on the differential expression of membrane receptors and channels. Different afferents and/or efferents for the aVTA and the pVTA are likely to contribute to the functional differences. The inputs/outputs of the VTA are well described (Yetnikoff et al., 2014), even though detailed differences between VTA subnuclei or along the VTA antero-posterior axis are yet to be completed. A widely studied projection of the VTA dopamine cells is the ventral striatum, with the nucleus accumbens constituting the densest efferent target of VTA cells. This VTA-ventral striatum projection displays a preferential, but not exclusive, posteromedio-anterolateral topography (Phillipson and Griffiths, 1985; Heimer et al., 1991; Berendse et al.,

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1992; Haber and Fudge, 1997; Haber et al., 2000; Hasue and Shammah-Lagnado, 2002; Ikemoto, 2007, 2010) that could partly explain why the pVTA is a preferential substrate for the intracranial self-administration of various substances. The aVTA and lateral portions of the VTA preferentially innervates the lateral part of the ventral striatum, formed by the lateral olfactory tubercle and the lateral parts of the shell and of the core of the nucleus accumbens, whereas the pVTA and the medial portions of the VTA preferentially projects to the medial part of the ventral striatum, formed by the medial olfactory tubercle and the medial shell of the nucleus accumbens (Ungerstedt, 1971; Heimer et al., 1991, 1997; Berendse et al., 1992; Usuda et al., 1998; Hasue and ShammahLagnado, 2002; Zhou et al., 2003; Ikemoto, 2007, 2010). In the mouse, the antero-posterior analysis of the VTA dopamine cells projecting to various forebrain regions also showed a lack of projection from the caudal-most part of the VTA to the lateral shell (Lammel et al., 2008). A topographical organization is also observed for the VTA projections to the dorsal striatum, which mostly arise in the lateral part of the VTA and preferentially the lateral aVTA (Ikemoto, 2007). Similarly, the striato-pallidal projections to the VTA also display a topographical organization, with an antero-posterior gradient and an inverted dorso-lateral gradient (for review see: (Yetnikoff et al., 2014)). The relation between the VTA and the prefrontal cortex still deserves a more detailed analysis. The meso-accumbens and meso-cortical pathways are mostly segregated (Deniau et al., 1980; Fallon, 1981; Lammel et al., 2008). In the rat, meso-cortical cells are distributed throughout the VTA (Deniau et al., 1980), but non-dopamine meso-cortical cells (TH-negative projecting to the cingulate cortex) appear to be more frequently observed in the aVTA (Swanson, 1982). In the mouse, dopamine meso-cortical projections to the prelimbic and infralimbic cortices preferentially arise from the medial pVTA, and non-dopamine ones from the aVTA and from cells in the caudal-most part of the VTA (see supplemental data in Lammel et al., 2008). The neurochemical nature of VTA cell types may thus be important to consider. Moreover, it would be useful to determine whether the prelimbic, infralimbic and cingulate components of the meso-cortical projections arise or not from the same cells, and/or display a topographical organization within the VTA. Differences in the serotonergic (Herve et al., 1987) inputs have also been proposed, as well as for cholinergic inputs from the laterodorsal tegmental nucleus that differently target meso-accumbens and meso-cortical neurons (Omelchenko and Sesack, 2005). It is also noteworthy that some aspects of the pVTA strongly innervate the aVTA, and that the paranigral nucleus project to the interfascicular nucleus (Ferreira et al., 2008), highlighting the existence of intra-VTA circuitries. However, there are few studies aimed at providing a precise analysis of input heterogeneity within the VTA; and a comprehensive re-assessment of the VTA subnuclei connectivity would be likely useful to the field. The VTA contains a relatively large number of neurons, between 10,000 and 20,000 dopamine neurons unilaterally in the rat according to different

studies (Swanson, 1982; German and Manaye, 1993; Nair-Roberts et al., 2008), constituting around 2/3 of the VTA neuronal population (Swanson, 1982; German and Manaye, 1993; Harris and Nestler, 1996; Nair-Roberts et al., 2008). GABA cells and glutamate cells (Morales and Root, 2014; Yetnikoff et al., 2014), including glutamate-dopamine cells, are also present in the VTA. Thus, a differential distribution of the VTA cell types along the antero-posterior axis could be an important factor underlying the functional differences observed between the aVTA and the pVTA after local manipulations. The distribution of dopamine cells indeed differs along the anteroposterior and medio-lateral axes (Swanson, 1982; Fallon and Loughlin, 1995; Ikemoto, 2007; Nair-Roberts et al., 2008). While the dopamine neurons are present throughout the rostro-caudal extent of the VTA, they are more prevalent in the pVTA. Tyrosine hydroxylase-immunoreactive cells are particularly dense in the antero-lateral part of the pVTA, in the paranigral and the parabrachial pigmented nuclei. This density progressively decreases rostrally and caudally to this region. A decreasing lateromedial gradient is also present; however, another region rich in dopamine neurons is also observed in the midline nuclei, corresponding to the interfascicular and the caudal linear nuclei. These midline cell bodies are much smaller but more densely packed than the lateral VTA neurons. While the pVTA is richer in dopamine cells, the aVTA is relatively richer in GABA neurons (Olson et al., 2005; Ikemoto, 2007; Olson and Nestler, 2007) and the VTA glutamate (VGluT2-positive) neurons are also more present within the anterior midline nuclei even though that are found in each VTA subnucleus (Morales and Root, 2014). Different antero-posterior gradients between neuronal cell types could partly explain differences in responses after local drug administration. It has also been proposed that neurons of the aVTA and of the pVTA may express different types of receptors or different subunits of a same receptor. Inactivating GABAA receptors in aVTA is for example reinforcing, while activating these receptors is reinforcing in the pVTA (Ikemoto et al., 1997b,1998). The perfusion of GABAA antagonists into the aVTA also increases the extracellular levels of dopamine in the nucleus accumbens, suggesting that GABAA receptors tonically inhibit the aVTA dopamine neurons projecting to the nucleus accumbens (Ikemoto et al., 1997a), and more specifically to the nucleus accumbens shell (Ding et al., 2009a). Thus, GABAA receptors might be differently localized in the aVTA and in the pVTA, being on dopamine neurons in the aVTA but on inhibitory interneurons in the pVTA. However, such differences in the location of the GABA receptors has not been demonstrated, and another explanation could be that intra-pVTA GABA agents could also modulate nearby tVTA GABA neurons that are known to control the activity of midbrain dopamine cells (Barrot et al., 2012; Bourdy and Barrot, 2012). The pVTA dopamine neurons projecting to the nucleus accumbens seem to be under tonic inhibition through D2 receptors, since the pVTA administration of the D2 antagonist sulpiride increases the extracellular dopamine levels in nucleus accumbens (shell and core),


but also locally into the pVTA (Ding et al., 2009a). It has also been shown that the activation of 5HT3 receptors has a stronger action on dopamine levels in the pVTA than in the aVTA (Liu et al., 2006). The aVTA/pVTA differences in behavior, or in changes in extracellular dopamine levels or dopamine cell activity, that are observed after local manipulation of GABA, dopamine, serotonin, cannabinoid, opioid and nicotinic receptors (see the ‘‘VTA antero-posterior functional heterogeneity’’ section) might reflect some differences in the distribution of these receptors, but specific analyses are still needed to evaluate this.

THE tVTA In the past decade, a new mesopontine region associated to the VTA has been defined: the tVTA or RMTg (Perrotti et al., 2005; Kaufling et al., 2009; Jhou et al., 2009a,b; Barrot and Thome, 2011; Bourdy and Barrot, 2012). As the tVTA is partially embedded in the paranigral nucleus of the VTA and exerts a major control on the activity of dopamine cells, it is likely a new actor to consider when studying and/or interpreting functional antero-posterior differences of the VTA. Detecting the tVTA Experimentally, the easiest way to visualize the tVTA in rats is to expose them acutely or chronically, either through injections or self-administration procedures, to a psychostimulant drug, such as cocaine, amphetamines (D-amphetamine, methamphetamine, or (±)-3,4-methylenedioxymethamphetamine (MDMA)) or even modafinil, and to process the midbrain for immunohistochemistry against either cFos or FosB/DFosB (Scammell et al., 2000; Perrotti et al., 2005; Geisler et al., 2008; Jhou et al., 2009a,b; Kaufling et al., 2009, 2010a,b; Rotllant et al., 2010; Zahm et al., 2010; Lecca et al., 2011; Matsui and Williams, 2011; Cornish et al., 2012; Lavezzi et al., 2012). Within the posterior part of the VTA, a cluster of Fos-positive nuclei can be observed after exposure to any of these drugs. This cluster is located dorso-laterally

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to the interpeduncular nucleus, in a subpart of the region that is designated as the paranigral nucleus in the rat brain atlas (Paxinos and Watson, 2007) (Figs. 3 and 4). Both immunohistochemistry against the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD67) (Olson and Nestler, 2007), and Nissl staining (Ikemoto, 2007) support the idea that this cluster of cells should be differentiated from the surrounding paranigral nucleus. This highly localized Fos staining extends caudally, beyond borders of the VTA as defined by 6th edition of the rat brain atlas (Paxinos and Watson, 2007). In fact, some difference is even present between this continuous cell group and the posterior-most drawings of the ‘‘VTA’’ in this atlas. Indeed, the Fos-stained cell group shifts dorsally along its anteroposterior axis (Kaufling et al., 2009, 2010b) (Figs. 3 and 4), following the position of the superior cerebellar peduncle fibers, laterally to the median raphe nuclei. At some point it is even partly embedded within the superior cerebellar peduncle. At this level, it might correspond to the ‘‘interstitial nucleus of the decussation of the superior cerebellar peduncle’’ newly proposed in the plates 89–92 of the rat brain atlas (Paxinos and Watson, 2007). This mesopontine group of cells, starting within the pVTA and spanning over 1 mm along the antero-posterior axis in rats, corresponds to the tVTA or RMTg (Perrotti et al., 2005; Kaufling et al., 2009; Jhou et al., 2009a,b; Lavezzi and Zahm, 2011; Barrot et al., 2012; Bourdy and Barrot, 2012). The psychostimulant-induced Fos staining allows an easy visualization of the tVTA because surrounding structures are unstained and because almost no staining is present in the tVTA of control animals. It is to be noted that the Fos induction in the tVTA is selectively observed after exposure to arousing psychostimulant drugs, but it is not present after exposure to various other drugs. Indeed, the opiate morphine, ethanol, the benzodiazepine diazepam, the cannabinoid D9-tetrahydrocannabinol, the NMDA antagonists and dissociative drugs ketamine and phencyclidine (PCP), the antidepressants reboxetine, nortriptyline, venlafaxine, and fluoxetine, the 5-HT releaser dexfenfluramine, and the anticonvulsants valproic acid and gabapentin, do not induce Fos in the tVTA (Perrotti et al., 2005; Kaufling et al., 2010b). A lack

tVTA

Fig. 4. Schematic of the consequences of tVTA manipulations. Abbreviations: aVTA, anterior VTA; CPA, conditioned place aversion; CPP, conditioned place preference; DA, dopamine; FC, fear conditioning; ICSA, intracranial self-administration; IP, interpeduncular nucleus; pVTA, posterior VTA; tVTA, tail of the VTA; VTA, ventral tegmental area.

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of tVTA Fos expression is also observed after exposure to stress (Perrotti et al., 2005), to the exception of electric foot-shocks that induce a tVTA Fos response (Jhou et al., 2009a; Brown and Shepard, 2013). Based on connectivity, the tVTA has also been observed in monkeys (Hong et al., 2011) and in mice (Stamatakis and Stuber, 2012; Wasserman et al., 2013). However, the borders of this structure are not yet been clearly defined in these species, and the psychostimulant-induced Fos that is often used in rats might be less pertinent to visualize the tVTA in mice (unpublished observations). tVTA control of dopamine cells The tVTA is mostly composed of GABA neurons (Perrotti et al., 2005; Olson and Nestler, 2007; Kaufling et al., 2009; Jhou et al., 2009b; Balcita-Pedicino et al., 2011), with a notable expression of the l-opioid receptor (Jhou et al., 2009b; Jalabert et al., 2011). Afferents of the tVTA mostly arise in brain regions that also project to the VTA (Kaufling et al., 2009; Jhou et al., 2009b); even though inputs to the VTA and to the tVTA likely originate from different cell populations within these brain regions. For example, the tVTA inputs from the dorsal raphe and the locus cœruleus are non-aminergic and those from the lateral hypothalamus are mostly non-orexinergic (Kaufling et al., 2009), and the VTA and tVTA inputs from the lateral habenula preferentially arise from its medial and lateral subdivisions respectively (Goncalves et al., 2012). Presently, the most studied input to the tVTA remains the lateral habenula (Herkenham and Nauta, 1979; Jhou et al., 2009a, 2013; Brinschwitz et al., 2010; Balcita-Pedicino et al., 2011; Hong et al., 2011; Goncalves et al., 2012; Lammel et al., 2012; Stamatakis and Stuber, 2012; Good et al., 2013; Stamatakis et al., 2013). The output from the tVTA targets relatively few forebrain regions. One of the main forebrain outputs is the lateral hypothalamus. The efferents of the tVTA are more prominently directed toward the brainstem, in particular toward the dopamine cell areas (the VTA, the substantia nigra compact part, and to a lesser extent the retrorubral field) (Ferreira et al., 2008; Jhou et al., 2009a,b; Kaufling et al., 2010a; Balcita-Pedicino et al., 2011; Bourdy and Barrot, 2012). This connectivity and the fact that tVTA fibers do form synapses with dopamine cells of the VTA (Balcita-Pedicino et al., 2011) and of the substantia nigra compact part (Bourdy et al., 2014) and the results of electrophysiological analyses support the hypothesis that the tVTA may be an inhibitory control center for dopamine cell activity (Hong et al., 2011; Jalabert et al., 2011, 2012; Lecca et al., 2011; Matsui and Williams, 2011; Bourdy et al., 2014). The stimulation of the tVTA inhibits midbrain dopamine cells, while its inhibition increases their firing (Hong et al., 2011; Jalabert et al., 2011; Lecca et al., 2011, 2012; Matsui and Williams, 2011; Melis et al., 2013; Bourdy et al., 2014), which indicates the presence of both phasic and tonic controls. This inhibitory control can also be recruited by the stimulation of the lateral habenula inputs to the tVTA (Hong et al., 2011; Lammel et al., 2012; Stamatakis and Stuber, 2012), and a

VTA-lateral habenula-tVTA feedback loop has been recently proposed (Good et al., 2013; Jhou et al., 2013; Stamatakis et al., 2013). Both morphine and the l-opioid agonist, DAMGO, can inhibit the tVTA cells (Lecca et al., 2011; Matsui and Williams, 2011; Matsui et al., 2014). Moreover, the l-opioid receptors expressed by the tVTA GABA cells and their terminals within the VTA are critical to the acute recruitment of dopamine neurons by opiates (Jalabert et al., 2011; Matsui and Williams, 2011; Matsui et al., 2014). This led to the proposal that the classic disinhibition model for acute opiate action on dopamine cells should be updated (Johnson and North, 1992; Barrot et al., 2012; Bourdy and Barrot, 2012). The inhibitory action of a cannabinoid agonist on tVTA neurons (Lecca et al., 2011., 2012) supports the idea that the role of the tVTA in disinhibition models could also be extended to cannabinoids. It remains to be explored whether the tVTA exerts a differential inhibitory control on the aVTA and on the pVTA, which could also participate to VTA anteroposterior functional heterogeneity. Moreover, no information is available yet on developmental aspects of the tVTA, either concerning the origin of the tVTA cells or the development of the tVTA inhibitory innervations of the VTA and of the substantia nigra. Such information would be useful to the field, for example to appreciate whether the tVTA participates to the known heterogeneity in dopamine neuron activity across age or across individuals (Marinelli and McCutcheon, 2014). tVTA and behavior The above data are supportive of a particular role of the tVTA in the response to opiates. This role is behaviorally confirmed by the fact that rats preferentially selfadminister EM-1 and develop conditioned place preference to this opioid when it is microinjected into the tVTA (Jhou et al., 2012) but not into surrounding regions. The local administration of EM-1 likely inhibits tVTA GABA cells. Accordingly, the inhibition of the tVTA by local muscimol administration also sustains selfadministration (Jhou et al., 2012). For both EM-1 and muscimol, this reinforcing effect decreases with the distance of the cannula from the tVTA core. These findings led to reconsideration of previous reports of intra-pVTA muscimol (Ikemoto et al., 1998) and EM-1 (Zangen et al., 2002; Terashvili et al., 2004) reinforcing and rewarding properties (see section on ‘‘VTA antero-posterior functional heterogeneity’’), and suggest that these properties might in fact have been due to an inhibition of what has been designed as the tVTA a few years later. The question is open as to whether other findings previously associated with the manipulation of the pVTA should be revisited by taking the tVTA into consideration (Fig. 4, Table 1). The tVTA has also been associated with the coding of errors in reward prediction (Hong et al., 2011), but the largest set of behavioral data in relation to the tVTA concerns aversive and avoidance-related responses. Lesion of the tVTA inhibits fear-conditioned freezing, passive


(but not active) response to a predator odor, and the anxiety-like behavior in an elevated plus-maze (Jhou et al., 2009a). It also suppresses cocaine-induced avoidance behavior in a runway operant paradigm (Jhou et al., 2013). Reciprocally, the pharmacological stimulation of the tVTA by AMPA is sufficient to induce a conditioned place aversion (Jhou et al., 2013), and the stimulation of the lateral habenula terminals in a midbrain region that includes the tVTA induces active, passive and conditioned avoidance of the stimulation (Lammel et al., 2012; Stamatakis and Stuber, 2012). It should also be considered that the tVTA control not only the VTA, but also the substantia nigra compact part. In this context, a lesion of the tVTA chronically stimulates the nigrostriatal pathway and increases the motor coordination performances and the motor learning in a rotarod task (Bourdy et al., 2014). These last data highlight the critical influence that the tVTA has on basal ganglia circuitry and function.

CONCLUSION There is strong evidence for a functional antero-posterior heterogeneity of the VTA. However, the morphofunctional substrate(s) for this heterogeneity is(are) not clearly identified yet. Differences related to the sub-regions of the VTA, including the recently defined tVTA, and how they may be differently inserted into larger brain circuitries is likely critical. The neurochemical and molecular heterogeneity of VTA cell populations are also important to be considered. Important progress, benefiting from technical advances, has recently been made in relation to some aspects of VTA heterogeneity. Many questions remain unanswered. Detailed reassessments of the VTA cytoarchitecture across species, of the definition of its sub-nuclei, of their cell composition and of their connectivity and of the molecular heterogeneity of these cells, are required. These, together with the search for specific molecular markers that would also allow designing transgenic tools, are among challenges that need to be addressed in order to progress in our understanding of the physiological and pathophysiological influences of the VTA. Acknowledgments—Supported by the Centre National de la Recherche Scientifique, Universite´ de Strasbourg, Universite´ Bordeaux Segalen, and by the Agence Nationale de la Recherche (ANR-11-bsv4-002). We thank Pr. Paul Bolam for his comments on the manuscript.

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(Accepted 10 September 2014) (Available online 18 September 2014)

The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context.

Dopamine and reward seeking: the role of ventral tegmental area.

Activation of the ventral tegmental area increased wakefulness in mice.

Multiplexed neurochemical signaling by neurons of the ventral tegmental area.

Prefrontal Regulation of Neuronal Activity in the Ventral Tegmental Area.

GABAergic inhibition of neurons in the ventral tegmental area.

Separating analgesia from reward within the ventral tegmental area.

Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.

The Vulnerable Ventral Tegmental Area in Parkinson's Disease.

Haloperidol treatment downregulates DCC expression in the ventral tegmental area.

Opioid and hypocretin neuromodulation of ventral tegmental area neuronal subpopulations.

Obesity decreases excitability of putative ventral tegmental area GABAergic neurons.

The action of baclofen on neurons of the substantia nigra and of the ventral tegmental area.

The development of ventral tegmental area (VTA) projections to the visual cortex of the rat.

The cytoarchitecture of the interfascicular nucleus and ventral tegmental area of Tsai in the rat.

Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference.

A Golgi study of the ventral tegmental area of Tsai and interfascicular nucleus in the rat.

Neonatal onset of leptin signalling in dopamine neurones of the ventral tegmental area in the rat.

Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior.

Efferent connections of the substantia nigra and ventral tegmental area in the rat.

Antidepressant-like effect of neurotensin administered in the ventral tegmental area in the forced swimming test.

Stimulation of the mesencephalic ventral tegmental area blunts the sensitivity of cardiac baroreflex in decerebrate cats.

Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro.

Sources of input to the rostromedial tegmental nucleus, ventral tegmental area, and lateral habenula compared: A study in rat.