Dopamine Receptor Supersensitivity Research Articles

Does peripheral neuropathy allow for the clinical expression of tardive dyskinesia by unmasking central nervous system changes?

Tardive dyskinesia (TD) is a severe and troubling complication of long-term typical neuroleptic use whose etiology remains obscure. While it is widely believed that central nervous system (CNS) dopamine receptor super-sensitivity is involved in the pathogenesis of the condition, it is unclear why some patients develop TD while others do not. It is proposed that a subclinical peripheral motoneuropathy with consequent enlarging of the motor units may act to unmask neuroleptic-induced CNS changes allowing for the expression of TD. To investigate this hypothesis we examined motor unit size with electrographic examinations in 14 patients (six with mild TD; eight without and all with psychotic illness). There were no differences between the two groups of patients. While the data do not appear to support the hypothesis, a larger study with more severely affected patients is required to more adequately test the hypothesis.

Inhibition of Baclofen on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity

The effects of baclofen on the development of reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine were examined in mice. A single administration of morphine induced hyperactivity and the morphine-induced hyperactivity was inhibited dose dependently by the administration of a GABABreceptor agonist, baclofen (1.25, 2.5 and 5 mg kg−1, i.p.). Daily repeated administration of morphine developed reverse tolerance to the hyperactivity of morphine. The concomitant administration of baclofen inhibited the morphine-induced hyperactivity and the baclofen administration prior to and during the chronic administration of morphine in mice inhibited the development of reverse tolerance to the hyperactivity of morphine (10 mg kg−1, s.c.). Postsynaptic dopamine receptor supersensitivity was also developed in reverse-tolerant mice that had received the same morphine. The development of postsynaptic dopamine receptor supersensitivity was evidenced by the enhanced ambulatory activity of apomorphine (2 mg kg−1, s.c.). Baclofen also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine may be modulated via the activation of GABABreceptors induced by baclofen.

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.

The current status of tardive dyskinesia.

This paper aims to provide an overview of the current knowledge on neuroleptic-induced tardive dyskinesia (TD) in relation to its clinical features, risk factors, pathophysiology and management. The published literature was selectively reviewed and assessed. Tardive diskinesia is a common neurological side-effect of neuroleptic medication, the cumulative incidence of which increases with increasing duration of treatment. Its clinical manifestations are diverse and subsyndromes have been described. Many risk factors for TD are now recognised, but increasing age remains pre-eminent as a risk factor. The pathophysiology of TD is not completely understood. Of the neurotransmitter hypotheses, the dopamine receptor supersensitivity hypothesis and the gamma-aminobutyric acid insufficiency hypothesis are the main contenders. There is increasing recognition that TD may in fact be caused by neuroleptic-induced neuronal toxicity through free radical and excitotoxic mechanisms. The occurrence of spontaneous dyskinesias in schizophrenic patients and even healthy subjects suggests that neuroleptics act on a substratum of vulnerability to dyskinesia. As no effective treatment for TD is available, the primary emphasis is on prevention. Many drugs can be tried to reduce symptoms in established cases. The increasing use of atypical neuroleptics has raised the possibility of a lower incidence of TD in the future. After four decades of clinical recognition, the pathophysiology of TD is still not understood and no effective treatment is available. Its prevention with the optimal usage of currently available drugs and regular monitoring of patients on long-term neuroleptic treatment remain the best strategies to reduce its impact.

Haloperidol-induced neurotoxicity--possible implications for tardive dyskinesia.

Tardive dyskinesia (TD) is one of the major side effects of long term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. The traditional concept of supersensitivity of striatal dopamine receptors as the mechanism involved in the development of TD is not satisfying, and current studies have focused on the role of neuroleptic-induced neuronal toxicity in the development of TD. We performed a series of experiments to gain a better understanding on the mechanisms involved in induction of TD. We have evaluated the direct neurotoxic effect of haloperidol (HP), a widely--used neuroleptic drug, and its three metabolites, in mouse neuronal cultures and in PC-12 cells. We found that the features of HP-induced cell death were apoptotic rather than necrotic, as indicated by different DNA-staining methods and specific caspases inhibitors. Moreover, cotreatment with antioxidants such as vitamin E and N-acetylcysteine (NAC) significantly protected the cultures. Further studies on the mechanisms underlying HP-induced toxicity may lead to the development of new neuroprotective therapeutic strategies.

Detection of the effects of dopamine receptor supersensitivity using pharmacological MRI and correlations with PET.

Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. (11)C-PET studies of ligands which bind to the dopamine transporter (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1, 5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding.

Opposite modulation of apomorphine- or amphetamine-induced stereotypy by antagonists of CCK receptors

Stereotyped behavior is elicited by activation of dopaminergic systems with drugs such as apomorphine and amphetamine. In previous studies, we have reported that the sulfated cholecystokinin octapeptide (CCK-8) decreased apomorphine-induced stereotypy in animals with normal and supersensitive dopamine receptors. The aim of the present study was to evaluate the effects of CCK 1 and CCK 2 receptor antagonists on stereotyped behavior induced by apomorphine or amphetamine. Rats were pretreated with the CCK 1 (SR 27897B; 1-[[2-(4-(2-chlorophenyl) thiazol-2-yl) aminocarbonyl]indolyl]acetic acid; 500 μg/kg; i.p.) or CCK 2 (L-365,260; 3R-(+)- N-(2,3-dihydro-1-methyl-2-oxo-5 phenyl-1 H-1,4-benzodiazepine-3-yl)- N′-(3-methyl phenyl)-urea; 500 μg/kg; i.p.) receptor antagonists or saline 15 min before apomorphine (0.6 mg/kg; s.c.) or amphetamine (9.0 mg/kg; i.p.) injection. Both CCK 1 and CCK 2 receptor antagonists significantly increased apomorphine-induced stereotypy. In contrast, only the blockade of CCK 2 receptors significantly decreased amphetamine-induced stereotypy. The results suggest a dual opposite mechanism for CCK–dopamine interactions. These data also suggest that both apomorphine- and amphetamine-induced stereotypy should be used whenever effects of drugs acting on dopaminergic systems are being assessed.

Conditioning to Injection Procedures and Repeated Testing Increase SCH 23390-Induced Catalepsy in Mice

The cataleptic behavior induced by the dopamine D1 antagonist SCH 23390 (SCH) has proven to be a useful assay for investigating the sensitivity of D1-like dopamine receptor-mediated effects during chronic drug administration. A fundamental flaw in most of these studies may be the involvement of the “repeated measures effect,” a behavioral phenomenon well demonstrated for neuroleptic-induced catalepsy but not yet investigated for dopamine D1 antagonists. In this study, mice exposed for various sessions to the bar test presented a strong sensitization to the cataleptic behavior induced by repeated SCH treatment. Conversely, single tested animals exhibited a trend toward decreased catalepsy after repeated SCH treatment, which was in line with the development of a D1-like dopamine receptor supersensitivity suggested by an increase in SKF 38393-induced grooming behavior. Surprisingly, a challenge intraperitoneal saline injection increased the cataleptic behavior of single tested mice after long-term SCH treatment. This “injection-conditioned catalepsy” was also observed after repeated treatment with the dopamine D2 antagonists, haloperidol and metoclopramide. While these findings seem to explain some important contradictory data in the literature, they provide a new and simple animal model of the placebo effect.

Dopamine receptor-modulated [ [formula omitted]]GTPγS binding in striatum of 6-hydroxydopamine-lesioned rats

The role of dopamine receptor–G protein coupling in the development of striatal dopamine receptor supersensitivity was studied in rats with a 6-hydroxydopamine (6-OHDA)-induced unilateral lesion of the nigrostriatal pathway. This coupling was assessed by the measurement of dopamine agonist-induced guanosine 5′- O-(γ[ 35 S ]thio)triphosphate ([ 35 S ]GTPγS) binding in striatal membranes, at different periods of time (1–5 weeks) following the microinjection of the neurotoxin. From the first to the fifth week following the lesion, basal and dopamine-stimulated [ 35 S ]GTPγS-specific binding were found to be enhanced in the denervated striata as compared to their control counterpart. D 2 dopamine receptors were clearly demonstrated to be involved in this supersensitivity, as assessed by measuring N-propylnorapomorphine (NPA)-, quinpirole- and bromocriptine-induced [ 35 S ]GTPγS-specific binding. The involvement of D 1 dopamine receptors was indirectly studied by the combination of dopamine with a saturating concentration of the selective and potent D 2 antagonist domperidone. In these conditions, the remaining response to dopamine was also found to be significantly increased following the lesion. These results are consistent with the hypothesis that, in addition to D 2 dopamine receptor upregulation, modulation of dopamine receptor–G protein interaction is involved in the hypersensitivity accompanying striatal dopamine depletion.

Inhibitory effects of ginseng total saponin on nicotine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity

A single administration of a low dose of nicotine produced hyperactivity in mice. A repeated administration of nicotine developed reverse tolerance to the ambulation-accelerating activity of nicotine and also developed postsynaptic dopamine (DA) receptor supersensitivity. The development of reverse tolerance was evidenced by an increased ambulatory response to nicotine, and the development of postsynaptic DA receptor supersensitivity was evidenced by the enhanced response in ambulatory activity to apomorphine, a DA receptor agonist. Administration of ginseng total saponin (GTS) prior to and during the nicotine treatment in mice inhibited not only nicotine-induced hyperactivity and reverse tolerance, but also postsynaptic DA receptor supersensitivity in nicotine-induced reverse tolerant mice. These results suggest that inhibition by GTS of nicotine-induced hyperactivity and reverse tolerance may be closely related with the inhibition of the dopaminergic activation induced by nicotine and that the development of nicotine-induced reverse tolerance may be associated with enhanced DA receptor sensitivity.

Rat Strain Differences in the Ability to Disrupt Sensorimotor Gating Are Limited to the Dopaminergic System, Specific to Prepulse Inhibition, and Unrelated to Changes in Startle Amplitude or Nucleus Accumbens Dopamine Receptor Sensitivity

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.

Inhibition by Ginsenosides Rb 1 and Rg 1 of Cocaine-Induced Hyperactivity, Conditioned Place Preference, and Postsynaptic Dopamine Receptor Supersensitivity in Mice

A single or repeated administration of cocaine (15 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). Ginsenoside Rb 1 (Rb 1) and ginsenoside Rg 1 (Rg 1), prior to and during the cocaine treatment in mice, inhibited cocaine-induced hyperactivity and CPP. The development of enhanced postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). Rb 1 and Rg 1 inhibited the development of postsynaptic DA receptor supersensitivity. However, Rb 1 and Rg 1 did not show any antidopaminergic activity at the postsynaptic DA receptors, because the apomorphine-induced climbing behavior was not inhibited by Rb 1 and Rg 1. Therefore, it is presumed that Rb 1 and Rg 1 modulate DA activity induced by cocaine at the presynaptic DA receptors, and this modulation results in the inhibition of postsynaptic dopaminergic activation. These results suggest that the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity. The inhibition by Rb 1 and Rg 1 of cocaine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by cocaine at the presynaptic DA receptors.

Inhibitory effects of velvet antler water extract on morphine-induced conditioned place preference and DA receptor supersensitivity in mice

The repeated administration of morphine in mice produced conditioned place preference (CPP) and postsynaptic dopamine (DA) receptor supersensitivity. CPP effects were evaluated assessing the increased time spent by the mice to morphine and the inhibition of CPP by the decreased time spent by the mice in the nonpreferred compartment. Postsynaptic DA receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist. The oral administration of velvet antler water extract (VAWE) from Cervus elaphus, prior to the morphine treatment in mice inhibited the development of morphine-induced CPP and postsynaptic DA receptor supersensitivity. These results suggest that the inhibitory effects of VAWE on morphine-induced CPP may be closely related to the recovery of dysfunction in the dopaminergic system produced by morphine because both phenomena were inhibited by VAWE. But a single administration of VAWE did not inhibit apomorphine-induced climbing behavior, indicating that antidopaminergic activity was not produced by a single administration of VAWE at the postsynaptic DA receptors. From the above results, it is presumed that VAWE may be useful for prevention and therapy of the adverse actions of morphine.

Ginseng total saponin inhibits nicotine-induced hyperactivity and conditioned place preference in mice

A single or repeated administration of nicotine in mice produced hyperactivity and conditioned place preference (CPP). Postsynaptic dopamine (DA) receptor supersensitivity was also developed in nicotine-induced CPP mice. The hyperactivity induced by nicotine was evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. CPP effects were evaluated assessing the increased time spent by the mice to nicotine and the inhibition of CPP by the decreased time spent by the mice in the nonpreferred compartment. Postsynaptic DA receptor supersensitivity was evidenced by the enhanced response in ambulatory activity to the apomorphine, a DA receptor agonist. Administration of ginseng total saponin (GTS) prior to and during the nicotine treatment in mice inhibited not only nicotine-induced hyperactivity and CPP but also postsynaptic DA receptor supersensitivity in nicotine-induced CPP mice. These results suggest that inhibition by GTS of the nicotine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by nicotine and that the development of nicotine-induced CPP may be associated with the enhanced DA receptor supersensitivity. From these results, it is presumed that GTS may be useful for the prevention and therapy of these adverse actions of nicotine.

Antinarcotic effects of the velvet antler water extract on morphine in mice

The present study was undertaken to investigate the antinarcotic effects of velvet antler water extract (VAWE) from Cervus elaphus on morphine. Morphine-induced analgesic action was measured by tail-flick method. Morphine-induced hyperactivity and reverse tolerance were evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. Dopamine (DA) receptor supersensitivity in mice displaying morphine-induced reverse tolerance was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine. The repeated administration of VAWE significantly inhibits the development of morphine-induced analgesic tolerance, physical dependence, reverse tolerance and postsynaptic DA receptor supersensitivity. But a single administration of VAWE did neither antagonize morphine-induced analgesia nor inhibit morphine-induced hyperactivity. From the above results, it is presumed that VAWE may be useful for prevention and therapy of the adverse actions of morphine caused by the repeated administration of morphine.

The role of nigrostriatal dopamine in metabotropic glutamate agonist-induced rotation

Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptors subtypes have been cloned and have been classified into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. Previous results have shown that striatal group I metabotropic glutamate receptor stimulation produces vigorous contralateral rotation in intact rats, thought to be due to increased striatal dopamine release. Examination of FOS-like immunoreactivity and local cerebral glucose metabolism suggests that this occurs secondary to activation of the subthalamic nucleus. We sought to determine the contribution of dopamine by examining metabotropic glutamate receptor agonist-induced rotation in rats following acute dopamine depletion by reserpine/α-methyl-para-tyrosine treatment, or chronic dopamine depletion by 6-hydroxydopamine treatment. In unilateral 6-hydroxydopamine lesioned rats, the group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine induced contralateral rotation with a coincident increase in striatal 3,4-dihydroxyphenylacetic acid. The rotation was attenuated by the group I antagonist 1-aminoindan-1,5-dicarboxylate. Examination of FOS-like immunoreactivity and [ 14C]2-deoxyglucose uptake in chronically dopamine depleted rats also revealed similar patterns to those seen previously in intact rats. However, acutely dopamine depleted rats do not exhibit metabotropic glutamate receptor agonist-induced rotation and show a different pattern of [ 14C]2-deoxyglucose uptake, with no increase in glucose utilization in the intermediate and deep layers of the superior colliculus. These results suggest that there are compensatory changes under conditions of chronic dopamine denervation which permit metabotropic glutamate receptor agonist-induced rotation to occur, which may include dopamine receptor supersensitivity, increased dopamine turnover, and/or changes in sensitivity of striatal group I metabotropic glutamate receptors. The group III metabotropic glutamate receptor agonist l-(+)-2-amino-4-phosphonobutyrate induced contralateral rotation in 6-hydroxydopamine lesioned rats, while it had no effect in intact rats. Additionally, examination of FOS-like immunoreactivity revealed a distinct pattern following l-(+)-2-amino-4-phosphonobutyrate administration in 6-hydroxydopamine lesioned versus intact rats. These results suggest that there is a change in the effect of striatal group III stimulation under conditions of dopamine depletion.

Inhibition by Ginsenosides Rb 1 and Rg 1 of Methamphetamine-Induced Hyperactivity, Conditioned Place Preference and Postsynaptic Dopamine Receptor Supersensitivity in Mice

The ginsenosides Rb 1 and Rg 1, the major components of ginseng saponin, inhibited not only methamphetamine-induced hyperactivity but also conditioned place preference (CPP) in mice following a single or repeated administration. Dopamine (DA) receptor supersensitivity, which developed in methamphetamine-induced CPP mice, was also inhibited by both Rb 1 and Rg 1. Therefore, the present results suggest that Rb 1 and Rg 1 may be the active components of ginseng saponin in the modulation of methamphetamine-induced dopaminergic behaviors such as hyperactivity and CPP, supporting our previous conclusion that ginseng saponin might modulate methamphetamine-induced dysfunction at both the pre- and postsynaptic DA receptors.

Effects of ginseng total saponin on morphine-induced hyperactivity and conditioned place preference in mice

A single or repeated administration of morphine in mice produced hyperactivity, conditioned place preference (CPP) and postsynaptic dopamine (DA) receptor supersensitivity. The hyperactivity induced by morphine was evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. CPP effects were evaluated assessing the increased time spent by the mice to morphine and the inhibition of CPP by the decreased time spent by the mice in the white compartment. Postsynaptic DA receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg, s.c.). The intraperitoneal injection of ginseng total saponin (GTS) from the root of Panax ginseng C.A. Meyer ( Araliaceae), prior to and during the morphine treatment in mice inhibited morphine-induced hyperactivity and CPP. GTS inhibited the development of postsynaptic DA receptor supersensitivity. A single dose administration of GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic action of GTS at the postsynaptic DA receptor. These results suggest that the development of morphine-induced CPP may be associated with the enhanced DA receptor sensitivity and that GTS inhibition of the morphine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by morphine.

The Role of Striatal Glutamatergic System in Haloperidol-Induced Dopamine Receptor Supersensitivity and Effects of Monosialoganglioside GM1

The mechanism underlying the action of ganglioside GM1 on the increase of haloperidol-induced dopamine receptor supersensitivity was studied using the method of chemically stimulated ( 3H)-d-aspartate release in rat striatal slices. After a 3-week chronic haloperidol treatment the transmitter release was reduced by about 30%, with a further reduction to 40% when GM1 was applied chronically as well. This suggests that the downregulation of the glutamatergic system by chronic haloperidol treatment is potentiated by gangliosides. The acute effect of gangliosides on the stimulated ( 3H)-d-aspartate release from striatal slices was tested by adding GM1 to the superfusion medium. When given at a concentration of 10 24 M, GM1 did not alter the amino acid release itself. GM1 did, however, reduce the haloperidol-enhanced ( 3H)-d-aspartate release to control levels and elevated the glutamate-stimulated ( 3H)-d-aspartate release. Binding experiments indicate that gangliosides do not directly interact with glutamate or dopamine receptors. The data are discussed in view of earlier findings that GM1 potentiates the behavioral supersensitivity following chronic haloperidol treatment without directly altering dopamine receptor supersensitivity.

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.