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Annu. Rev. Neurosci. 1990. 13:387-401 Copyright © 1990 by Annual Reviews Inc. All rights reserved
NEUROTRANSMITTERS IN THE MAMMALIAN CIRCADIAN Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
SYSTEM Benjamin Rusak and K. G. Bina Department of Psychology, Life Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada B3H 411
INTRODUCTION
Background Circadian (daily) rhythms in behavior and physiology are regulated in mammals by a neural mechanism centered in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (Rusak & Zucker 1977, Moore 1983). Although other oscillators exist in the circadian system, the SCN remains the only one that has been localized, demonstrated to oscillate endogen ously, and shown to regulate overt rhythms (Rusak 1989). Its pacemaker properties have been confirmed by the demonstration that an SCN trans planted into an animal made arrhythmic by a previous SCN lesion restores circadian organization (Sawaki et al 1984, Lehman et al 1987); most importantly, the period of the restored rhythm is determined by the genetic makeup of the donor, not the host, animal (Ralph et al 1988). As the pacemakcr for the circadian system, the SCN serves two primary functions: the internal generation of circadian rhythms and their synchronization (entrainment) to local time cues, primarily those provided by environ mental lighting cycles. It has been more than 15 years since the identification of the SCN as the mammalian pacemaker sparked an interest in the anatomy and physiology of this small population of neurons (
�
24 000 in rats; Giildner
1983). The purpose of this chapter is to review and evaluate the evidence relating to one aspect of the neurobiology of the SCN; namely, the neuro transmitters that have been proposed to play a role in rhythm generation and entrainment. This task is complicated by the extraordinary variety of neurotransmitters, receptors, and transmitter-related enzymes that have 387 0147-006X/90/0301-0387$02.00
388
RUSAK & BINA
been identified in this small nucleus. Among the putative neurotransmitters represented in some way in the SCN are serotonin (Aghajanian et al 1969), acetylcholine (Ichikawa & Hirata 1986, Miller et aI1984), excitatory amino acids (Moffett et al 1987, Liou et al 1986), and GABA (van den Pol & Gorcs 1986, Card & Moore 1984). A large number of peptides are also represented in the SCN, including vasopressin (Vandesande et al 1975), vasoactive intestinal polypeptide (Card et al 1981), somatostatin (Card & Moore 1984), neuropeptide Y (Card & Moore 1982, Harrington et al
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
1985), nerve growth factor (Sofroniew et al 1989), and cholecystokinin (Miceli et aI1987), among others (van den Pol & Tsujimoto 1985). That circadian systems are virtually immune to chemical manipulation was once a common assertion. The substances first demonstrated to affect rhythms (D20, lithium, alcohol) have such broad effects on cellular metab olism that they provided no sharp insights into the underlying mechanisms they influenced (Rusak & Zucker 1975). More recently, many neuroactive substances, each with a different cellular impact, have been shown to influence mammalian circadian rhythms (Turek 1987). Their variety has, in fact, become an impediment to the construction of models of neuro chemical pathways in the circadian system.
Analysis of Neurochemical Effects on Rhythms Two methods are commonly used to analyze the roles of neurotransmitters in the circadian system. One is to manipulate a neurochemical system (either systemically or locally in the SCN) in an intact organism and to observe the consequences on the overt expression of rhythms. The second is to study the effects of pharmacological manipulations on cellular activity in the SCN, on the assumption that SCN neural activity reflects some aspect of pacemaker function. Both approaches are predicated on ana tomical and chemical evidence that the neurochemical system being manipulated is actually represented in the SCN by appropriate receptors, enzymes, or transmitters. Unfortunately, these anatomical, behavioral, and physiological analyses of the role of a transmitter often fail to yield convcrgent conclusions. The effects of drugs on overt rhythms are usually evaluated in one of two ways: (a ) efTects of chronic changes in a neurotransmitter system on the free-running period of the rhythm are measured in constant conditions, and (b) effects of transient manipulations on the phase of the rhythm arc measurcd in either cntrained or free-running conditions. A typical approach is to determine the shape of the phase response curve for drug administration, or to ask how altering a neurotransmitter system (acutely or chronically) affects the shape of the phase response curve for light pulses.
CIRCADIAN SYSTEM NEUROTRANSMITTERS
389
The phase response curve is a plot of the amount and direction (advance or delay) of phase shift generated at different circadian phases by exposure to a standard stimulus, typically a light pulse delivered against a back ground of continuous darkness (DeCoursey 1964). It is a uniquely useful tool in the analysis of photic entrainment of rhythms that has been extended to the study of pharmacological agents (Turek 1987). Interpreting phase response curves related to pharmacological agents can, however, be difficult. Light, as a natural entraining agent, can be assumed to activate
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
a functionally coherent neural mechanism. There is no certainty that any drug acts similarly to influence an identifiable functional system, and the interpretation of drug effects is therefore complex. For cxample, activating a particular transmitter system may cause rhythm delays without implying a role for that transmitter in mediating delaying effects oflight. Similarly, neurotransmitter antagonists may alter responses to light pulses, without implying that the related neurotransmitter normally plays a role in medi ating photic effects on rhythms (cf. Ralph & Menaker 1988, Shinozaki 1988). An analysis of the role of neurotransmitters in the circadian system based on phase response curves is a natural choice for circadian physi ologists who have used these tools so successfully in other contexts. Their use in this analysis, however, may entail unstated and untested assumptions that need careful examination.
NEUROCHEMICALS AND THE CIRCADIAN SYSTEM
Acetylcholine One of the earliest suggested transmitters in the circadian system was acetylcholine (ACh), proposed to act through a nicotinic binding site to mediate the effects of light. This suggestion came from studies showing that a putative nicotinic antagonist, a-bungarotoxin (BTX) injected near the SCN could prevent light effects on daily rhythms of pineal N-acetyltransferase (NAT) activity, that a nonspecific cholinergtic agonist (carbachol) could mimic the effects of light, and that SCN cells showed similar responses to light and to cholinergic agents (Nishino & Koizumi 1977, Zatz & Brownstein 1979, 1981, Zatz & Herkenham 1981). Consistent with these reports is evidence that the ACh content of the SCN increases after a light pulse (Murakami et al 1 984). The interpretation that nicotinic sites mediate the light-like effects of carbachol depended on the effectiveness of selective nicotinic agonists and antagonists and the lack of effect of muscarinic agents in modifying the influence of carbachol (Zatz & Brownstein 1 981). A role for a muscarinic
390
RUSAK & BINA
mechanism should not be ruled out, however, since published data indicate that treatment with atropine, a muscarinic antagonist, mimicked the effects of light on pineal NAT (Zatz & Brownstein 198 1). These data suggest that carbachol exerts opposite effects on NAT activity through muscarinic and nicotinic receptors. The dichotomy between muscarinic and nicotinic receptors that is sat isfactory for peripheral sites is inadequate in the central nervous system. A variety of central cholinergic receptors do not fall neatly into either
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
category. The peripheral nicotinic antagonist BTX, for example, does not bind to most sites in the brain that bind ACh and nicotine. BTX binds strongly at the dorsolateral edge of the SCN and bey
Further
Quick links to online content
Annu. Rev. Neurosci. 1990. 13:387-401 Copyright © 1990 by Annual Reviews Inc. All rights reserved
NEUROTRANSMITTERS IN THE MAMMALIAN CIRCADIAN Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
SYSTEM Benjamin Rusak and K. G. Bina Department of Psychology, Life Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada B3H 411
INTRODUCTION
Background Circadian (daily) rhythms in behavior and physiology are regulated in mammals by a neural mechanism centered in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (Rusak & Zucker 1977, Moore 1983). Although other oscillators exist in the circadian system, the SCN remains the only one that has been localized, demonstrated to oscillate endogen ously, and shown to regulate overt rhythms (Rusak 1989). Its pacemaker properties have been confirmed by the demonstration that an SCN trans planted into an animal made arrhythmic by a previous SCN lesion restores circadian organization (Sawaki et al 1984, Lehman et al 1987); most importantly, the period of the restored rhythm is determined by the genetic makeup of the donor, not the host, animal (Ralph et al 1988). As the pacemakcr for the circadian system, the SCN serves two primary functions: the internal generation of circadian rhythms and their synchronization (entrainment) to local time cues, primarily those provided by environ mental lighting cycles. It has been more than 15 years since the identification of the SCN as the mammalian pacemaker sparked an interest in the anatomy and physiology of this small population of neurons (
�
24 000 in rats; Giildner
1983). The purpose of this chapter is to review and evaluate the evidence relating to one aspect of the neurobiology of the SCN; namely, the neuro transmitters that have been proposed to play a role in rhythm generation and entrainment. This task is complicated by the extraordinary variety of neurotransmitters, receptors, and transmitter-related enzymes that have 387 0147-006X/90/0301-0387$02.00
388
RUSAK & BINA
been identified in this small nucleus. Among the putative neurotransmitters represented in some way in the SCN are serotonin (Aghajanian et al 1969), acetylcholine (Ichikawa & Hirata 1986, Miller et aI1984), excitatory amino acids (Moffett et al 1987, Liou et al 1986), and GABA (van den Pol & Gorcs 1986, Card & Moore 1984). A large number of peptides are also represented in the SCN, including vasopressin (Vandesande et al 1975), vasoactive intestinal polypeptide (Card et al 1981), somatostatin (Card & Moore 1984), neuropeptide Y (Card & Moore 1982, Harrington et al
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
1985), nerve growth factor (Sofroniew et al 1989), and cholecystokinin (Miceli et aI1987), among others (van den Pol & Tsujimoto 1985). That circadian systems are virtually immune to chemical manipulation was once a common assertion. The substances first demonstrated to affect rhythms (D20, lithium, alcohol) have such broad effects on cellular metab olism that they provided no sharp insights into the underlying mechanisms they influenced (Rusak & Zucker 1975). More recently, many neuroactive substances, each with a different cellular impact, have been shown to influence mammalian circadian rhythms (Turek 1987). Their variety has, in fact, become an impediment to the construction of models of neuro chemical pathways in the circadian system.
Analysis of Neurochemical Effects on Rhythms Two methods are commonly used to analyze the roles of neurotransmitters in the circadian system. One is to manipulate a neurochemical system (either systemically or locally in the SCN) in an intact organism and to observe the consequences on the overt expression of rhythms. The second is to study the effects of pharmacological manipulations on cellular activity in the SCN, on the assumption that SCN neural activity reflects some aspect of pacemaker function. Both approaches are predicated on ana tomical and chemical evidence that the neurochemical system being manipulated is actually represented in the SCN by appropriate receptors, enzymes, or transmitters. Unfortunately, these anatomical, behavioral, and physiological analyses of the role of a transmitter often fail to yield convcrgent conclusions. The effects of drugs on overt rhythms are usually evaluated in one of two ways: (a ) efTects of chronic changes in a neurotransmitter system on the free-running period of the rhythm are measured in constant conditions, and (b) effects of transient manipulations on the phase of the rhythm arc measurcd in either cntrained or free-running conditions. A typical approach is to determine the shape of the phase response curve for drug administration, or to ask how altering a neurotransmitter system (acutely or chronically) affects the shape of the phase response curve for light pulses.
CIRCADIAN SYSTEM NEUROTRANSMITTERS
389
The phase response curve is a plot of the amount and direction (advance or delay) of phase shift generated at different circadian phases by exposure to a standard stimulus, typically a light pulse delivered against a back ground of continuous darkness (DeCoursey 1964). It is a uniquely useful tool in the analysis of photic entrainment of rhythms that has been extended to the study of pharmacological agents (Turek 1987). Interpreting phase response curves related to pharmacological agents can, however, be difficult. Light, as a natural entraining agent, can be assumed to activate
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
a functionally coherent neural mechanism. There is no certainty that any drug acts similarly to influence an identifiable functional system, and the interpretation of drug effects is therefore complex. For cxample, activating a particular transmitter system may cause rhythm delays without implying a role for that transmitter in mediating delaying effects oflight. Similarly, neurotransmitter antagonists may alter responses to light pulses, without implying that the related neurotransmitter normally plays a role in medi ating photic effects on rhythms (cf. Ralph & Menaker 1988, Shinozaki 1988). An analysis of the role of neurotransmitters in the circadian system based on phase response curves is a natural choice for circadian physi ologists who have used these tools so successfully in other contexts. Their use in this analysis, however, may entail unstated and untested assumptions that need careful examination.
NEUROCHEMICALS AND THE CIRCADIAN SYSTEM
Acetylcholine One of the earliest suggested transmitters in the circadian system was acetylcholine (ACh), proposed to act through a nicotinic binding site to mediate the effects of light. This suggestion came from studies showing that a putative nicotinic antagonist, a-bungarotoxin (BTX) injected near the SCN could prevent light effects on daily rhythms of pineal N-acetyltransferase (NAT) activity, that a nonspecific cholinergtic agonist (carbachol) could mimic the effects of light, and that SCN cells showed similar responses to light and to cholinergic agents (Nishino & Koizumi 1977, Zatz & Brownstein 1979, 1981, Zatz & Herkenham 1981). Consistent with these reports is evidence that the ACh content of the SCN increases after a light pulse (Murakami et al 1 984). The interpretation that nicotinic sites mediate the light-like effects of carbachol depended on the effectiveness of selective nicotinic agonists and antagonists and the lack of effect of muscarinic agents in modifying the influence of carbachol (Zatz & Brownstein 1 981). A role for a muscarinic
390
RUSAK & BINA
mechanism should not be ruled out, however, since published data indicate that treatment with atropine, a muscarinic antagonist, mimicked the effects of light on pineal NAT (Zatz & Brownstein 198 1). These data suggest that carbachol exerts opposite effects on NAT activity through muscarinic and nicotinic receptors. The dichotomy between muscarinic and nicotinic receptors that is sat isfactory for peripheral sites is inadequate in the central nervous system. A variety of central cholinergic receptors do not fall neatly into either
Annu. Rev. Neurosci. 1990.13:387-401. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/05/15. For personal use only.
category. The peripheral nicotinic antagonist BTX, for example, does not bind to most sites in the brain that bind ACh and nicotine. BTX binds strongly at the dorsolateral edge of the SCN and bey
