Kaur, Simranjit; (1997) The investigation of the antiparkinsonian effects of glutamate receptor antagonists. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

1. This study investigated the locomotor effects of glutamate antagonists in drug-naive and reserpine-treated mice. The NMDA channel blockers, dextromethorphan, memantine, amantadine and phencyclidine (PCP), enhanced the locomotor activity of drug-naive mice. Two clear populations could be differentiated after the administration of 40 mg/kg dextromethorphan, i.e non-responders and responders. We postulated that the responders were able to metabolise dextromethorphan to the more potent dextrorphan. Only high doses of memantine, PCP and ketamine reversed the akinesia induced by reserpine. Due to the induction of motor deficits, these drugs are not a viable option, at present, for use as monotherapy in PD. These drugs may be more beneficial as adjuncts to the dopamine- based therapy of PD. When interactions with the dopamine D1 agonist, SKF 38393, the D2 agonist, RU 24213, and the dopamine precursor, L-Dopa, were investigated in reserpine-treated mice, only dextromethorphan interacted positively with SKF 38393, while MK 801, the glutamate release blockers, lamotrigine and clonidine, the glycine site antagonist, (±) HA-966 and the competitive NMDA antagonist, CPP, interacted synergistically with L-Dopa. It is conceivable that subthreshold doses of the NMDA channel blockers are needed to potentiate the response to L-Dopa, as very low doses of MK 801 synergised with L-Dopa while higher doses induced motor deficits, which impeded locomotion. This curvilinear response is a hallmark of the glutamate antagonists, as low doses increase locomotion by possibly acting at the level of the striatum and/or the nucleus accumbens (NAc) and facilitating dopaminergic transmission by enhancing synthesis and/or release of dopamine, while high doses decrease locomotion by inducing motor deficits, which may result from the action of these drugs at sites outside the basal ganglia, such as the motor cortex. 2. Stereotaxic injections of the glutamate antagonists were then administered into the corpus striatum (CS) or the substantia nigra pars reticulata (SNr) of reserpine-treated rats to determine the site of action of these compounds. Only a subgroup of competitive NMDA receptor antagonists, CPP and CGP 40116, induced behavioural arousal from the CS whereas MK 801, PCP, the competitive NMDA receptor antagonist, AP-5, which was ineffective in the CS, and the AMPA receptor antagonist, NBQX in addition to CPP and CGP 40116 produced activity from the SNr. As there is a narrow window between doses which are beneficial and doses which induce motor deficits, careful titration of doses is necessary to separate out the beneficial effects from the detrimental effects. Our results indicate that both the CS and the SN are involved in the locomotor-stimulant as well as side-effect inducing properties of these drugs. 3. The effects of MK 801 were then determined in the cataleptic rat model of PD. Systemic MK 801 alleviated the catalepsy induced by systemic haloperidol and by intrastriatal or intraaccumbens haloperidol. MK 801 administered into the CS, NAc, SNr, subthalamic nucleus (STN) or the entopeduncular nucleus (EPN), attenuated the catalepsy induced by systemic haloperidol. However, systemic MK 801 was ineffective against the catalepsy induced by intrapallidal or intrathalamic muscimol. These results indicate that catalepsy induced by neuroleptics and the anticataleptic ability of MK 801 can arise from regions apart from the CS. The finding that MK 801 was ineffective against intracerebral muscimol-induced catalepsy supplements evidence for theories advanced by Chesselet and Delfs (1996) and Levy et al. (1997), stating that the hyperactivity of the STN may not depend directly on the hyperactivity of the GP, but instead the cortico-subthalamic glutamatergic pathway may be responsible.

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