Development Of Dopamine Receptor Supersensitivity Research Articles

Dopamine D1 receptor antagonist reduces stimulant-induced conditioned place preferences and dopamine receptor supersensitivity.

Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals; however, dopamine receptor subtypes associated with the development of supersensitivity in CPP animals are largely unknown. The present preclinical study aimed to examine whether dopamine D1 or D2 receptor antagonists exert inhibitory effects on stimulant-induced psychological behaviors. Additionally, the authors aimed to elucidate the role of dopamine receptor supersensitivity on the development of reward-related behavior. Sprague Dawley rats subjected to methamphetamine- and cocaine-induced CPP tests were treated with dopamine D1 (SCH23390) or D2 (sulpiride) receptor antagonists. Following the CPP experiment, rats were challenged with apomorphine (dopamine receptor agonist), and locomotor activity was measured. Methamphetamine- and cocaine-induced CPP was reduced with the administration of SCH23390, but not sulpiride. In addition, the apomorphine challenge evoked an increase in locomotor activity in stimulant-pre-treated rats, reflecting dopamine receptor supersensitivity. SCH23390 pre-treatment inhibited the development of dopamine receptor supersensitivity, while sulpiride demonstrated no inhibitory effects. These results suggest that the dopamine D1 receptor antagonist SCH23390 inhibits the development of dopamine receptor supersensitivity which is associated with the development of CPP.

Residual dopamine receptor desensitization following either high- or low-dose sub-chronic prior exposure to the atypical anti-psychotic drug olanzapine

Anti-psychotic drugs are antagonists of dopamine D2 receptors and repeated administration may lead to the development of dopamine receptor supersensitivity. The objective of this study is to investigate the effects of sub-chronic olanzapine treatments upon the induction of dopamine receptor supersensitivity. Rats were administered ten daily low or high doses of the atypical anti-psychotic drug olanzapine (0.01 or 1.0 mg/kg). After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on five successive days. Five days after the apomorphine sensitization protocol, in separate experiments, either a conditioning test or an apomorphine sensitization test was conducted. During the anti-psychotic treatment the high dose of olanzapine induced profound locomotion suppression, whereas the low dose had no effect upon locomotion. The apomorphine treatments given to the vehicle control group generated locomotor sensitization. This sensitization effect was attenuated by the same degree for both the low or high dose prior olanzapine treatments. Also, the low and high-dose olanzapine pre-treatments diminished subsequent apomorphine-conditioned and apomorphine-sensitized locomotor responses. The equivalent attenuation of the apomorphine sensitization produced by both olanzapine doses indicates that this effect was unrelated to the direct effects of olanzapine upon locomotion. Furthermore, the persistence of the desensitization effects well after the termination of the olanzapine treatments is indicative of a residual desensitization of the dopamine system. These findings are of importance when considering the use of atypical anti-psychotic drugs in the treatment of psychoses and other disorders in which overactivity of the dopamine system is considered a contributory factor.

Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: Evidence that at a very low dose haloperidol acts as an indirect dopamine agonist

Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.

Chronic lithium prevents REM sleep deprivation-induced increased responsiveness to apomorphine.

REM sleep deprivation of rats induces an increased responsiveness to dopaminergic agonists. Chronic lithium (Li) has been reported to prevent the development of dopamine receptor supersensitivity induced by other agents. The effects of chronic dietary Li administration (producing a mean serum level of 0.96 mequiv. litre-1) and 96 h REM sleep deprivation were studied. Chronic Li completely blocked the increased stereotypy, and partially prevented the aggressive behaviour induced, respectively, by 0.6 and 5 mg kg-1 of apomorphine in REM sleep deprived rats compared with the appropriate control groups. This study constitutes the first attempt to evaluate chronic lithium effects on rats undergoing REM sleep deprivation, chosen as another method of inducing alteration of dopaminergic sensitivity.

Altered Regulation of Dopaminergic Activity and Impairment in Motor Function in Rats After Subchronic Exposure to Styrene

Animal and human studies suggest a dopamine-mediated effect of styrene neurotoxicity. However, the results reported to date are incomplete and not consistent. As such, the mechanism of its neurotoxicity is still unclear. The present study has, therefore, reexamined the central dopaminergic system in relation to some neurobehavioral effects in rats following subchronic exposure to styrene. Groups of adult male Sprague–Dawley rats received 0, 0.25, or 0.5 g styrene per kg b.wt. by gavage for 13 consecutive weeks. Twenty-four hours after cessation of such treatment with the higher dose (0.5 g/kg), the contents of dopamine (DA) and its metabolites were significantly reduced in the corpus striatum, hypothalamus, and lateral olfactory tract regions. In vitro styrene showed a significant increase in DA release from rat striatal synaptosomes similar to that of tyramine. Significant loss of motor function was observed on days 56, 70, and 84 during the styrene treatment with the higher dose, and lasted over a month after such treatment. However, the treated animals recovered their motor function within 45–60 days after cessation of such treatment, along with the recovery of normal levels of dopamine and its metabolites. Furthermore, styrene-induced initial impairments in measures of dopaminergic activity cannot be attributed to altered regulation of tyrosine hydroxylase activity. Specific [ 3H]-spiroperidol binding was also unaltered 7 or 15 days after subchronic treatment with styrene. These data imply that despite the dopaminergic neuronal loss due to styrene, dopaminergic transmission was not reduced to a level that would result in an overall development of dopamine receptor supersensitivity in the striatum. Collectively, these studies indicate that the subchronic neurotoxic action of styrene may be primarily presynaptic in nature and may involve impaired regulation of DA content and stimulation of DA release.

Blockade by naloxone of cocaine-induced hyperactivity, reverse tolerance and conditioned place preference in mice

Cocaine-induced hyperactivity was inhibited by a single administration of naloxone (2 and 5 mg/kg, i.p.), an opioid receptor antagonist, and naloxone administered prior to and during the chronic injection of cocaine attenuated the development of both cocaine-induced reverse tolerance and conditioned place preference (CPP). Dopamine (DA) receptor supersensitivity which developed in cocaine-induced reverse tolerant or CPP mice, was also inhibited by naloxone. Furthermore, naloxone reduced an apomorphine-induced striatal dopaminergic action, climbing behavior. Therefore, the present studies suggest that cocaine-induced dopaminergic behaviors, such as hyperactivity, reverse tolerance and CPP, may be commonly produced via activation of an opioid receptor. The development of DA receptor supersensitivity may be a possible common mechanism of cocaine-induced reverse tolerance and CPP, since cocaine-induced changes in sensitivity to apomorphine, as well as apomorphine-induced climbing behavior in mice, were both inhibited by naloxone.

Chronic morphine increases hippocampal acetylcholine release: possible relevance in drug dependence

Previous studies have shown that cocaine and amphetamine stimulate acetylcholine release in the hippocampus via an action of endogenously released dopamine on dopamine D 1 and D 2 receptors. The present study was aimed at clarifying if the property of stimulating hippocampal acetylcholine release was shared by morphine. The acute administration of morphine (10 mg/kg i.p.) failed to modify acetylcholine release in the hippocampus. However, after repeated administration (10 mg/kg i.p. twice daily) morphine acquired the ability to stimulate hippocampal acetylcholine release. Thus, at days 5 and 7 of chronic morphine treatment, a challenge dose of morphine (10 mg/kg i.p.) increased acetylcholine release by 50 and 100%, respectively. Concomitantly with the development of the stimulant property on acetylcholine release, morphine also acquired that of producing behavioural stimulation and lost that of producing sedation and catalepsy. The morphine-induced increase in acetylcholine output was suppressed by the blockade of dopamine D 1 receptors with SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.1 mg/kg s.c.), which also suppressed the morphine-induced motor stimulation. Moreover, repeated morphine administration markedly potentiated the stimulant effect of the dopamine D 1 D 2 receptor agonist apomorphine (R(-)-10,11-dihydroxyaporphine) (0.1 or 0.5 mg/kg s.c.) both on hippocampal acetylcholine release and on behaviour. These results may suggest that the enhancement of hippocampal acetylcholine release as well as the development of behavioural sensitisation after chronic morphine could be related to the development of dopamine receptor supersensitivity. Moreover, increased acetylcholine transmission in the hippocampus may play a role in the ‘memory’ of the rewarding effects of drugs of abuse.

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice

1. 1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine. 2. 2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days. 3. 3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

Blockade by Ginseng Total Saponin of the Development of Methamphetamine Reverse Tolerance and Dopamine Receptor Supersensitivity in Mice

Repeated administration of methamphetamine (2 mg/kg) developed reverse tolerance to the ambulation-accelerating effect. Intraperitoneal administration of ginseng total saponin (GTS, 200 mg/kg of body weight) prior to and during chronic administration of methamphetamine inhibited the development of reverse tolerance. Dopamine receptor supersensitivity was also developed in reverse tolerant mice which had received the same methamphetamine. The development of dopamine receptor supersensitivity was evidenced by the enhanced hypothermic response to apomorphine (1 mg/kg) and the enhanced ambulatory activity of apomorphine (4 mg/kg). GTS also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of methamphetamine. These results show that GTS may be useful for the prevention of and therapy for the adverse action of methamphetamine. It is concluded that the development of reverse tolerance to methamphetamine may be associated with the enhanced dopamine receptor supersensitivity since both phenomena were blocked by GTS.

Blockade by ginseng total saponin of the development of cocaine induced reverse tolerance and dopamine receptor supersensitivity in mice

Daily repeated administration of cocaine (15 mg/kg, over a 7-day period) developed reverse tolerance to the ambulation-accelerating effect of cocaine. Intraperitoneal administration of ginseng total saponin (GTS, 100 and 200 mg/kg of body weight) prior to and during chronic administration of cocaine inhibited the development of reverse tolerance. Dopamine receptor supersensitivity was also developed in reverse tolerant mice that had received the same cocaine. The development of dopamine receptor supersensitivity was evidenced by the enhanced hypothermic response to apomorphine (1 mg/kg) and the enhanced ambulatory activity of apomorphine (4 mg/kg). GTS also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of cocaine. These results provide that GTS may be useful for the prevention and therapy of the adverse action of cocaine. It is concluded that the development of reverse tolerance to the ambulation-accelerating effect of cocaine may be associated with the enhanced dopamine receptor sensitivity because both phenomena were blocked by GTS.

Early L-DOPA treatment initially retards but later enhances dopamine receptor supersensitivity following unilateral dopamine denervation

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice per day or saline in separate treatment groups for 13 days. Treatment was initiated within 18–20 h postoperative, well-before the onset of denervation supersensitivity. Contralateral rotation emerged as a response to L-DOPA on day 7 postoperative first in the L-DOPA once/day group and then on day 9 for the L-DOPA twice/day group. Thus, early postoperative L-DOPA treatment retarded but did not prevent the development of dopamine receptor supersensitivity. Following a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L-DOPA challenge as compared to a drug-naive group with comparable 6-OHDA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical tissue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neurochemical impact of L-DOPA on frontal cortex vs. striatum. In the striatum but not the cortex, L-DOPA concentrations were higher in the 6-OHDA than the intact hemisphere and, L-DOPA increased dopamine concentrations in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the state of dopamine receptors. Prior to the onset of dopamine receptor supersensitivity L-DOPA suppressed locomotor behavior and delayed the emergence of denervation supersensitivity. Once denervation supersensitivity developed, however, the L-DOPA engaged sensitization mechanisms and enhanced locomotor behavior and dopamine receptor supersensitivity. These findings suggest that the initiation of antiparkinsonian treatment prior to the onset of denervated dopamine receptor supersensitivity in the 6-OHDA model is a valuable strategy to determine if a drug treatment retards or facilitates the development of dopamine receptor supersensitivity.

Opposite effects of intranigral ibotenic acid and 6-hydroxydopamine on motor behavior and on striatal neuropeptide Y neurons

Unilateral lesions of the basal ganglia circuitry induce a disequilibrium of motor processing, most obviously expressed by the resulting circling behavior. Compensatory events, which reduce the motor asymmetry, could be accompanied by changes in neurotransmitter/modulator parameters in the involved brain regions. In the present investigation, the effects of an interruption of the striato-nigro-thalamic loop by ibotenic acid (IBO)-induced lesions of total substantia nigra (SN) on circling behavior and on striatal neuropeptide Y (NPY) neurons were compared with those after the selective destruction of the dopaminergic nigrostriatal projection with 6-hydroxydopamine (6-OHDA). Directly after the operation, IBO-lesioned rats showed a high circling rate to the side contralateral to the lesion, whereas 6-OHDA-lesioned rats showed ipsiversive circling. With the lesion-induced development of dopamine receptor supersensitivity, 6-OHDA-treated rats, when stimulated with the dopaminergic agonist apomorphine, change their circling direction to the contralateral side. Complete IBO lesions of the SN abolished this effect: rats continued to circle to the contralateral side. These observations suggest that not only the dopaminergic denervation of the striatum but also the imbalance in the activity of the thalamo-cortical projection (reduced after 6-OHDA, augmented after IBO) are instrumental in determining the degree and direction of circling. Quantification of NPY-immunoreactive neurons in striatum revealed a decrease in 6-OHDA lesioned rats after 3 days on the side contralateral to the lesion, an effect even more pronounced after 4 month's survival time. IBO-induced lesions of the SN had an opposite effect on NPY-immunoreactivity in the striatum: neuron counts were lower on the ipsi- than on the contralateral side. In addition, a time-dependent variation in total number of NPY- neurons was noted: during the early postoperative periods an increase, followed by a prolonged decrease to values below 50% of the controls after 4 months. Taken together, these results provide evidence that a dopaminergic deafferentation and its consequences on the nigro-thalamo-cortical loop will determine NPY expression in the striatal interneurons. In particular, it is suggested that the number of striatal NPY-neurons and the imbalance in cortical activity are tightly coupled in terms of a negative correlation.

Breaking points on a progressive ratio schedule reinforced by intravenous apomorphine increase daily following 6-hydroxydopamine lesions of the nucleus accumbens

It has been shown previously that 6-hydroxydopamine (6-OHDA)-induced lesions of the nucleus accumbens cause extinction of cocaine self-administration behavior, yet fail to affect the rate of apomorphine self-administration on a Fixed Ratio 1 schedule of reinforcement. Since the dopamine (DA) receptors in this nucleus should become supersensitive, and since these receptors are thought to mediate the reinforcing effects of apomorphine, then some change in apomorphine self-administration would be expected. We have therefore reinvestigated the effect of 6-OHDA lesions on apomorphine self-administration using a progressive ratio schedule of reinforcement. Rats were trained to self-administer apomorphine (0.033 mg/inj, IV) on a schedule in which the response requirements increased after each reinforcement. The breaking point was defined as the final ratio completed during each daily session. Sham lesions had no effect on the breaking points, and a steady increase in the breaking point was observed in the 6-OHDA-lesioned animals which may parallel the development of DA receptor supersensitivity.

Effects of lithium on dopamine behavioural supersensitivity induced by rapid eye movement sleep deprivation.

The effects of lithium on the potentiation of d-amphetamine-induced hyperlocomotion were evaluated in rapid eye movement (REM) sleep deprived rats. Under control conditions, pretreatment with lithium during 7 days did not modify the hyperlocomotion produced by d-amphetamine. REM sleep deprivation induced a pronounced potentiation of the locomotor response to d-amphetamine. In a stress control group this potentiation also occurred, but to a lesser degree than in the REM sleep deprived group. Lithium pretreatment prevented the increased response to d-amphetamine in both REM sleep deprived and stress control animals. The effects of lithium in REM sleep deprived rats are in accordance with reports that lithium is able to prevent the development of dopamine receptor supersensitivity. However, it cannot be excluded that in both REM sleep deprived and stress control groups the increased response to d-amphetamine is related to noradrenergic changes and/or noradrenergic-dopaminergic interactions. REM sleep deprivation seems to be an interesting model to study the underlying mechanisms of manic-depressive illness.

Down-regulation of haloperidol-induced striatal dopamine receptor supersensitivity by active analogues of L-prolyl-L-leucyl-glycinamide (PLG)

Tardive dyskinesia, a clinical syndrome, is one of the major side effects of protracted treatment with neuroleptics in schizophrenic patients. Functional supersensitivity of striatal dopamine receptors is believed to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. In a rodent model of neuroleptic-induced dopamine receptor supersensitivity, we investigated the efficacy of structurally modified analogues of PLG to down-regulate the striatal dopamine receptor supersensitivity as determined by alterations in [ 3H]spiroperidol binding to striatal membranes in vitro. The PLG analogue, L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide-HCl, when given at the dose of 10 mg/kg IP for 5 days prior to haloperidol (3 mg/kg IP 21 days) significantly prevented the up-regulation of striatal dopamine receptor supersensitivity, thus demonstrating a prophylactic effect. Two other analogues, L-prolyl-L-leucyl-5-aminomethyltetrazole and L-prolyl-L-leucyl-glycine-dimethylamide at a dose of 10 mg/kg IP when given concurrently with haloperidol for 21 days, suppressed the development of dopamine receptor supersensitivity. None of the analogues tested in the post-haloperidol session reversed the haloperidol-induced increase in the density of striatal dopamine receptors. Active PLG analogues hold promise as potential therapeutic agents for the amelioration of tardive dyskinesia.

Further evidence that a single dose of an opiate can increase dopamine receptor sensitivity in mice

Previous findings in our laboratory indicated that a single administration of morphine or levorphanol to mice could induce the development of supersensitive dopamine receptors. To further study this phenomenon, the ability of haloperidol to inhibit dopamine agonist-induced climbing was determined in mice 3 h following morphine (10 mg/kg i.p.) or levorphanol (2.0 mg/kg i.p.) pretreatment. The dose of haloperidol required to inhibit climbing behavior induced by 2.4 mg/kg (i.p.) of apomorphine or (−)N-n-propylnorapomorphine was increased significantly in the opiate-pretreated mice. Morphine pretreatment did not significantly affect the apparent pA 2 of apomorphine-haloperidol for climbing behavior suggesting that the affinity of the dopamine receptor was not altered. This observation was supported by a lack of difference in the K d of haloperidol binding sites between saline- and morphine-pretreated mice. There was, however, a significant increase in the B max in the morphine-pretreated animals. This increase was blocked when 5 mEq/kg of lithium (i.p.) or 5 mg/kg naloxone (i.p., administered twice) was administered concurrently with the morphine. Concurrent lithium or naloxone administration also attenuated the morphine-induced increase in dose of haloperidol required to inhibit dopamine agonist-induced climbing behavior. These results suggest that a single administration of an opiate can cause the development of dopamine receptor supersensitivity which is due to an increase in dopamine receptor density.

Pharmacological effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine receptor system

In mice, chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an increase in the maximum number of [ 3H]spiperone binding sites in the striatum. The sensitivity of striatal protein phosphorylation to calcium plus calmodulin is also potentiated in MPTP-treated mice. These observations are associated with an enhancement of apomorphine-induced climbing behavior in the drug-treated animals. The results of this study suggest that in an animal model for Parkinson's disease, MPTP interrupts the dopamine (DA) transmission by chemically denervating the nigrostriatal neurons and through a compensatory mechanism, it increases the number of DA receptors as well as the sensitivity of protein phosphorylation to calcium plus calmodulin in mouse striatum. The latter two events may contribute to the development of DA receptor supersensitivity.

Effects of discontinuous drug administration on the development of dopamine receptor supersensitivity during chronic trifluoperazine or cis-flupenthixol administration to rats.

Rats received continuous or discontinuous administration of trifluoperazine or cis-flupenthixol in drinking water for up to 12 months. Continuous and discontinuous trifluoperazine administration had no consistent effect on apomorphine-induced stereotyped behaviour and there was no difference between drug treatments. Continuous and discontinuous cis-flupenthixol administration enhanced apomorphine-induced stereotypy, but there was no difference in the effect of the two drug treatments. Both continuous and discontinuous administration of trifluoperazine increased the number of specific striatal 3H-spiperone binding sites (Bmax). Over the period of treatment there was no difference in the effects of the different treatments. Continuous or discontinuous cis-flupenthixol intake did not increase Bmax after 6 or 12 months intake. Continuous or discontinuous neuroleptic treatment produced no difference in functional striatal dopamine receptor activity as judged by apomorphine-induced stereotyped behaviour. Ligand binding studies also suggest that the overall change in striatal receptor function is not affected by the use of a discontinuous drug regime.

Modulation of CNS dopamine receptors by peptides

1. 1. L-prolyl-L-leucyl-glycinamide (PLG), when administered concurrently with neuroleptic drug, blocked the development of dopamine receptor supersensitivity both at the behavioral and biochemical level. 2. 2. Chronic administration of haloperidol resulted in development of cholecystokinin (CCK) receptor supersensitivity in the mesolimbic regions of the brain. There was no change in equilibrium dissociation constant (KD) for CCK binding. 3. 3. The results are discussed in relation to modulation of dopamine receptor by peptides and possible models of Interaction of peptides with dopamine receptors are proposed.

Characterization of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides.

Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that 3H-N-propylnorapomorphine (3H-NPA) binding sites and 3H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor supersensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of 3H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for 3H-NPA could be demonstrated in the striatum. However, at this time interval the total number of 3H-NPA binding sites was not increased. The functional significance of these two binding sites for 3H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for 3H-bromocriptine, 3H-spiperone, 3H-ADTN and 3H-NPA binding sites in vitro. It is suggested that the Ki ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specific in vivo binding of 3H-spiperone and 3H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for 3H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of normal dopamine receptors by reducing the density of such receptors. Evidence has also been presented that CCK-8 and the desulphated CCK-8 (10(-6) M) can in vitro reduce the number of 3H-NPA binding sites in the striatum. These results indicate that cholecystokinin peptides via activation of cholecystokinin receptors can regulate the movements of the 3H-NPA binding sites across the plane of the membrane in such a way as to make them less available to the external surface of the membrane...