Interaction between glutamatergic and dopaminergic tone in the nucleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control.
TL;DR: The rotation induced by a unilateral injection of the competitive NMDA receptor antagonist AP-5 was studied in mice with different tone in the central dopaminergic systems, finding that it induces predominantly ipsilateral rotation in monoamine-depleted mice treated with a mixed D-1/D-2 or a D-2 selective dopamine agonist.
Abstract: The rotation induced by a unilateral injection of the competitive NMDA receptor antagonist AP-5 was studied in mice with different tone in the central dopaminergic systems. AP-5 induced contralateral rotation in monoamine-depleted mice and in monoamine-depleted mice treated with a dopamine D-1 receptor agonist. In contrast, AP-5 induced predominantly ipsilateral rotation in monoamine-depleted mice treated with a mixed D-1/D-2 or a D-2 selective dopamine agonist and in mice with intact monoaminergic systems.
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TL;DR: Progress has been made in understanding the function of DA-containing discrete brain nuclei and the functional consequence of the DA's interaction with other neurotransmitters, and some of the latest advances in these various areas are explored.
515 citations
TL;DR: A critical look at the motor characteristics of this new class of drugs in rodent and primate models of parkinsonism and assesses the clinical potential and pitfalls of this radical new approach.
Abstract: The recent availability of selective ligands for NMDA and AMPA receptors has enabled neuroscientists to test the hypothesis that Parkinson's disease is a glutamate hyperactivity disorder and hence treatable with glutamate antagonists. This review takes a critical look at the motor characteristics of this new class of drugs in rodent and primate models of parkinsonism and assesses the clinical potential and pitfalls of this radical new approach. Monotherapy of Parkinson's disease with glutamate antagonists appears impractical at the present time, due to their low efficacy and unacceptable side effects, but polypharmacy with L-DOPA and a glutamate antagonist as adjuvant is a more realistic prospect. This review will focus on the ways in which glutamate receptor blockade facilitates motor recovery with L-DOPA and will examine whether the basis for this beneficial effect can be traced to a specific interaction with dopamine at D1 or D2 receptors, and therefore to discrete motor pathways within the basal ganglia.
218 citations
TL;DR: Taking together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of theBasal ganglia, suggesting functional differences of the output structures.
214 citations
TL;DR: The results indicate that DA modulates the response of accumbens neurons to cortico-accumbens fiber stimulation via D2 receptors, and provides evidence for a tonic basal level of D2 receptor stimulation in the Accumbens slice preparation.
176 citations
TL;DR: PCP‐induced locomotion (PLOC) was potently blocked by the selective serotonin (5‐HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine‐induced Locomotion (ALOC), which is, correspondingly, more potents blocked than ALOC by antipsychotics displaying marked affinity at 5‐HT2A receptors.
Abstract: In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.
139 citations
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TL;DR: Recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit is discussed, which represents a significant departure from earlier concepts of basal ganglia organization.
4,011 citations
"Interaction between glutamatergic a..." refers background in this paper
...The mesencephalostriatal dopaminergic projections excite the direct loop and inhibit the indirect loop, and consequently dopamine facilitates movement by acting on both pathways (Penney and Young, 1986; Alexander and Crutcher, 1990)....
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TL;DR: The possibility that a deficient activity within the corticostriatal glutamatergic/aspartergic pathway may be an important pathophysiological component in schizophrenia is discussed, and that glutamatorgic agonists may be beneficial in the treatment of this disease.
1,111 citations
TL;DR: It has always been something of a mystery as to why different diseases of the basal ganglia may produce completely opposite effects on movement, but more detailed examination of the exact sites of striatal damage in the two opposing conditions may resolve this theoretic paradox.
Abstract: It has always been something of a mystery as to why different diseases of the basal ganglia may produce completely opposite effects on movement. Thus, defective dopaminergic inhibitory input into the striatum in Parkinson’s disease causes an akinetic-rigid syndrome, while destruction of the striatum in Huntington’s disease usually causes chorea. This theoretic paradox may be resolved by more detailed examination of the exact sites of striatal damage in the two opposing conditions (1). C. D. Marsden
330 citations
"Interaction between glutamatergic a..." refers background in this paper
...The mesencephalostriatal dopaminergic projections excite the direct loop and inhibit the indirect loop, and consequently dopamine facilitates movement by acting on both pathways (Penney and Young, 1986; Alexander and Crutcher, 1990)....
[...]
314 citations
TL;DR: A synergistic interaction between MK-801 and the α-adrenergic agonist clonidine in monoamine-depleted mice is demonstrated and may have important neuropsychiatric implications related to, e.g. the treatment of Parkinson's disease and the pathogenesis of schizophrenia.
Abstract: The present study corroborates previous findings showing that the selective, non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo(a,d)-cyclohepten-5,10-imine] produces a dose-dependent increase in locomotion in mice pretreated with a combination of the monoamine-depleter reserpine and the catecholamine synthesis inhibitor α-methyl-para-tyrosine. Moreover, the present investigation demonstrates a synergistic interaction between MK-801 and the α-adrenergic agonist clonidine in monoamine-depleted mice: MK-803 in a dose of 1 mg/kg and clonidine in a dose of 2 mg/kg hardly affected locomotion when given separately, but when the two drugs were combined a dramatic enhancement of motor activity was observed. This effect was effectively antagonized by the α2-adrenergic blockers idazoxan and yohimbine, as well as by the “atypical” neuroleptic clozapine.
169 citations
"Interaction between glutamatergic a..." refers result in this paper
...Whereas the behavioural stimulation induced by the D-1 agonist SKF 39393 or the mixed D-l/D-2 agonist apomorphine, given in threshold doses, was potentiated by the N-methyl-D-aspartate (NMDA) antagonist MK-801 (Carlsson and Carlsson, 1989, 1990), the stimulant actions of D-2 agonists were antagonized by the NMDA antagonist (Svensson et al., 1992). Similar results have been obtained by Morelli and Di Chiara (1990) and by Goodwin et al....
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...Whereas the behavioural stimulation induced by the D-1 agonist SKF 39393 or the mixed D-l/D-2 agonist apomorphine, given in threshold doses, was potentiated by the N-methyl-D-aspartate (NMDA) antagonist MK-801 (Carlsson and Carlsson, 1989, 1990), the stimulant actions of D-2 agonists were antagonized by the NMDA antagonist (Svensson et al., 1992). Similar results have been obtained by Morelli and Di Chiara (1990) and by Goodwin et al. (1992), using somewhat different experimental models....
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