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At least 595 records · Page 33Linked to original sources
PubMed1975

Differences in the nature of the stereotyped behaviour induced by aporphine derivatives in the rat and in their actions in extrapyramidal and mesolimbic brain areas.

Apomorphine, (minus)-N-n-propylnorapomorphine [ (minus)-NPA ] and (plus or minus)-N-n-propylnorapomorphine [ (plus or minus)-NPA ] each caused stereotyped behaviour patterns in the rat which could be differentiated into two components, sniffing and repetitive head and limb movements (low intensity component) and gnawing, biting and licking (high intensity component). Low intensity components occurred at low doses of apomorphine and high intensity components at larger doses but the two components never occurred independently for (minus)-NPA or (plus or minus) NPA. Biting was the predominant effect of these agents which were shown to be at least twenty times more potent than apomorphine. The (minus)-isomer of NPA was the more potent. The two components of stereotypy were differentiated both pharmacologically (using amantadine, reserpine plus alpha-methyl-p-tyrosine and haloperidol) and by lesions placed in areas of the extrapyramidal (caudate--putamen, globus pallidus, substantia nigra) and mesolimbic (nucleus accumbens septi, tuberculum olfactorium, nucleus amygdaloideus centralis) systems. However, both sniffing and biting responses were reduced by lesions of the serotonergic raphe nuclei. The two stereotypic components were differentially induced by intracerebral injections of apomorphine and (minus)-NPA into the caudate--putamen, nucleus accumbens septi and tuberculum olfactorium. Injections into the central nucleus of the amygdala were ineffective. The degree of involvement of the different areas was shown to differ for apomorphine and (minus)-NPA, in particular the nucleus accumbens septi appeared more important for the action of (minus)-NPA and the tuberculum olfactorium for apomorphine. Intracaudate (minus)-NPA was less active than apomorphine but, generally, intracerebrally applied (minus)-NPA was twice as potent as apomorphine. Both (minus)-NPA and apomorphine caused circling behaviour in animals with asymmetric medial raphe nucleus lesions (contralateral) or unilateral lesions of the substantia nigra (ipsilateral). In these experiments (minus)-NPA was ten times more potent than apomorphine.

Amantadine↗
PubMed1975

The importance of extrapyramidal function for the induction and antagonism of harmine tremor.

The brain lesion technique was used to investigate the role of the paleostriatum and the nigro-neostriatum in harmine-induced tremor and in its antagonism by dopaminergic agonists, apomorphine, 1-dopa, piribedil, d- and l-amphetamine. Bilateral lesions of the caudate--putamen or substantia nigra failed to modify the intensity of tremor or its antagonism by dopaminergic agonists. Bilateral lesions of the globus pallidus markedly reduced the intensity of tremor and the results indicated that such lesions were also able to reduce the effectiveness of dopaminergic agonists as tremor antagonists. The data suggest that the integrity of the paleostriatum is more important than that of the neostriatum for the mediation of harmine tremor and its antagonism by dopaminergic agonists. The results are discussed in relation to the proposed clinical relationship between paleostriatal dopamine dysfunction and tremor mechanisms.

Alkaloids↗
PubMed1976

A comparison of the abilities of typical neuroleptic agents and of thioridazine, clozapine, sulpiride and metoclopramide to antagonise the hyperactivity induced by dopamine applied intracerebrally to areas of the extrapyramidal and mesolimbic systems.

Dopamine injected directly into the caudate--putamen, nucleus accumbens or tuberculum olfactorium of rat brain, following a nialamide pretreatment, caused dose-dependent hyperactivity. The hyperactivity was more intense after injections into the nucleus accumbens, but was limited by the development of stereotyped biting when larger doses of dopamine were injected into the caudate--putamen or tuberculum olfactorium. Haloperidol, fluphenazine and pimozide were shown to antagonise, in a dose-dependent manner, the hyperactivity induced by dopamine from all 3 areas. Pimozide appeared equieffective against the 3 hyperactivity mediated from the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium. Sulpiride, clozapine and thioridazine also caused dose-dependent reductions in the hyperactivity induced by dopamine injections into the caudata--putamen, nucleus accumbens and tuberculum olfactorium, although the doses required to effect this inhibition were notably larger than for the typical neuroleptics. Generally, these atypical agents were also least effective as antagonists of the hyperactivity following intrastriatal dopamine. Metoclopramide differed from all other agents tested in failing to antagonise the hyperactivity induced by dopamine injections into the nucleus accumbens. However, the responses to dopamine from the caudate-putamen and tuberculum olfactorium were both antagonised by metoclopramide, the striatal response being the least sensitive. The alpha- and beta-adrenergic blocking agents, aceperone and propranolol, failed to reduce the hyperactivity induced by dopamine injections into the caudate-putamen, nucleus accumbens or tuberculum olfactorium. The abilities of the agents tested to antagonise a hyperactivity induced by dopamine in the striatum or in the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium, are compared with the potential of these agents to induce extrapyramidal side effects and to exert an antipsychotic action in man.

Animals↗
PubMed1978

The effect of gamma-acetylenic GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase, on dopamine pathways of the extrapyramidal and limbic systems.

gamma-Acetylenic GABA (100 mg/kg i.p.) inhibited GABA-transaminase activity and caused a several-fold increase in the concentration of GABA in rat brain. This increased GABA concentration was associated with a decreased rate of dopamine depletion following alpha-methyl-p-tyrosine treatment and a decrease in homovanillic acid in extrapyramidal and limbic structures suggesting a decrease in dopamine turnover in both pathways. In addition, gamma-acetylenic GABA injected into the ventral mesencephalic tegmentum decreased dopamine turnover in the mesolimbic forebrain. These results are consistent with a modulatory function of GABAergic neurons on extrapyramidal and limbic dopamine pathways. Inhibitory effects on dopaminergic functions of the extrapyramidal and limbic systems were also indicated by the amphetamine and apomorphine-induced ipsilateral turning after unilateral substantia nigral injections of gamma-acetylenic GABA and by the attenuation of dopamine-induced hypermotility after bilateral injections of gamma-acetylenic GABA into the nucleus accumbens.

4-Aminobutyrate Transaminase↗
PubMed1989

Response by the neurotensin systems of the basal ganglia to cocaine treatment.

Multiple administrations of high doses of cocaine had profound effects on the neurotensin (NT) systems of the basal ganglia. Approximately 200-300% increases in striatal content of neurotensin-like immunoreactivity (NTLI) were observed 1-8 h following five doses of 30 mg/kg per dose of cocaine. The effect subsided by 48 h after treatment. Significant changes in striatal NTLI levels were not observed after a single dose of this stimulant. The nigral NT systems appeared to be even more sensitive to cocaine administration. Compared to striatal changes, increases in nigral NTLI content were greater (as much as 455% of control), required lower cocaine doses (20 mg/kg per dose), lasted longer (still elevated to 200% of control after 48 h) and were significant following a single cocaine exposure. The response of the striatal NT systems to cocaine appeared to be mediated principally by dopamine D-1 receptors, while both D-1 and D-2 receptors contributed to the response by the nigral NT projections. Specific dopamine, but not serotonin, uptake blockers caused increases in striatal and nigral NTLI concentrations similar to that seen with cocaine treatments, suggesting that interference with the dopamine uptake carrier complex by cocaine was responsible for its actions on extrapyramidal NT systems.

Animals↗
PubMed1989

CY 208-243, a novel dopamine D-1 receptor agonist, fails to modify dopamine release in freely moving rats.

CY 208-243, a novel D-1 agonist structurally unrelated to other D-1 agonists, at doses which elicited behavioural stimulation with locomotion, sniffing and grooming, failed to modify the release and metabolism of dopamine (DA) in the nucleus accumbens and in the dorsal caudate of freely moving rats, as estimated by transcerebral dialysis. CY 208-243 prevented the increase of DA release and metabolism elicited by the specific D-1 antagonist, SCH 23390, but not by the specific D-2 antagonist, sulpiride. The results support the conclusion that CY 208-243 is an effective and specific D-1 agonist in vivo.

Animals↗
PubMed1990

Dopamine-mediated changes in central nervous system neurotensin systems: a role for NMDA receptors.

A role for N-methyl-D-aspartate (NMDA)-type glutamate receptors in mediating the dopaminergic regulation of neurotensin (NT) systems was observed in extrapyramidal and limbic structures. Blockade of the NMDA receptor with the non-competitive antagonist, MK801, prevented increases in striatal and nigral levels of NT following both single and multiple administrations of methamphetamine. Significant attenuation of the methamphetamine-induced changes in the striatal NT system were observed with MK801 doses as low as 0.01 mg/kg per dose. In contrast, administration of NMDA caused significant increases in both striatal and nigral NT. The NMDA-induced increase in striatal NT content, like that caused by methamphetamine, was blocked by MK801. The NT system associated with the nucleus accumbens responded in a similar manner in that MK801 (0.1 mg/kg per dose) totally blocked the methamphetamine-induced increases and NMDA administration elevated the NT levels in this structure. Since the methamphetamine-related changes in NT content have been previously shown to be due to increased activity at dopamine D1 receptors, these results strongly suggest that NMDA receptors play an important role in mediating the dopamine D1 regulation of neurotensin systems. Interestingly, the presence of MK801 had no impact on sulpiride-mediated changes in striatal NT levels, suggesting that the NMDA receptor is not linked with the dopamine D2 receptor regulation of NT pathways.

Animals↗
PubMed1991

Blockade of the 3,4-methylenedioxymethamphetamine-induced changes in neurotensin and dynorphin A systems.

The levels of neurotensin-like immunoreactivity (NTLI) and dynorphin-like immunoreactivity (DLI) in the neostriatum, nucleus accumbens and substantia nigra were increased 18 h after a single administration of MDMA (3,4-methylenedioxymethamphetamine, 10 mg/kg). Coadministration of SCH 23390, a dopamine D1 receptor antagonist, or MK-801, a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor complex, prevented the MDMA-induced increase of NTLI and DLI in all three brain structures while the administration of sulpiride, a dopamine D2 receptor antagonist, failed to alter the MDMA effects. These findings suggest that MDMA-induced changes in neurotensin and dynorphin involve both the dopaminergic and the glutamatergic systems.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Low dose raclopride spares the extrapyramidal system in rat brain from metabolic effects.

The effect of a highly selective dopamine D2 receptor antagonist, raclopride ((-)-(S)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl) methyl-6-methoxysalicylamide tartrate), on regional cerebral glucose metabolism in rat brain was determined using [14C]2-deoxyglucose autoradiography, and compared to a typical neuroleptic, haloperidol. Based on preclinical biochemistry and early clinical trial reports, it was hypothesized that raclopride would fail to functionally affect brain regions putatively involved with motor function, while altering psychosis-related regions. Raclopride at a low dose (1.5 mg/kg) significantly reduced regional cerebral glucose metabolism in neocortical areas. It showed a trend toward a similar reduction in limbic structures. But the drug did not have an effect in the extrapyramidal system at this dose. While, at a higher dose, raclopride (10.0 mg/kg), significantly reduced regional glucose metabolism throughout the susceptible grey matter areas of the brain including extrapyramidal regions, an effect similar to haloperidol. Based on approximate antipsychotic dose equivalence between haloperidol and raclopride, the clinically relevant low dose used in this study, failed to functionally alter metabolism in motor regions of brain while exerting a haloperidol-like effect in other areas traditionally linked to cognitive and affective behaviors. This suggests that a low dose of raclopride can exert regionally selective actions. The high dose of raclopride is metabolically active in all brain areas, and, therefore, in clinical application might produce involuntary motor syndromes, like parkinsonism and late onset dyskinesias, along with its antipsychotic effects.

Animals↗
PubMed1994

Dynamic dopaminergic regulation of neuropeptide Y systems in discrete striatal and accumbens regions.

In this study we evaluated the effects of multiple administrations of selective dopamine D1 and D2 receptor agonists and antagonists on striatal, nigral, accumbens, pallidal and cortical neuropeptide Y systems. Treatment with the D1 receptor agonist, SKF 38393, decreased, while that with the D1 receptor antagonist, SCH 23390, increased neuropeptide Y-like immunoreactivity in the globus pallidus and several regions within the caudate-putamen. SCH 23390 did not change accumbens neuropeptide Y-like immunoreactivity levels but SKF 38393 increased neuropeptide Y-like immunoreactivity levels in anterior and decreased neuropeptide Y-like immunoreactivity levels in the posterior nucleus accumbens. Interestingly, reductions in neuropeptide Y-like immunoreactivity content occurred in response to administrations of both D2 receptor agonist, quinpirole, or antagonist, sulpiride, in all identified regions of each structure at some time point. These data suggest that the neuropeptide Y systems studied may be regulated by selective activity at postsynaptic or presynaptic dopamine receptors. They further suggest that within structures such as the caudate-putamen and nucleus accumbens are multiple distinct neuropeptide Y systems which are uniquely influenced by dopamine receptors.

Animals↗
PubMed1995

Response of extrapyramidal and limbic neurotensin systems to phencyclidine treatment.

Although phencyclidine (PCP) has several neurochemical effects, the most pharmacologically relevant are thought to be its ability to antagonize the activity of N-methyl-D-aspartate (NMDA)-type glutamate receptors and to increase extracellular dopamine concentrations. In order to elucidate the nature and consequence of PCP actions on glutamatergic and dopaminergic pathways, this study examined the response of extrapyramidal and limbic neurotensin systems to this drug. Multiple, but not single, doses of PCP caused increases in striatal neurotensin-like immunoreactivity content of 150-200% of control. These effects were blocked by the dopamine D1 receptor antagonist, SCH 23390, suggesting they were caused by PCP-mediated enhanced dopamine activity at dopamine D1 receptors. In contrast, MK-801 (dizocilpine), a selective NMDA receptor antagonist that acts at the same site as PCP, had no effect on neurotensin-like immunoreactivity content when given alone. In addition, coadministration of MK-801 with PCP did not alter the effect of PCP on striatal neurotensin-like immunoreactivity content. This lack of effect suggests that the actions of PCP on NMDA receptors was not involved in the neurotensin response. The PCP effect on neurotensin striatal pathways also appeared not to be associated with the dopamine D2 or gamma-aminobutyric acid (GABA) systems: a possible role for the sigma receptor in this effect could not be eliminated. Administration of multiple doses of PCP also affected neurotensin-like immunoreactivity content in the nucleus accumbens (160% compared to control) and frontal cortex (40% compared to control), but not the substantia nigra. The neurotensin effects of PCP are compared to those of another psychotomimetic drug of abuse, methamphetamine.

Animals↗
PubMed1996

Different effects of chronic administration of haloperidol and pimozide on dopamine metabolism in the rat brain.

We investigated the differences between the action of haloperidol and pimozide on dopamine metabolism and on catalepsy in periods up to 6 weeks after cessation of chronic administration of the neuroleptics to male Wistar rats. Dopamine and its metabolites (dihydroxyphenylacetic and homovanillic acids) were measured, using high-performance liquid chromatography (HPLC), in the frontal cortex, nucleus accumbens, and striatum. Both neuroleptics produced similar effects after a single dose: catalepsy and an increase of dopamine metabolism in the brain structures. However, haloperidol and pimozide differed after chronic treatment. In haloperidol-treated rats hypersensitivity of the dopaminergic system developed at the end of 2 weeks' administration, as evidenced by depression of dopamine metabolism. The biochemical changes were accompanied by behavioral hyperactivity that lasted up to 3 weeks. Dopamine metabolism in rats treated with pimozide was normal from 24 h after the end of the treatment, while catalepsy was maintained at the high level for up to 8 days and was observable up to 3 weeks after the last dose. Our results suggest that in contrast to haloperidol, pimozide is not able to produce adaptive changes leading to supersensitivity of the dopaminergic system. This may be the consequence of its potent Ca2+ channel blocking action.

Animals↗