Research reportDopamine D1- and D2-dependent catalepsy in the rat requires functional NMDA receptors in the corpus striatum, nucleus accumbens and substantia nigra pars reticulata
Introduction
The ways in which dopamine and glutamate systems interact to control motor behaviour are the source of considerable interest and confusion (for reviews, see 25, 41, 42). It is now well recognised that certain antagonists of N-methyl-d-aspartate (NMDA)-type glutamate receptors (e.g. the prototypic agent MK-801) are in many respects behaviourally similar to dopamine agonists, either because they liberate endogenous dopamine in the brain, or because they inhibit effects of glutamate which are functionally opposite to those of dopamine 28, 32. Since various NMDA receptor antagonists are capable of reversing the motor deficits occasioned by dopamine depletion or dopamine receptor blockade, it has been suggested that impairment of glutamatergic neurotransmission in the basal ganglia might not only constitute a novel approach to the therapeutic management of Parkinson's disease 5, 14, 34, 41, 42, but may in fact be the mechanism by which the clinically useful aminoadamantanes exert their antiparkinsonian action [8].
Blocking dopamine receptors with neuroleptic drugs induces akinesia and a state of cataleptic rigidity that provides a simple and useful animal model for investigating the antiparkinsonian potential of drugs 25, 34. A wide variety of competitive (e.g. AP-5, CGP 37849) and non-competitive (e.g. MK-801, ketamine) NMDA receptor antagonists have been shown to attenuate the catalepsy induced by mixed dopamine D1/D2 receptor antagonists 10, 15, 20, 30, 37, 39, 46, 50, 51, but the involvement of NMDA receptor blockers with specific D1 and D2 dopaminergic mechanisms has been less well defined. D1 and D2 receptor antagonists have been reported to elicit catalepsy both from the striatum and from the nucleus accumbens 11, 35, but there is some suggestion that D1- and D2-dependent catalepsy are mediated via different efferent pathways [33]. Nevertheless, MK-801 has been shown to suppress the cataleptic activity of the D2-selective antagonists raclopride [37], clebopride [31]and sulpiride [10], and also that of the D1-selective antagonist SCH 23390 31, 35, 37, 46, indicating that excessive glutamatergic neurotransmission is probably involved in the mediation of both types of catalepsy. What is not clear is whether MK-801 interferes with the initiation and/or the maintenance of catalepsy, since glutamatergic neurones not only provide the major input to the striatum, but are also involved in the propagation of output signals from the striatum via the subthalamic nucleus (STN) 2, 3, 12, 41.
Yoshida et al. [50]have provided evidence that haloperidol can increase the amount of glutamate that is released from corticostriatal neurones, possibly by disinhibiting dopamine-dependent suppression of this release, which presumably then stimulates the striatopallidal output neurones and renders the animals akinetic and rigid (see [44]). These authors have consequently argued that NMDA antagonists are anticataleptic by virtue of suppressing this excessive cortical driving of the indirect striatopallidal output pathway, at the level of the striatum. A similar situation may obtain in the nucleus accumbens (NAc), which is also capable of supporting neuroleptic-induced catalepsy [16]. Alternatively, glutamate antagonists may alleviate catalepsy at the level of the subthalamic nucleus (STN), whose branched efferent neurones to the substantia nigra pars reticulata (SNr) and entopeduncular nucleus (EPN) are also glutamatergic and overactive in the dopamine-deficient animal 1, 2, 3, 41. It is known, for example, that the competitive NMDA receptor antagonist CPP is capable of reversing reserpine-induced akinesia when it is injected directly into the EPN or SNr [23], and we have recently demonstrated that intraEPN or intraSNr injections of MK-801 strongly antagonise haloperidol-induced catalepsy [20].
The purpose of the present study was to extend these earlier observations, to determine the possible striatal, accumbal and nigral involvement of glutamate in catalepsy originating more discretely from the selective blockade of dopamine D1 and D2 receptors. Accordingly, the D2 receptor-selective antagonist raclopride, the D1 receptor-selective antagonist SCH 23390 and the non-competitive NMDA receptor antagonist MK-801, were employed both systemically and intracerebrally in an attempt to address these issues.
Section snippets
Materials
SCH 23390 (Schering), raclopride (Astra) and MK-801 (Research Biochemicals) were dissolved in distilled water. Injections were administered systemically in a dose volume of 1 ml/kg, and intracerebrally in a volume of 0.5 μl. Control animals received an equivalent volume of distilled water.
Animals and surgery
Male Wistar albino rats (A.R. Tuck) weighing 200–300 g were used for these experiments. All experiments were conducted in accordance with the Animals (Scientific Procedures) Act 1986. Animals were initially
Pre- and post-treatment with systemic MK-801 versus systemic raclopride- or SCH 23390-induced catalepsy
Raclopride, 3 mg/kg i.p., produced an intensity and duration of catalepsy in the horizontal bar test that was indistinguishable from that evoked by 1 mg/kg i.p. SCH 23390 (drug×drug by ANOVA, F1,134=1.01, P=0.08; Fig. 1). With both treatments rats sat still and assumed a hunched posture, and exhibited none of the usual species-typical behaviours (e.g. rearing, sniffing, grooming). Systemic injection of MK-801 (0.2 mg/kg i.p.) demonstrated anticataleptic activity within 30 min, both versus
Discussion
The results of this study uphold the view that catalepsy can be: (1) elicited by independently blocking dopamine D1 or D2 receptors 6, 10, 17, 31, 37, (2) induced from anatomically discrete sites in the CS and the NAc 9, 11, 35, 50, and (3) inhibited by the NMDA receptor-channel antagonist MK-801 10, 20, 30, 31, 37, 39, 46. In addition, we have now provided evidence that D1- and D2-dependent catalepsy are both susceptible to inhibition by NMDA receptor blockade in the CS, NAc and SNr,
Acknowledgements
H.Ö. was supported by the British Council and the Turkish Scientific and Technical Research Council. This work was also supported by grants from The Sir Jules Thorn Charitable Trust and the Parkinson's Disease Society. Raclopride was generously donated by Astra and SCH 23390 was a gift from Schering.
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