Neuropeptide-dopamine interactions. I. Dopaminergic mechanisms in cyclo(His-Pro)-mediated hypothermia in rats

Administration of cyclo(His-Pro) to rats produces a dose-dependent hypothermia that is attenuated by dopaminergic antagonists. Chronic treatment with cyclo(His-Pro) potentiates hypothermia induced by apomorphine. These results suggest that cyclo(His-Pro) acts via a dopaminergic mechanism to modulate body temperature.     

Changes in blood-brain barrier permeability are associated with behavioral and neurochemical indices of recovery following intraventricular adrenal medulla grafts in an animal model of Parkinson's disease.

Intraventricular adrenal medulla grafts were found to produce dissociable effects on rotational behavior induced by amphetamine and apomorphine in rats with unilateral striatal dopamine depletions. Some animals showed a decrease in the behavioral response to apomorphine, some showed a decrease to amphetamine, and some showed a decrease to both amphetamine and apomorphine. Using in vivo microdialysis, the experiments reported demonstrate that in animals with decreased rotational behavior, assessed with either amphetamine or apomorphine, there was an increase in the permeability of the blood-brain barrier to dopamine. The increased blood-brain barrier permeability was visually confirmed with horseradish peroxidase. The extent of the blood-brain barrier disruption, however, was greater in animals with a decreased response to amphetamine. Animals that exhibited decreased amphetamine-induced turning after adrenal medulla grafts also had a greater amphetamine-stimulated increase in striatal dopamine and greater extracellular striatal dihydroxyphenylacetic acid concentrations compared to controls and animals with a graft-induced decrease in the response to apomorphine. We conclude that more than one mechanism is involved in mediating the behavioral effects of adrenal medulla grafts.     

Behavioral sensitization following subchronic apomorphine treatment--possible neurochemical basis

Subchronic treatment with the dopamine agonist apomorphine produces a sensitization to the stereotypic effects of subsequent apomorphine challenge. The present study investigated the effects of this subchronic treatment on apomorphine induced stereotypic behavior and striatal dopamine synthesis, release, metabolism, and D2 receptor binding. The pretreatment, which enhanced the behavioral response to apomorphine challenge, also elevated basal dopamine synthesis and metabolism, but left the ability of a challenge dose of apomorphine to inhibit dopamine synthesis and metabolism unaltered. Thus, ongoing dopamine synthesis and extracellular levels of metabolites would be higher following apomorphine challenge in animals treated subchronically with the agonist. In contrast, neither synaptosomal dopamine release in response to depolarizing stimuli nor the density of D2 dopamine receptors was altered by the treatment. Overall, the results suggest that, while we did not find evidence of autoreceptor desensitization per se, apomorphine treatment may result in enhanced extracellular dopamine levels following dopamine agonist challenge to provide a greater stimulation of an intact dopamine receptor system.     

The effect of bilateral kainic acid-induced lateral habenula lesions on dopamine-mediated behaviors

Bilateral kainic acid-induced lateral habenula lesions produced dose specific alterations in dopamine mediated behaviors in the rat. Intermediate doses of apomorphine and amphetamine produced potentiated stereotypic responsiveness while higher doses produced a behavioral response similar to that observed in sham-operated and virgin controls. Autoreceptor specific doses of apomorphine and its associated behavioral hypoactivity was unaffected by lesions. Animals with lesions did not exhibit the response potentiation normally induced by chronic haloperidol treatment.     

Hypothalamic regulation of histidyl-proline diketopiperazine binding sites in the rat liver

The effects of hypothalamic hormones and electrolytic lesioning of the ventromedial hypothalamic nuclei (VMH) on histidyl-proline diketopiperazine (cyclo(His-Pro] binding in the rat liver were studied. VMH-lesioning markedly decreased cyclo(His-Pro) binding in the liver. Scatchard analysis revealed that the loss of cyclo(His-Pro) binding induced by VMH lesioning was due to a decrease in the number and affinity of binding sites. Somatostatin (SS) administration decreased cyclo(His-Pro) binding. The SS-induced changes in cyclo(His-Pro) binding were due to changes in the binding affinity. On the other hand, the administration of TRH or LH-RH did not affect cyclo(His-Pro) binding in the liver, although cyclo(His-Pro) has been proposed to be a metabolite of TRH. These findings suggest that the hypothalamus may regulate the cyclo(His-Pro) binding sites in the liver probably by controlling pancreatic SS secretion, since a VMH-lesion is reported to cause hypersecretion of pancreatic SS.     

Nicotine Induces Sensitization of Turning Behavior in 6-Hydroxydopamine Lesioned Rats

Nicotinic drugs have been proposed as putative drugs to treat Parkinson’s disease (PD). In this study, we investigated whether nicotine can sensitize parkinsonian animals to the effect of dopaminergic drugs. Testing this hypothesis is important because nicotine has been shown to present neuroprotective and acute symptomatic effects on PD, but few studies have addressed the question of whether it may induce long-lasting effects on dopamine neurotransmission. We tested this hypothesis in the 6-hydroxydopamine (6-OHDA) rat model of PD. A pretreatment of these rats with 0.1–1.0 mg/kg nicotine induced a dose-dependent sensitization of the turning behavior when the animals were challenged with the dopamine receptor agonist apomorphine 24 h later. In agreement with previous studies, while apomorphine induced contraversive turns, nicotine, as well as amphetamine, induced ipsiversive turns in the 6-OHDA rats. This result suggests that, like amphetamine, nicotine induces turning behavior by promoting release of dopamine in the non-lesioned striatum of the rats. However, it is unlikely that the release of dopamine may also explain the nicotine-induced sensitization of turning behavior. First, the dopamine amount that could be released in the lesioned hemi-striatum by the nicotine pretreatment was minimum—less than 3%, as detected by HPLC–EC. Second, a pretreatment with amphetamine did not induce this behavioral sensitization. A pretreatment with apomorphine-induced sensitization, but it was minimal when compared to that induced by nicotine. Therefore, it is unlikely that the sensitization of the turning behavior induced by nicotine was consequent of the release of dopamine. However, the expression of such sensitization seems to depend on the activation of dopaminergic receptors, since it was seen when the nicotine-sensitized animals were challenged with apomorphine, but not with a second nicotine challenge. These findings are relevant for PD drug therapy since they suggest that the doses of dopaminergic drugs used to treat PD could be reduced if a nicotinic drug were co-administered.     

The distribution of Histidyl-Proline Diketopiperazine [cyclo(His-Pro)] in discrete rat hypothalamic nuclei

The distribution of Histidyl-Proline Diketopiperazine [cyclo(His-Pro)], a metabolite of thyrotropin-releasing hormone (TRH), was determined by specific RIA in Palkovits micropunch pools derived from discrete hypothalamic nuclei. Highest concentrations of cyclo(His-Pro) were identified in the anterior nucleus (3.5 ng/mg protein) and the paraventricular nucleus (2.95 ng/mg protein), while lower concentrations of cyclo(His-Pro) were seen in the other 6 nuclei. In contrast, TRH concentrations were highest in the ventromedial nucleus pars medialis (3.2 ng/mg protein) and arcuate nucleus (2.7 ng/mg protein). This qualitatively different distribution of cyclo(His-Pro) from that of TRH suggests that not all of cyclo(His-Pro) is derived exclusively from TRH.     

Subthalamic responses to amphetamine and apomorphine in the behaving rat with a unilateral 6-OHDA lesion in the substantia nigra.

The activity of neurons in the subthalamic nucleus (STN) of the behaving rat, before and after a unilateral 6-OHDA lesion of the substantia nigra, was recorded with the extracellular technique to determine whether it was altered following systemic amphetamine, 5 mg/kg, apomorphine, 3 mg/kg, and apomorphine, 0.3 mg/kg, and whether in cases of altered activity, it was related to the drug-induced motor response expressed concurrently. Activity in the STN of intact rats increased dramatically after amphetamine, 5 mg/kg. This excitatory response had the same latency, similar magnitude, and the same duration as the motor response expressed in terms of locomotion and oral stereotypy. Motor and unit responses were also induced by amphetamine after the lesion with 6-hydroxydopamine (6-OHDA), but now the excitatory response was attenuated while the motor response was not. The effects of the 6-OHDA lesion were the same in all animals with loss of the nigra dopamine neurons, regardless of whether they were rotators or non-rotators. Activity in the STN of intact rats also increased after apomorphine, 3 mg/kg, and again, this increase was correlated with the increase in motor behavior, but both responses were of shorter duration than the responses to amphetamine. The increases in unit activity and motor behavior induced by apomorphine in the 6-OHDA-lesioned rats had the same magnitude but lasted longer than in the intact rats. Treatment with apomorphine, 0.3 mg/kg, of the intact rats produced small and very brief increases in the activity of the STN and in motor behavior. The same treatment given the 6-OHDA-lesioned rats produced responses of larger magnitude but no change in duration. These findings demonstrate a role for STN neurons in the mediation of the motor behaviors induced by stimulation of the dopamine receptor. The results also show that a unilateral lesion of the substantia nigra with 6-OHDA did not block these responses but altered them in a manner consistent with a dopaminergic deafferentation of the basal ganglia. The increased activity in the STN during the expression of dopamine-dependent motor behavior conflicts with the current model of basal ganglia function that assumes prejudicial effects of excessive STN activity on the expression of motor behavior. An explanation for this conflict suggests that it is more apparent than real.     

Behavioral demonstration of a reciprocal interaction between dopamine receptor subtypes in the mouse striatum: Possible involvement of the striato-nigral pathway

It is well known that stimulation of the D-2 dopamine receptor in vitro inhibits the increased efflux of cyclic adenosine monophosphate caused by D-1 receptor agonists. Furthermore, behavioral data suggest that the striato-nigral pathway is more involved with the dopamine agonist-induced expression of oral behaviors, which are, in turn, mediated by stimulation of the D-1 receptor. We examined an in vivo model to determine whether this D-1/D-2 reciprocal interaction is detectable at a behavioral level. First, mice were pretreated with wide range of doses of the D-2 antagonist, spiperone, and then injected with a behaviorally active dose of apomorphine (a nonspecific direct dopamine agonist) and were observed for incidence of oral behavior and rated for stereotypic behavior. A biphasic effect of spiperone pretreatment was observed, at some low doses both stereotypy and oral behavior were enhanced, while at high doses, both agonist-induced behaviors were progressively inhibited. To test the specificity of this effect for the striato-nigral pathway, mice were administered discrete electrolytic lesions in the ventral portion of the internal capsule in one hemisphere. The animals that responded to apomorphine by rotating ipsilaterally to the lesion were used in two, five-point apomorphine dose-response curves, one with, and one without, pretreatment with the dose of spiperone which most enhanced stereotypic behavior and incidence of oral behavior. The spiperone pretreatment caused a clear increase in the maximum rotational response to apomorphine without affecting the ED50. These data suggest that behavior associated with the striato-nigral efferent from striatum is marked by the opposition of D-1 and D-2 receptors.     

Spontaneous and drug-induced locomotor activity after partial dopamine denervation of the ventral striatum

Spontaneous and drug-induced locomotor behavior was investigated in rats subjected to lesions of the ventral striatum, using the neurotoxin 6-hydroxydopamine to produce selective depletions of dopamine. Locomotor activity changed with time after lesion. At 2 weeks postoperative less spontaneous rearings were observed compared to controls, a reduced response to 1.0 mg/kg amphetamine and an increased response to 0.1 mg/kg apomorphine. These changes were not observed 9 weeks postoperative; that is, spontaneous locomotor activity and the response to amphetamine were not different from those of controls, and the rearing response to apomorphine was now reduced. The neurochemical assays of the lesioned ventral striate showed equivalent dopamine depletions of about 48% in both lesion groups relative to controls.     

D1 and D2 dopamine receptor mechanisms in dopaminergic behaviors

SKF 38393, a selective D1 dopamine receptor agonist, was investigated when administered alone and in combination with dopaminergic agonists in animal models of extrapyramidal behavior. SKF 38393 did not induce stereotypy in normal rats but enhanced apomorphine-induced stereotypy in a dose-dependent manner. SKF 38393 also augmented and altered the stereotypic response of dopaminergic agonists (+)-4-propylhydronaphthoxazine quinpirole, and ciladopa. The addition of SKF 38393 with ciladopa changed the behavioral response of ciladopa from a partial to a full agonist. SKF 38393 did not alter locomotor behavior; however, it augmented the stimulatory but not the inhibitory response of apomorphine on locomotion. In unilateral 6-hydroxydopamine-lesioned animals, SKF 38393 caused contralateral rotation that were similar to those of other dopaminergic agonists. The addition of SKF 38393 to both mixed D1/D2 (levodopa, pergolide) and selective D2 (PHNO, quinpirole) dopamine agonists resulted in a synergistic rather than an additive effect. No changes in behavior were observed in rats challenged with apomorphine after being treated 21 days with SKF 38393, PHNO, SKF 38393 plus PHNO, or saline. D1 agonism is capable of augmenting and altering dopaminergic behavior of both mixed D1/D2 and D2 dopamine receptor agonists. A combination of D1 and D2 dopamine agonists may represent optimal drug treatment for Parkinson's disease.     

Effects of dopaminergic stimulation on functional brain metabolism in rats with unilateral substantia nigra lesions

We have studied regional cerebral glucose utilization (RCGU) in awake, unrestrained rats 21 days after unilateral substantia nigra lesions following treatment with either apomorphine (0.5 mg/kg s.c.) ord-amphetamine (2.5 mg/kg s.c.). In ‘control’ rats with a unilateral SN lesion, there was a 30–40% increase in RCGU in the ipsilateral globus pallidus (GP) and a 15–25% increase in the ipsilateral lateral habenular nucleus (LH).Apomorphine treatment produced contralateral whiled-amphetamine elicited ipsilateral turning in the lesioned rats. Apomorphine administration led to an increase in RCGU in the ipsilateral striatum, entopeduncularis (EP), and substantia nigra pars reticulata (SNPR); whiled-amphetamine elicited similar changes in the same structures contralateral to the lesion. Both apomorphine andd-amphetamine treatment led to bilateral increases in RCGU in the subthalamic nuclei.The increased RCGU found in the ipsilateral GP in ‘lesioned controls’ was reduced to control levels by apomorphine administration, while amphetamine treatment increased RCGU in the contralateral GP without affecting glucose utilization in the ipsilateral GP. Furthermore, apomorphine treatment markedly reduced RCGU in the LHN bilaterally while amphetamine reduced RCGU only in the contralateral LHN. The effects of apomorphine were dose-dependent. Haloperidol (1 mg/kg s.c.) pretreatment completely blocked the development of asymmetric changes in RCGU in nigral lesioned rats after apomorphine administration.These results suggest that apomorphine, a direct dopamine agonist, selectively activated basal ganglia pathways ipsilateral to substantia nigra lesion by interacting with supersensitive dopamine receptors in the ipsilateral striatum. In contrast,d-amphetamine, an indirect dopamine agonist, selectively activated pathways in the contralateral basal ganglia by releasing endogenous dopamine from the intact nigrostriatal pathway. Furthermore, the data suggest that striatal efferents to the GP are not controlled in the same manner as efferents to the EP and SNPR. Finally, these asymmetric changes in RCGU in basal ganglia structures produced by apomorphine ord-amphetamine do not appear to be a consequence of the turning behavior, but rather appear to be proximate effects of the drugs administered.     

Globus pallidus lesions depress the excitatory responses to apomorphine but not amphetamine in the subthalamic nucleus of the behaving rat with a 6-OHDA nigra lesion

The role of the dopaminergic innervation of the basal ganglia on the activity in the subthalamic nucleus (STN) evoked by amphetamine and apomorphine in the behaving rat was examined. The aim was to determine the relationship between that neural activity and the movements evoked by the drugs. Bilateral electrolytic lesions of the globus pallidus (GP), superimposed on the earlier unilateral lesion in substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) affected differently the excitatory responses in the STN evoked by amphetamine and apomorphine and the motor responses to the drugs recorded concurrently. Before the GP lesions, the administration of amphetamine, 5 mg/kg, to the unilaterally deafferented rat induced increased activity in the STN and simultaneously increased movement in the animal. After the GP lesions, the excitatory response to amphetamine in the STN was not different from that seen before the GP lesions. The motor response was also unchanged. In contrast, the GP lesions altered the excitatory response to apomorphine, 3 mg/kg. Before these lesions, the administration of apomorphine to the 6-OHDA lesioned animal evoked a robust and long-lasting excitatory response in the STN and, concurrently, a long-lasting motor response. After the GP lesions, both responses to apomorphine were attenuated. These differential effects of the GP lesions on the unit and motor responses to the two drugs are viewed as representing the effects of the damage in the GP on the dopaminergic innervation contributing to the regulation of activity in the STN. In the 6-OHDA animal, the dopamine afferents innervating the basal ganglia had already been dramatically reduced by 6-OHDA. The GP lesions did not significantly add to the number of these afferents previously eliminated; therefore, the excitatory and motor responses to amphetamine were not changed by the GP lesions. But the GP damage served to eliminate the dopamine receptor in the GP and thus reduced the density of the dopamine receptor in the basal ganglia available for binding to apomorphine. Therefore, the excitatory and motor responses to apomorphine were attenuated after the GP lesions compared to the responses before these lesions.     

Distribution of histidyl-proline diketopiperazine [cyclo (His-Pro)] and thyrotropin-releasing hormone (TRH) in the primate central nervous system

The concentrations of cyclo (His-Pro) and its precursor, thyrotropin-releasing hormone (TRH) were measured in 47 different loci of monkey brain using specific radioimmunoassays. Cyclo (His-Pro) concentrations were higher than those of TRH in all loci excepting the hypothalamus, where TRH concentration was found to be the highest of all the loci and twice those of cyclo (His-Pro). The high levels of cyclo (His-Pro) were seen within the cerebellar system (inferior olivary nucleus>nucleus interpositus>fastigial nucleus>posterior vermis). The great variations in TRH-cyclo (His-Pro) ratios among different loci suggest that other factors in addition to TRH concentration must play roles in determining the unique distribution pattern of cyclo (His-Pro) in the primate brain.     

Cyclo(His-Pro) and the development of tolerance to the hypothermic effect of ethanol

Acute intraperitoneal administration of ethanol to rats causes a dose-dependent transient hypothermia. On repeated exposure, however, rats develop tolerance to hypothermic effects of ethanol. Cyclo(His-Pro), an endogenous brain peptide, modifies both acute and chronic themomodulatory effects of alcohol. For example, a) acute pretreatment of rats with increasing amounts of cyclo(His-Pro) produces a progressive decrease in ethanol hypothermia, and b) chronic cyclo(His-Pro) administration augments the development of tolerance to hypothermic effects of alcohol. While the mechanism of cyclo(His-Pro) action is not clear, these data are interpreted to suggest that this peptide may play important roles in ethanol intoxication, preference, tolerance, and/or addiction.     

Neurotoxic regimen of methamphetamine produces evidence of behavioral sensitization in the rat

A neurotoxic regimen of methamphetamine (MA) produces long-term depletions in neostriatal dopamine and serotonin concentrations. In addition to evidence of dopaminergic and serotonergic neurotoxicity, there is evidence of MA-induced behavioral changes. In this regard, stereotypic behavior elicited by MA is greater in rats treated previously with a neurotoxic regimen of MA than in control animals. The present study was designed to determine whether the enhanced stereotypy observed in MA-treated rats is due to the MA-induced loss of dopamine (neurotoxicity) or to the repeated exposure to MA (sensitization). Rats were treated with MA (10 mg/kg every 2 h for four injections) or vehicle at either a normal (24 degrees C) room temperature or a cold (4 degrees C) room temperature, which has been shown to attenuate the MA-induced loss of dopamine. Stereotypy was assessed 7 days after treatment. Rats that had received a neurotoxic regimen of MA at 24 degrees C exhibited 49% and 45% reductions in neostriatal dopamine and serotonin concentrations, respectively, whereas rats treated with MA at 4 degrees C had no significant neurochemical depletions. Stereotypy elicited by MA (5.0 mg/kg) was significantly greater in rats treated with a neurotoxic regimen of MA regardless of the initial treatment temperature. In addition, an injection of apomorphine (0.5 mg/kg) elicited an enhanced stereotypic response in MA-treated rats. These data suggest that the augmented stereotypic behavior observed in rats treated with a neurotoxic regimen of MA is not due to the loss of dopamine, but rather the manifestation of behavioral sensitization, possibly due to an increase in dopamine receptor sensitivity.     

Cyclo (His-Pro), d-amphetamine and striatal dopamine: a microdialysis study

Extracellular levels of dopamine (DA) and its metabolites (DOPAC and HVA) were monitored in the striatum of rats using in vivo microdialysis, in an attempt to elucidate the mechanism of cyclo (His-Pro) (histidyl-proline-diketopiperazine, CHP) on dopaminergic activity. Pretreatment with CHP (0.5 mg/kg SC) (n = 5) or the equivalent volume of saline (n = 5) was followed 30 min later by 5 mg/kg IP of d-amphetamine. Dialysate samples were collected and analyzed by high performance liquid chromatography with electrochemical detection (HPLC-EC). Following the initial increase in DA caused by d-amphetamine, DA levels of CHP-treated rats were significantly lower than saline-treated rats across time (p less than 0.05). No difference was observed for DOPAC or HVA. It is therefore unlikely that CHP interferes with the d-amphetamine-induced inhibition of DA reuptake. Other neurotransmitter systems may be involved in the CHP-induced augmentation of amphetamine's behavioral effects. Our data, as well as previous findings, suggest that attenuation of the dopaminergic response to d-amphetamine might be best explained on the basis of striatal DA depletion, possibly via tyrosine hydroxylase (TH) inhibition. This study also indicates that a dissociation may exist between the behavioral and the striatal DA response to acute amphetamine. The data support the hypothesis that amphetamine releases DA from a newly synthesized, extravesicular cytoplasmic pool, and that intracellular striatal DA is present in considerable excess relative to the extracellular DA.     

Genotypic influences on striatal dopaminergic regulation in mice

Genotypic influences on dopaminergic-induced behaviors and striatal dopaminergic receptors were evaluated in CBA/J, C57BL/6J and BALB/cJ male mice. CBA/J mice were less behaviorally sensitive to apomorphine (stereotypic behavior), but more sensitive to haloperidol (catalepsy) than C57BL/6J and BALB/cJ mice. Striatal dopaminergic receptors, assayed by binding of [³H]spiroperidol (antagonist) and [³H]ADTN (agonist), were 50% fewer in CBA/J compared to BALB/cJ mice; C57BL/6J mice had low to intermediate numbers of receptors.

Striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were similar in all strains. However, a 20% higher DOPAC/dopamine ratio in CBA/J mice suggests greater dopamine turnover. Median eminence dopamine was similar in all strains, but norepinephrine was 30% higher in BALB/cJ mice.

CBA/J mice failed to show antagonist-induced supersensitivity-type responses to chronic haloperidol treatment: enhanced stereotypic response to apomorphine and a 30% increase of dopaminergic receptors occurred in C57BL/6J and BALB/cJ mice, but not in CBA/J mice. These data suggest that CBA/J mice either cannot respond to chronic haloperidol treatment or have an elevated threshold for induction of supersensitivity response.

Chronic treatment with the dopamine agonist bromocriptine (7d) depressed apomorphine-induced stereotypic behavior in C57BL/6J mice and eliminated stereotypy in BALB/cJ mice, but caused no change in stereotypic behavior in CBA/J mice. Dopaminergic receptors were 15% lower after bromocriptine treatment in all strains.

These results suggest that some striatal dopaminergic functions are impaired in CBA/J mice relative to BALB/cJ and C57BL/6J mice. The impaired haloperidol-induced supersensitivity responses in the CBA/J mouse may be a useful model for analyzing similar impairments of supersensitivity responses in old rodents.     

Thyrotropin-releasing hormone: its distribution and metabolism during development in bullfrog (Rana catesbeiana)

The development changes in the metabolism of thyrotropin-releasing hormone (TRH), cyclo (His-Pro) formation from TRH, and the levels of endogenous TRH in frog brain and skin were determined. The results indicated that TRH concentrations were considerably higher in brain than in skin, and in both of these structures TRH content increased significantly following metamorphosis to adulthood. This increase in TRH concentration is probably a reflection of a marked decrease in TRH-metabolism in adult frogs compared to tadpoles. However, the formation of cyclo (His-Pro) from TRH increased during the developmental period reaching to a maximum in adulthood. The possible role of cyclo (His-Pro) in the amphibian developmental process is discussed in relation to our recent observation showing cyclo (His-Pro) inhibition of prolactin secretion.     

Intra-cerebral cysteamine infusions attenuate the motor response to dopaminergic agonists

Previous studies have suggested that somatostatin neurons in the basal ganglia may be involved in motor activity. In the present experiments, the effects of cysteamine, a drug which reduces somatostatin levels, on the basal and dopamine-mediated motor activities were examined in the rat. Neither intra-striatal nor intra-accumbens infusions of cysteamine had any effect on motor activity prior to the administration of dopamine agonists. However, intra-striatal cysteamine infusions reduced the duration of the stereotypic behavior induced by systemic apomorphine. In addition, intra-accumbens infusions of cysteamine produced a slight reduction in the locomotor response induced by amphetamine. The direct intra-cerebral infusion of cysteamine produced a significant depletion in the levels of somatostatin at the site of injections as measured by radioimmunoassay. These results indicate that somatostatin neurons in the basal ganglia may modulate the motor responses following dopaminergic activation, and further support the presence of a dopamine-somatostatin interaction in this region.