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Previous single exposure (priming) to a dopamine receptor agonist greatly enhances the contralateral turning behaviour elicited by dopamine D1 receptor agonists in unilaterally 6-hydroxydopamine lesioned rats. In the present study we have investigated the levels of glutamate decarboxylase 67 and glutamate decarboxylase 65 messenger RNA in the striatum of 6-hydroxydopamine-lesioned rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) and challenged with the D1 receptor agonist SKF 38393, three days thereafter. As previously reported, levels of glutamate decarboxylase 67 messenger RNA increased in the striatum denervated by the 6-hydroxydopamine lesion as compared with the intact one. Striatal glutamate decarboxylase 67 messenger RNA levels, measured three days after priming with L-DOPA (50 mg/kg), further increased in the lesioned striatum while were not modified in the intact one. Administration of SKF 38393 (3 mg/kg) elicited a more intense contralateral turning behaviour in primed than in drug-naive 6-hydroxydopamine-lesioned rats but did not induce any change in striatal glutamate decarboxylase 67 messenger RNA. In contrast, striatal levels of glutamate decarboxylase 65 messenger RNA were not modified by either 6-hydroxydopamine lesions or priming with L-DOPA. The results show that priming with L-DOPA induces long-lasting changes in GABAergic neurons of the 6-hydroxydopamine-lesioned striatum. These changes might play a role in the increased behavioural response of striatal D1 receptors induced by priming.

The induction of the early-gene c-fos after administration of the adenosine A2a receptor agonist CGS 21680, was studied in the striatum of normal rats or in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal neurons. CGS 21680 (2.25 mg/kg) induces c-fos expression in the 6-hydroxydopamine-lesioned striatum, while up to 40 mg/kg fails to induce c-fos in the intact striatum or in the striatum of normal rats. Blockade of muscarine receptors by scopolamine (5 mg/kg) partially prevents, and stimulation of dopamine D2 receptors by quinpirole (0.5 mg/kg) completely reverses, CGS 21680-induced c-fos expression in the 6-hydroxydopamine-lesioned striatum. In turn, CGS 21680 partially reverses c-fos expression induced by quinpirole in the lesioned globus pallidus. CGS 21680, in addition, dose-dependently reduces the turning behavior induced by quinpirole (0.5 mg/kg) in 6-hydroxydopamine-lesioned rats. The results suggest that CGS 21680 induces c-fos expression in the striatum through direct and indirect mechanisms related to the ability of A2a receptors to stimulate cyclic AMP formation or acetylcholine release which in turn would activate c-fos through muscarinic receptors.

The role of vesicular and newly synthesized dopamine in the action of amphetamine was investigated by studying the effect of reserpine and alpha-methyl-p-tyrosine pretreatment on amphetamine-induced changes in extracellular dopamine and acetylcholine, estimated by brain microdialysis, and on c-fos expression, estimated by quantitative immunohistochemistry of the Fos antigene, in the dorsal caudate-putamen of rats. Blockade of dopamine synthesis by alpha-methyl-p-tyrosine pretreatment (1 or 2 h) only partially prevented the increase in extracellular dopamine concentrations elicited by 0.5 and 2 mg/kg s.c. of amphetamine. Inactivation of vesicular amine uptake by reserpine pretreatment (3 h) reduced the increase in extracellular dopamine by 2 mg/kg but not by 0.5 mg/kg of amphetamine. Combined pretreatment with reserpine (3 h) and alpha-methyl-p-tyrosine (1 h) drastically reduced the increase in extracellular dopamine by both doses of amphetamine (0.5 and 2 mg/kg s.c.). alpha-Methyl-p-tyrosine pretreatment reduced c-fos expression stimulated by amphetamine (2 mg/kg) in the dorsomedial and dorsolateral caudate-putamen while reserpine pretreatment reduced it only in the dorsolateral caudate-putamen. Amphetamine (2 mg/kg s.c.) stimulated acetylcholine release but this effect was not modified by reserpine or alpha-methyl-p-tyrosine pretreatment. The results indicate that blockade of dopamine synthesis, by itself, is insufficient to prevent the stimulation of dopamine transmission by amphetamine and, conversely, that inactivation of vesicular dopamine significantly reduces amphetamine effects at pre- and postsynaptic levels. Therefore, vesicular dopamine appears to contribute to the stimulation of dopamine transmission elicited by amphetamine in the dorsal caudate-putamen.

“Priming” is a phenomenon of behavioural sensitization observed in unilaterally 6-hydroxydopamine lesioned rats following exposure to a dopamine agonist. After priming, a single dose of the D 1 agonist SKF 38393 (3 mg/kg) produces contralateral turning, while the same dose is inactive in drug-naive, lesioned animals. The molecular mechanisms of “priming” were investigated here by studying the phosphorylation of dopamine and adenosine 3′–5′ monophosphate regulated phosphoprotein (DARPP32), a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D 1 receptors in striatum. Dephospho-form of DARPP-32 was measured by a back-phosphorylation assay. All assays were performed in striata from both lesioned and unlesioned sides. A significant decrease of dephosphoDARPP-32 (27%) was observed in the denervated striatum of primed rats, indicating an increased Phosphorylation in vivo of DARPP-32 in response to the D 1 agonist. The levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged in all experimental groups. This study shows that priming is expressed as an increased transduction of the D 1 receptor message.

Repetitive stimulation of dopamine receptors located in the basal ganglia may lead to the manifestation of sensitized, abnormal, motor responses in dopamine-denervated rats. In order to study the role of motor behavior execution on the expression of these altered motor responses, we evaluated how "priming", a phenomenon displaying neurochemical and behavioral features peculiar to a sensitized abnormal motor response in dopamine-denervated rats, depends on actual movement performance. To this end, unilaterally 6-hydroxydopamine-lesioned rats received apomorphine (0.2 mg/kg s.c.), being either allowed to move or immobilized (1 h) before, concomitantly to, or after its administration, respectively. Three days after apomorphine, the dopamine D(1) receptor agonist 1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393, 3 mg/kg s.c.) was administered to all animals. Rats that had performed rotational behavior following apomorphine administration displayed robust contraversive rotational behavior in response to SKF 38393, whereas rats that had been immobilized concomitantly to, but neither before nor after apomorphine, did not. To clarify whether stress, which may be increased by immobilization, mediated the results observed, additional rats received apomorphine paired with immobilization plus the corticosterone-synthesis inhibitor metyrapone (100 mg/kg i.p.), or apomorphine paired with a tail stressor, being not immobilized. Metyrapone did not affect the capacity of immobilization to prevent priming and tail stressor imposition did not affect priming magnitude, suggesting that stress has minimal or no effect on the results observed. This study demonstrates how movement performance following initial dopaminergic stimulation governs the occurrence of a sensitized, abnormal, motor response to a subsequent dopaminergic challenge in dopamine-denervated rats.

Quantitative autoradiography of [3H]SCH 23390 and [3H](-)-sulpiride binding was performed in the brain of rats of various ages (3, 11 and 24 months) in order to study the changes in D1 and D2 receptor density with age. Binding of [3H]SCH 23390 in the caudate-putamen decreased progressively and markedly at rostral levels in 11- and 24- compared with 3-month-old rats (max. decrease -63%) while at caudal levels significant decrease was observed only in 24-month-old rats. [3H](-)-Sulpiride binding progressively decreased during aging in the caudate-putamen at rostral levels and the decrease was more pronounced laterally (-70% at 24 months), while at caudal levels no significant decrease was observed. D1 and D2 binding sites also decreased in the nucleus accumbens and olfactory tubercle of aged rats, while in the substantia nigra only the D1 receptors appeared to be modified with aging. No change was found in the entopeduncular nucleus, amygdala, frontoparietal, suprarinal-prefrontal and anterior cingulate cortex. The results indicate that the age-associated decrease of D1 and D2 receptors is not widespread, being confined to dopaminergic areas with high density of dopamine receptors.

We used a previously reported model of morphine sensitization that elicited a complex behavioral syndrome involving stereotyped and non stereotyped activity. To identify the mechanism of these long-lasting processes, we checked the density of mu opioid receptors, receptor-G-protein coupling and the cyclic AMP (cAMP) cascade. In morphine-sensitized animals mu opioid receptor autoradiography revealed a significant increase in the caudate putamen (30% versus controls), nucleus accumbens shell (16%), prefrontal and frontal cortex (26%), medial thalamus (43%), hypothalamus (200%) and central gray (89%). Concerning morphine's activation of G proteins in the brain, investigated in the guanylyl 5'-[gamma-(35)S]thio]triphosphate ([(35)S]GTPgammaS) binding assay, a significant increase in net [(35)S]GTPgammaS binding was seen in the caudate putamen (39%) and hypothalamus (27%). In the caudate putamen this was due to an increase in the amount of activated G proteins, and in the hypothalamus to a greater affinity of G proteins for guanosine triphosphate (GTP). The main second messenger system linked to the opioid receptor is the cAMP pathway. In the striatum basal cAMP levels were significantly elevated in sensitized animals (70% versus controls) and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) significantly inhibited forskolin-stimulated cAMP production in control (30%) but not in sensitized rats. In the hypothalamus no significant changes were observed in basal cAMP levels and DAMGO inhibition. These cellular events induced by morphine pre-exposure could underlie the neuroadaptive processes involved in morphine sensitization.

We investigated whether D 1 dopaminergic receptors modulate in vivo acetylcholine output in the shell and core areas of rat nucleus accumbens using the microdialysis technique. Subcutaneous injection (1, 2 and 3 mg/kg) of the D 1 agonist SKF 82958 enhanced acetylcholine output in both areas of the nucleus accumbens while the selective D 1 antagonist SCH 39166 (0.15 and 0.30 mg/kg, s.c.) lowered it. Both SKF 82958 and SCH 39166 were more effective in the shell than in the core region. The increase in acetylcholine release induced by SKF 82958 in the shell was tetrodotoxin-sensitive. The dopamine release inducer d-amphetamine (1 and 2 mg/kg, s.c.) and the dopamine uptake inhibitor cocaine (10 and 20 mg/kg, i.p.) dose-dependently raised acetylcholine release in the shell and core areas. The dopaminergic stimulants, like the direct-acting D 1 compounds, were more effective in the shell than in the core compartment of the nucleus accumbens. The acetylcholine increases in the shell induced by d-amphetamine (2 mg/kg), cocaine (20 mg/kg) and SKF 82958 (3 mg/kg) were antagonized by the D 1 antagonists SCH 39166 (5 μ M) and SCH 23390 (10 μ M), applied locally by reverse dialysis. The results suggest that dopamine acting at the D 1 receptors exerts a tonic stimulatory control over the cholinergic function of the shell and core compartments of the nucleus accumbens with the shell being more strongly influenced.

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate-putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompanied by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate-putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate-putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.

The nucleus accumbens septi is the major target of mesolimbic dopamine neurons originating in the ventral tegmental area of the mesencephalon. Studies involving experimental manipulation of dopamine transmission by drugs and by lesions, as well as in vivo monitoring of extracellular dopamine concentrations, have provided evidence that the dopamine transmission of the nucleus accumbens plays an important role in behaviour motivated by conventional (e.g., food, sex) and drug reinforcers. Motivated behaviour is distinguished into an appetitive (preparatory/anticipatory) phase consisting of flexible response patterns intended to search and approach the reward itself, and a consummatory phase, consisting of fixed response patterns (eating, drinking, copulating, etc.) finalized to the utilization of the biological resources of the reward (caloric, metabolic, genetic, etc.). While some studies reported a stimulation of dopamine transmission in the nucleus accumbens in relation to appetitive as well as consummatory behaviour, other studies reported a relationship exclusively with consummatory behaviour. Therefore, the precise relationship between dopamine transmission in the nucleus accumbens and specific phases of motivated behaviour is debated. On the basis of topographical, histochemical and connectional evidence, the nucleus accumbens has been subdivided into two compartments, a medioventral "shell" and a laterodorsal "core". This heterogeneity may be relevant to the current debate over the role of nucleus accumbens dopamine in behaviour. Thus, one might hypothesize that, depending on the specific compartment of the nucleus accumbens where dopamine transmission is monitored, a different relationship with specific stimuli which motivate behaviour is obtained. In order to verify this possibility we monitored by microdialysis the changes in dopamine transmission in the nucleus accumbens shell and core during appetitive and consummatory phases of behaviour motivated by food. As food we utilized a palatable snack food (Fonzies) whose consumption has been shown in previous studies from our laboratory to release dopamine in the nucleus accumbens shell and in the medial prefrontal cortex. Unpredicted consumption of Fonzies preferentially stimulated dopamine transmission in the shell as compared to the core. Appetitive food stimuli (perforated Fonzies-filled boxes) phasically stimulated dopamine transmission in the core but not in the shell and sensitized the dopamine response to feeding in the core but inhibited that in the shell. These clear-cut differences between nucleus accumbens shell and core suggest that phasic dopamine transmission in each compartment of the nucleus accumbens subserves different roles in motivated behaviour.

We investigated the involvement of glutamatergic neurotransmission in the modulation of D1 receptor-mediated stimulation of acetylcholine outflow in dorsal striatum in freely moving rats, and the relative roles of the thalamostriatal and corticostriatal pathways in this regulation using in vivo microdialysis. The selective N-methyl-D-aspartate non-competitive antagonist dizocilpine maleate (0.1 mg/kg i.p.), but not the kainate/quisqualate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (3 micrograms per side i.c.v.), completely prevented the rise in striatal extracellular acetylcholine elicited by maximal effective doses of the full D1 agonist SKF 82958 (3 mg/kg s.c.) and of the dopamine releaser d-amphetamine (2 mg/kg s.c.). Acute bilateral electrolytic lesions of the parafascicular nucleus of the thalamus prevented the stimulation of striatal acetylcholine output by SKF 82958 and d-amphetamine but only slightly reduced basal acetylcholine release. In contrast acute interruption of the corticostriatal pathway did not alter the effect of the two dopaminergic drugs although it markedly reduced basal striatal acetylcholine release. Lesions of the parafascicular thalamic nucleus, or a low dose of dizocilpine maleate (0.1 mg/kg i.p.), also prevented the acetylcholine-increasing effect of the neuroleptic remoxipride (10 mg/kg s.c.), an effect known to be D1 receptor dependent. The results suggest that striatal projections arising from the parafascicular thalamic nucleus and utilizing N-methyl-D-aspartate receptors play a critical role in the D1-mediated stimulation of acetylcholine release in dorsal striata.

The effect of pargyline on dopamine neurotransmission was investigated by transtriatal microdialysis combined with Fos immunohistochemistry. Pargyline, 75 mg/kg i.p., increased dopamine and acetylcholine output while drastically decreased dopamine deaminated metabolites. Administration of pargyline resulted in the appearance of Fos-positive nuclei distributed along a gradient around the dialysis probe. Pretreatment with the D1 antagonist SCH 23390 potentiated the effect of pargyline on dopamine output while preventing that on acetylcholine output and on Fos formation. Similarly, lack of calcium in the perfusion medium abolished the effect of pargyline on dopamine and acetylcholine output and on Fos formation. In rats not implanted with dialysis probes pargyline administration resulted in only rare Fos-positive nuclei in the dorsal caudate. The present study indicates that pargyline stimulates dopamine transmission in the dorsal caudate in the area around the dialysis probe but not distant from the fibre or in unimplanted rats. This effect appears to reflect an interaction between the drug-induced changes and those locally elicited by the probe.

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway, blockade of muscarinic receptors by scopolamine potentiates the contralateral turning induced by selective dopaminergic D1 agonists (SKF 38393, A 68930), but does not influence the contralateral turning induced by the D2 agonist LY 171555. Studies on the expression of the early gene c-fos as reflected by the immunohistochemical demonstration of the Fos protein, show that administration of scopolamine (5 mg/kg, i.p.) potentiates c-fos expression elicited by SKF 38393 (1.5 mg/kg, s.c.) in the caudate-putamen of the lesioned side. The results indicate that cholinergic transmission is differentially involved in the behavioral expression of D1 versus D2 receptor stimulation in a denervated condition and suggest that blockade of central cholinergic transmission might be useful in improving the antiparkinsonian efficacy of D1 receptor agonists.

Previous exposure to a dopaminergic agonist (priming) strongly potentiates contralateral turning behaviour in response to D 1 and D 2 agonists in unilaterally 6-hydroxydopamine-lesioned rats. In order to study the influence of priming on the behavioural interaction of D 1 and D 2 receptors, we examined the effect of selective D 1 and D 2 receptor blockade on the contralateral turning induced by the mixed D 1 /D 2 agonist apomorphine in drug-naive and primed 6-hydroxydopamine-lesioned rats. In drug-naive rats, apomorphine induced a dose-related, apparently monophasic rotation curve. Administration of selective D 1 (SCH 23390) or D 2 (raclopride) antagonists abolished the contralateral turning induced by 0.1 mg/kg of apomorphine and partially inhibited that induced by 0.5 mg/kg. In primed rats low doses of apomorphine (0.05 mg/kg) induced an apparently monophasic contralateral turning which was reduced by D 1 receptor blockade and completely abolished by D 2 receptor blockade; a higher dose of apomorphine (0.1 mg/kg) instead elicited a biphasic (two-peak) pattern of rotation. After this dose of the agonist, blockade of D 1 or D 2 receptors abolished the second peak of rotation but, while D 1 blockade reduced the total number of turns, D 2 blockade failed to do so. Quantitative analysis of the interaction between D 1 and D 2 receptors in the overall turning effect, as well as in the time-course of turning behaviour, indicates that D 1 and D 2 receptors interact not only positively but also negatively. After higher doses of apomorphine, both negative and positive interactions take place sequentially during the time-course of apomorphine action and provide a clue for explaining the two-peak pattern of rotation observed after apomorphine in rats previously exposed to the drug.

The transcerebral dialysis method has been utilized for measuring extracellular brain concentrations of serotonin and 5-hydroxyindolacetic acid. Dialysis fibres were implanted transversally in the rat frontal cortex and perfused by Ringer. Serotonin and 5-hydroxyindolacetic acid were quantified by reverse phase high performance liquid chromatography with electrochemical detection. Experiments were performed in freely-moving rats 20-24 h after the implant of the fibre. Basal output of serotonin and 5-hydroxyindolacetic acid was 0.12 and 22.8 pmol in 20 min, respectively. The output of serotonin was calcium-dependent and tetrodotoxin-sensitive (1 micron in the Ringer) while was stimulated by veratridine (50 microns) and by high concentrations of K+ (60 and 100 mM). Serotonin output was increased in a concentration-dependent manner by chlorimipramine (1-10 microM) in the Ringer; this drug stimulated serotonin release also when administered s.c. (20 mg/kg) in a tetrodotoxin-sensitive manner. The irreversible monoamine-oxidase inhibitor pargyline (75 mg/kg, i.p.) strongly stimulated serotonin output while reduced 5-hydroxyindolacetic acid output. A proposed serotonin releaser, fenfluramine (25 mg/kg, s.c.), stimulated serotonin release and this effect was strongly potentiated by local application of tetrodotoxin (1 microM). Agonists of serotonin receptors such as lisuride (0.03 mg/kg, s.c.), 8-hydroxy-2-(di-n-propilamino)tetraline (0.25 mg/kg, s.c.) and 5-methoxy 3(1,2,3,6-tetrahydro-4-pyridinil)-1H indole succinate (1 mg/kg, s.c.) reduced serotonin release. It appears that brain dialysis is a suitable method for the study of serotonin release in the cortex of freely-moving rats.

The effect of systemically administered amphetamine, cocaine, phencyclidine and nomifensine on the extracellular concentrations of dopamine in freely moving rats was estimated by microdialysis in the nucleus accumbens and in the dorsal caudate. All the drugs tested stimulated dopamine output in both areas but more effectively in the accumbens as compared to the caudate. Low doses of cocaine (1.0 mg/kg s.c.) stimulated dopamine output only in the nucleus accumbens. Nomifensine (1.25-5.0 mg/kg s.c.) increased by a similar extent peak dopamine output in the two dopaminergic areas but the duration of the effect was longer in the accumbens as compared to the caudate. The effect of cocaine, phencyclidine and nomifensine was prevented by systemic gamma-butyrolactone (700 mg/kg i.p.) and by omitting Ca2+ from the Ringer used for dialysis, the effect of amphetamine was insensitive to these manipulations. Thus, in contrast with amphetamine, cocaine, phencyclidine and nomifensine increase synaptic dopamine concentrations in vivo by a mechanism which depends on intact activity of dopaminergic neurons and by an exocytotic process.

Bilateral intrathalamic microinjections of nanogram amounts (5–50 ng) of muscimol, a γ-aminobutyrate (GABA) receptor agonist, elicited catalepsy in rats. Like neuroleptic-treated rats, those injected with muscimol in the thalamus remained suspended on a vertical grid but, unlike opioid-treated rats, they failed to remain horizontal on two book-holders. The righting reflex was present, while ptosis was absent. The areas with the highest sensitivity to the cataleptogenic effects of muscimol were the ventromedial and ventral-anterior nuclei of the thalamus. These thalamic areas were also characterized by the shortest latency for the induction of catalepsy. Injection of up to 50 ng of muscimol into the caudate, globus pallidus or entopeduncular nucleus failed to produce catalepsy. Catalepsy was also obtained after intrathalamic microinjection of other GABA analogs, such as 3-aminopropanesulphonic and imidazolacetic acid, which are known to be potent GABA receptor agonists, and β-p-chlorophenyl-GABA , a compound which has GABA mimetic activity. The catalepsy produced by 10 ng of muscimol was reversed by an intrathalamic microinjection of picrotoxin, a GABA receptor antagonist. Muscimol-induced catalepsy, unlike neuroleptic-induced catalepsy, was not reversed by systemic administration of high doses of apomorphine, a dopamine receptor agonist, or of scopolamine, a muscarine antagonist, or by intranigral injection of muscimol, and was not prevented by kainic acid-induced lesions of the striatum or of the nigra. Vice versa, injection of cataleptogenic doses of muscimol in the thalamus failed to prevent the stereotyped gnawing produced by systemic apomorphine or intranigral muscimol. Therefore, in these animals, catalepsy and stereotyped gnawing coexisted. The unilateral intrathalamic microinjection of muscimol resulted in a postural asymmetry consisting of turning towards the injected side. This ipsilateral posturing was converted into an ipsilateral circling by systemic administration of apomorphine. The results indicate that thalamic GABAergic mechanisms play an important role in the regulation of posture and in the mediation of certain motor responses arising in the striatum.

The effect of unilateral 6-hydroxydopamine lesions of the medial forebrain bundle on the specific binding of [125I]iodosulpride and [125I]SCH 23982 in the rat substantia nigra was determined by quantitative autoradiography of adjacent sections. The specific binding of [125I]iodosulpride was reduced by 40-70% on the lesioned side in the substantia nigra pars compacta, reticulata, lateralis and in the ventral tegmental area. In contrast, the specific [125I]SCH 23982 binding was unchanged in all subdivisions of the substantia nigra. The results indicate that dopamine autoreceptors are present in the substantia nigra and in the ventral tegmental area and that they are exclusively of the D2 type.