Parkinson Disease: Ishiwari K

Salamone JD, Ishiwari K, Betz AJ, Farrar AM, Mingote SM, Font L, Hockemeyer J, Müller CE, Correa M. · Behavioral Neuroscience Division, Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA. · Parkinsonism Relat Disord. · Pubmed #18585081 No free full text.

Abstract: Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function.

Salamone JD, Betz AJ, Ishiwari K, Felsted J, Madson L, Mirante B, Clark K, Font L, Korbey S, Sager TN, Hockemeyer J, Muller CE. · Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA. · Front Biosci. · Pubmed #18508458 No free full text.

Abstract: Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3. KW 6002 and MSX-3 suppressed pimozide-induced tremulous jaw movements, reduced catalepsy, and increased locomotion. MSX-3 also suppressed the jaw movements induced by haloperidol and reserpine. In addition, local injections of MSX-3 into the ventrolateral neostriatum suppressed pimozide-induced tremulous jaw movements. Thus, adenosine A2A antagonism can reverse the tremulous movements induced by antipsychotic drugs, which is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects. Adenosine A2A antagonists may be useful for their tremorolytic effects, and may help in treating both idiopathic and antipsychotic-induced parkinsonian symptoms.

Ishiwari K, Betz A, Weber S, Felsted J, Salamone JD. · Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA. · Pharmacol Biochem Behav. · Pubmed #15680188 No free full text.

Abstract: Drug-induced tremulous jaw movements (TJMs) in rats have been used as a model of parkinsonian tremor. Previous studies demonstrated that the typical antipsychotic haloperidol induced TJMs after acute or subchronic administration, while atypical antipsychotics did not. Moreover, it has been suggested that the relative potency for suppression of tacrine-induced TJMs relative to the suppression of lever pressing can be used to discriminate between typical and atypical antipsychotics. In order to validate this model with additional drugs, the present studies assessed the effects of the typical antipsychotic pimozide. In the first series of experiments, the effects of acute pimozide on tacrine-induced TJMs and lever pressing were examined. As with haloperidol, pimozide failed to suppress tacrine-induced TJMs, even at doses considerably higher than those that suppressed lever pressing. In the second group of experiments, rats were given single daily injections of pimozide (0.125-1.0 mg/kg) or tartaric acid vehicle for 13 days, and were observed for TJMs on days 1, 7, and 13. Pimozide induced TJMs in a dose-related manner on all days. The jaw movements occurred largely in the 3-7 Hz frequency range characteristic of parkinsonian tremor. These data support the hypothesis that typical antipsychotics can induce TJMs in rats, and demonstrate that chronic administration of typical antipsychotics is not necessary for induction of TJMs. TJMs induced by acute or subchronic pimozide may be related to early-onset motor syndromes such as drug-induced parkinsonism.

Ishiwari K, Mingote S, Correa M, Trevitt JT, Carlson BB, Salamone JD. · Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA. · J Neurosci Methods. · Pubmed #15589332 No free full text.

Abstract: Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.