European Journal o f Pharmacology, 44 (1977) 143--152

143

© Elsevier/North-Holland Biomedical Press

MESOLIMBIC INVOLVEMENT IN THE LOCOMOTOR STIMULANT ACTION OF T H Y R O T R O P I N - R E L E A S I N G H O R M O N E ( T R H ) IN R A T S MASAOMI MIYAMOTO and YUJI NAGAWA Medicinal Laboratories, Central Research Division, Takeda Chemical Industries, Ltd., Osaka 532, Japan

Received 16 November 1976, revised MS received 18 February 1977, accepted 24 March 1977

M. MIYAMOTO and Y. NAGAWA, Mesolimbic involvement in the locomotor stimulant action o f thyrotropinreleasing hormone (TRH) in rats, European J. Pharmacol, 44 (1977) 143--152. Thyrotropin-releasing hormone (TRH) injected i.p. in doses of 5 mg/kg and higher had a strong locomotor stimulant action with development of frequent rearing, mild sniffing, grooming, preening and other excitatory behaviours. The locomotor stimulation was also produced by bilateral injection of TRH and dopamine (DA) into the nucleus accumbens but not by bilateral injection of these substances into the caudate nucleus. Unilateral intracaudate injection of TRH provoked no behavioural changes in contrast to a distinct circling response to similarly injected DA. Either i.p. or bilateral intra-accumbens injection of haloperidol or pimozide in low doses effectively blocked the locomotor stimulant action of TRH. These results indicate that the DA system in the nucleus accumbens may be of importance in mediation of the locomotor stimulant action of TRH. Differential affinity of TRH to the two DA systems, the mesolimbic and nigrostriatal DA systems is also suggested. Thyrotropin-releasing hormone Locomotor stimulation

Nucleus accumbens Caudate nucleus

1. I n t r o d u c t i o n Thyrotropin-releasing hormone (TRH), one of t h e h y p o t h a l a m i c releasing f a c t o r s , is a p o t e n t releaser o f p r o l a c t i n as well as o f t h y r o t r o p i n . In a d d i t i o n t o t h e s e a c t i o n s , T R H has b e e n r e p o r t e d to p o t e n t i a t e an excit a t o r y a c t i o n o f L - D O P A in h y p o p h y s e c t o m i z e d m i c e as well as in n o r m a l m i c e (Plotnik o f f et al., 1 9 7 2 ) . R a d i o i m m u n o l o g i c a l a n d i m m u n o h i s t o c h e m i c a l studies have d e m o n s t r a t e d t h e d i s t r i b u t i o n o f T R H and T R H - c o n taining n e r v e t e r m i n a l s in t h e n u c l e u s a c c u m bens, lateral septal n u c l e u s a n d several m o t o r nuclei o f the brain s t e m a n d spinal c o r d outside t h e h y p o t h a l a m i c area ( W i n o k u r and Utiger, 1 9 7 4 ; H S k f e l t et al., 1 9 7 5 ) . T h e s e findings suggest t h a t , in the brain, T R H m a y p l a y p h y s i o l o g i c a l roles o t h e r t h a n t h a t o f a releasing h o r m o n e . D o p a m i n e (DA) is localised t o t w o specific a n a t o m i c a l s y s t e m s , t h e striatal p a t h w a y

Dopamlne

Circling

originating in t h e A8 and A9 g r o u p s o f cell b o d i e s in t h e s u b s t a n t i a nigra, and the m e s o limbic p a t h w a y w i t h cell b o d i e s o f its origin in t h e A 1 0 g r o u p l o c a t e d m e d i a l t o the A9 g r o u p in t h e m i d b r a i n and w i t h its nerve terminals in t h e nucleus a c c u m b e n s and t u b e r c u l u m o l f a c t o r i u m ( U n g e r s t e d t , 1971). T h e r e are m a n y r e p o r t s suggesting t h a t s t e r e o t y p y and l o c o m o t o r s t i m u l a t i o n i n d u c e d b y certain drugs are m e d i a t e d via the nigrostriatal D A s y s t e m and t h e m e s o l i m b i c D A s y s t e m , r e s p e c t i v e l y (Ernst and Smelik, 1966; A s h e r and A g h a j a n i a n , 1 9 7 4 ; K e l l y et al., 1 9 7 5 ) . An i m p o r t a n t role o f t h e m e s o l i m b i c D A s y s t e m in l o c o m o t o r a c t i v i t y has b e e n f u r t h e r evidenced by the observation that locomotor s t i m u l a t i o n is p r o d u c e d b y i n j e c t i o n of D A into t h e nucleus a c c u m b e n s in t h e rat pretreated with a monoamine oxidase inhibitor ( P i j n e n b u r g and Van R o s s u m , 1973; Pijnenb u r g et al., 1 9 7 5 ) . We h a v e o b s e r v e d m a r k e d l o c o m o t o r s t i m u l a t i o n also r e p o r t e d b y G o u -

144 jet et al. (1975), following the i.p. injection of T R H in rats. Until now little a t t e nt i on has been paid to these different DA systems with regard to this action of TRH. In the present study, an a t t e m p t to det er m i ne the site of the l o c o m o t o r stimulant action of T R H has been made by comparing the behavioural effect of T R H and DA injected into the nucleus accumbens or caudate nucleus of rats. Modification of the T R H effect by some DA r e c e pt or antagonists was also investigated.

M. MIYAMOTO, Y. NAGAWA counts of less than 50 during a 10-min period, the l o c o m o t o r activity was measured for 60 min following the drug injection. General behaviour was simultaneously observed. In anot her experiment, each rat was placed in a cylindrical cage measuring 60 cm in diameter and 40 cm in height, in which the number of circlings was c o u n t e d continuously by visual observation for 60 min following unilateral injection of the drug into the caudate nucleus.

2.3. Drugs and drug injection 2. Materials and m e t h o d s

2.1. Animals and surgery Male Sprague--Dawley (JCL : SD) rats weighing 2 0 0 - - 3 0 0 g, 6--8 weeks old, were used. In preparing the rats for intracerebral injection of the drug, under sodium pentobarbital anesthesia (40 mg/kg i.p.) stainless steel cannulae with an o u t er and inner diameter of 0.8 and 0.5 mm respectively were implanted bilaterally into th e nucleus accumbens or caudate nucleus. Coordinates for the nucleus accumbens were A 9.4, L 1.6, H 1.0; for the head o f the caudate nucleus A 8.2, L 2.8, H 1.0, according to the De G r o o t atlas (De G r o o t , 1959). Cannulae were fixed ont o the skull with acrylic dental cement. The rats were used for experiments at intervals of at least 5 days after a 7-day postoperative period.

2.2. Measurement o f locomotor activity and circling behaviour Each rat was placed in a perspex cage (26 X 42 X 15 cm) m o u n t e d on t op of a Varimex m e t e r (Columbus I ns t r um ent Co.), which was tuned to a sensitivity 20 pA in order to c o u n t mainly large mo v em e nt s , and l o c o m o t o r counts were recorded on a printer. All experiments were p e r f o r m e d be t w een 8:00 a.m. and 6:00 p.m. at an ambient t e m p e r a t u r e of 22 + 2°C. After the rat was well enough accust o m e d to the activity cage to show l o c o m o t o r

The following drugs were used: T RH (L-pyroglutamyl-L-histidyl-L-prolineamide L-tartrate m o n o h y d r a t e , c r y s t a l B described by Hatanaka et al., 1976: Takeda); dopamine h y d r o c h l o r i d e ( T o k y o Kasei); haloperidol (Serenase ®, Dainippon); pimozide (Orap ®, Fujisawa); p h e n o x y b e n z a m i n e h y d r o c h l o r i d e ( T o k y o Kasei). Pimozide was suspended in a 5% gum arabic solution and all ot her drugs were dissolved in physiological saline. Saline was used as a control. The doses q u o t e d refer to amounts of the salts used. Intracerebral injection of drug was made bilaterally or unilaterally by means of a microsyringe with a needle 0.4 mm out er and 0.2 mm inner diameter which e x t e n d e d into the brain tissues 1.5 mm below the tip of the p e r m a n e n t l y implanted cannula. The injection volume was 1 or 2 pl on each side. The volume for i.p. injection was 0.2 ml/100 g b.wt.

2.4. Statistics Statistical comparison between different treatments was made by means of Student's t-test and the Mann--Whitney's U-test. Twotailed probability values are given.

2.5. Histology At the end of the experiments the rats were perfused first with 30 ml of saline and t hen with 50 ml of a 10% formalin solution through t he left cardiac ventricle under

MESOLIMBIC SYSTEM AND LOCOMOTOR STIMULATION BY TRH A 9.4

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Fig. 1. Diagrams representing the location of the cannulae tips for injections into the nucleus accumbens (o) or the caudate nucleus (T) according to the De Groot atlas (1959). Only unilateral sites are shown here from histological data obtained from 30 rats, although bilateral sites were examined. Abbreviations: ACB: Nucleus accumbens septi; CC: Corpus callosum; CPU: Nucleus caudatus Putamen. s o d i u m p e n t o b a r b i t a l anesthesia. The brains were r e m o v e d and k e p t in a 10% f o r m a l i n solution for at least 7 days and t h e n s e c t i o n e d t o verify the site o f injection. Position o f the tips of t h e n e e d l e tracks are m a r k e d on a frontal diagram o f the rat brain (fig. 1).

3. Results

3.1. L o c o m o t o r stimulation and other behavioural changes induced by T R H The c o n t r o l rats injected with saline i.p. or i n t r a c e r e b r a l l y o n l y s h o w e d a mild l o c o m o t o r h y p e r a c t i v i t y d u r i n g the initial 10-rain p e r i o d , p r o b a b l y due t o s t i m u l a t i o n b y t h e i n j e c t i o n p r o c e d u r e b u t t h e r e a f t e r s p e n t m o s t o f the

remaining observation period in a resting state. Table I shows a c o m p a r i s o n o f behavioural changes i n d u c e d by a p p r o p r i a t e doses o f T R H and DA injected i.p. o r intracerebrally. The i.p. injection o f T R H in a dose o f 2.5 m g / k g p r o d u c e d n e i t h e r a significant increase in l o c o m o t o r activity n o r o t h e r behavioural changes. T h e rats receiving a 5 m g / k g d o s e s h o w e d significant h y p e r a c t i v i t y consisting o f f r e q u e n t a m b u l a t i o n and rearing. G r o o m i n g and p r e e n i n g were also f r e q u e n t l y observed during pauses b e t w e e n l o c o m o t i o n s . Higher doses (10 and 20 m g / k g ) a l s o p r o d u c e d , in a d d i t i o n to these behaviours, mild sniffing and h e a d - m o v e m e n t s such as head-shaking or h e a d - t w i t c h i n g in all animals, and mild tailelevation and self-biting o f forelegs in s o m e animals. The self-biting was, h o w e v e r , n o t

146

M. M I Y A M O T O , Y. N A G A W A

TABLE 1 C o m p a r i s o n o f behavioural changes i n d u c e d by i.p. and intracerebral injection o f T R H and DA in rats, Abbreviations : bi.N.Acc : bilateral Nucleus A c c u m b e n s : bi.Cd.N : bilateral C a u d a t e Nucleus ; LS : l o c o m o t o r s t i m u l a t i o n ; RE: rearing; SN: sniffing; HM: head m o v e m e n t such as shaking or t w i t c h i n g ; GR: g r o o m i n g ; PR: p r e e n i n g ; T E : tail-elevation; SB: self-biting o f forelegs. Degree o f behavioural changes: --: negative; +: mild; ++: m o d e r a t e or m a r k e d . The d o s e for intracerebral i n j e c t i o n is e x p r e s s e d as the a m o u n t i n j e c t e d o n each side. Drug

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Dose

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Fig. 2. The e f f e c t o f i.p. injections o f various doses o f T R H u p o n s p o n t a n e o u s m o t o r activity (SMA). Saline was used as a c o n t r o l . Each value is the m e a n activity o f rats and t h e vertical bars r e p r e s e n t the s t a n d a r d errors o f the means. N u m b e r o f rats u s e d is s h o w n in p a r e n t h e s e s . Level o f significance: * p < 0.05, ** p < 0.01, c o m p a r e d w i t h saline c o n t r o l ( S t u d e n t ' s t-test).

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Fig. 3. The e f f e c t o f bilateral o f T R H or DA into the nucleus a c c u m b e n s u p o n s p o n t a n e o u s m o t o r activity (SMA). Saline was used as a c o n t r o l . Each value is t h e m e a n activity o f rats and the vertical bars r e p r e s e n t t h e standard errors o f t h e means. N u m b e r o f rats used is s h o w n in p a r e n t h e s e s . Level o f significance: * p < 0.05, * * p < 0.01, c o m p a r e d w i t h saline c o n t r o l ( S t u d e n t ' s t-test).

hand, sniffing, grooming and preening were p ro d u ced to a slight e x t e n t by bilateral injection o f 50 pg of T R H and DA into the caudate nucleus b u t h e a d - m o v e m e n t only by TRH. L o c o m o t o r stimulation was never produced by either TRH or DA injected via this route. Neither tail-elevation nor self-biting was observed after the intra-accumbens or intracaudate injection of T R H or DA. The l o c o m o t o r stimulation induced by the i.p. injection of TR H in doses of 5--20 mg/kg and the intra-accumbens injection of T R H (5 and 10 pg) and DA (10 and 20 pg) was dosed e p e n d e n t (figs. 2 and 3). This effect appeared at its m a x i m u m during the initial 20- or 30-min period and t h e r e a f t e r declined gradually. With respect to the total l o c o m o t o r counts for 60 min as measured with a Varimex meter, a dose of 20 mg/kg o f T R H injected i.p. was roughly equivalent to 10 pg of T RH and 20 pg of DA injected into the nucleus accumbens.

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148

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Fig. 6. T h e e f f e c t of i.p. p r e t r e a t m e n t w i t h h a l o p e r i d o l ( H D P ) (10 m i n p r i o r t o T R H or D A ) o r p i m o z i d e ( P M Z ) (4 h p r i o r to T R H or D A ) u p o n s p o n t a n e o u s m o t o r activity ( S M A ) s t i m u l a t i o n i n d u c e d b y t h e bilateral intraa c c u m b e n s i n j e c t i o n o f T R H (A) or D A (B). E a c h value is t h e m e a n activity of rats a n d t h e vertical bars r e p r e s e n t t h e s t a n d a r d errors o f t h e means. N u m b e r o f rats used is s h o w n in p a r e n t h e s e s . Level o f significance: * p < 0.05, • * p < 0.01, c o m p a r e d w i t h T R H or D A c o n t r o l ( S t u d e n t ' s t-test).

MESOLIMBIC SYSTEM AND LOCOMOTOR STIMULATION BY TRH Unilateral injection of as much as 50 pg of T R H into the caudate nucleus produced no remarkable behavioural change, while similar injection of the same dose of DA caused mild b u t distinct circling behaviour contralateral to the injected side (fig. 4). 3.2. Effect o f DA and noradrenergic (NA) receptor antagonists on TRH-induced locomotor stimulation The l o c o m o t o r hyperactivity induced by the i.p. injection of TRH in a dose of 20 mg/kg was significantly suppressed for the initial 30- or 40-min by pretreatment with bilateral intra-accumbens injection of the DA receptor antagonist, haloperidol (2.5 and 5 pg). Haloperidol (5 pg) also blocked the locom o t o r stimulation induced by bilateral intraaccumbens injection of 20 pg of DA, for the initial 20-min period. However, pretreatment with similar intracerebral injection of a NA receptor antagonist, phenoxybenzamine (10 pg), had no significant effect on the locom o t o r stimulant action of TRH and DA (fig. 5). When the animals were pretreated with haloperidol (0.2 and 1 mg/kg i.p.) or pimozide (0.5 mg/kg i.p.); b o t h drugs markedly suppressed the l o c o m o t o r stimulation induced by the intra-accumbens injection of T R H or DA (fig. 6). 4. Discussion

The most significant sites of the mesolimbic DA system are the nucleus accumbens and tuberculum olfactorium. As mentioned in the Introduction, the DA system of the nucleus accumbens is o f great importance in the mediation of l o c o m o t o r activity. T R H has been already reported by several investigators to produce various types of behaviours. In this work, we noted that T R H injected i.p. caused marked l o c o m o t o r hyperactivity accompanied by rearing, sniffing, grooming, preening and other behaviours in rats. The effect is probably mediated by an action on the mesolimbic DA system. This assumption

149

is supported b y the fact that of the behavioural changes obtained b y the peripheral administration of TRH, l o c o m o t o r hyperactivity, rearing, sniffing, grooming and preening were reproduced by bilateral intra-accumbens injection of TRH and DA. On the other hand, no l o c o m o t o r hyperactivity was caused by bilateral injection of T R H into the caudate nucleus, where the nigrostriatal pathway terminates, although mild sniffing, grooming and preening did occur. Furthermore, the locom o t o r stimulation induced by T R H injected peripherally or into the nucleus accumbens was markedly blocked by the DA receptor antagonists haloperidol and pimozide injected either peripherally or into the nucleus accumbens. These findings strongly suggest that the peripherally administered T R H reaches the nucleus accumbens and exerts its l o c o m o t o r stimulant action, although an action on other levels of brain may be partly involved with the achievement of l o c o m o t o r hyperactivity. On a molar basis, TRH was about 5 times as active as DA in the l o c o m o t o r stimulation induced by intra-accumbens injection, suggesting that TRH may act in some other way on the DA system than as a direct receptor stimulant. In this respect, Cohn et al. (1975), using behavioural studies and Green et al. (1976), using biochemical studies have postulated that T R H acts as an indirect dopamine releaser. A TRH-mediated increase in sensitivity of the DA receptor at postsynaptic sites was also suggested by Plotnikoff et al. (1975). Our present results could be explained by either of these mechanisms. Antagonism of the depressant effects of chlorpromazine in various animals (Kruse, 1976) and o f prochlorperazine-induced catalepsy in rats (Goujet et al., 1975) by TRH appear to be due to its dopaminergic stimulation, as seen in the interaction of amphetamine with neuroleptics. Although the main catecholamine in the nucleus accumbens is DA, the presence of NA in this nucleus has also been described (Koob et al., 1974). However, the weak l o c o m o t o r stimulation induced by intra-accumbens injec-

MESOLIMBIC SYSTEM AND LOCOMOTOR STIMULATION BY TRH f o u n d an i m p r o v e m e n t o f p s y c h i c s y m p t o m s , especially facial expression, r a p p o r t and p s y c h o m o t o r activity, w h i c h are resistant to t h e r a p y w i t h n e u r o l e p t i c s alone, b y t r e a t m e n t with a c o m b i n a t i o n o f T R H in daily oral doses as l o w as 4 m g and n e u r o l e p t i c s in s c h i z o p h r e n i c patients. Similar m o o d - e l e v a tion or i m p r o v e m e n t in " i n s t i n c t i v e " behavi o u r b y T R H a d m i n i s t r a t i o n in depressive p a t i e n t s has been also described b y Wilson et al. ( 1 9 7 3 ) and Itil et al. (1975). This p s y c h o t r o p i c p r o p e r t y o f T R H appears to be m o r e important p h y s i o l o g i c a l l y t h a n useful in p s y c h o t h e r a p y . I n view o f the d i s t r i b u t i o n o f T R H in brain, o u r p r e s e n t s t u d y suggests t h a t T R H m a y p l a y a role as m o d u l a t o r o f D A a c t i v i t y in the m e s o l i m b i c s y s t e m t o c o n t r o l t h e e m o t i o n a l and m e n t a l f u n c t i o n s .

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