Increased Burst Firing in Substantia Nigra Pars Reticulata Neurons and Enhanced Response to Selective D2 Agonist in Hemiparkinsonian Rats After Repeated Administration of Apomorphine

Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, intraperitoneal, i.p.) twice daily for 6 days enhanced the rotation induced by apomorphine from 341 turns/hour at the beginning to 755 turns/hr at the end. At the same time, the response to selective D2 agonist quinpirole (0.26 mg/kg, i.p.) was also enhanced from 203 to 555 turns/hr. Extracellular single unit recording revealed no significant difference in the basal firing rates of substantia nigra pars reticulata (SNr) neurons between the ipsilateral and contralateral side of the 6-OHDA lesion regardless of the repeated administrations of apomorphine. In SNr of the lesion side, the units with burst firing pattern were found more frequently after repeated administrations of apomorphine and the suppressive effect of quinpirole on the firing rate was enhanced. These findings suggest that the increased percentage of the burst units is the important electrophysiological change in the development of enhanced response to selective D2 agonist.

Bromocriptine-induced tachycardia in conscious rats: blunted response followin isoproterenol pretreatment for 5 days

Previous studies have shown that tachycardia induced by intravenous injection of bromocriptine, which persisted after adrenalectomy, was mediated by central dopamine D2 receptor stimulation. Such stimulation could activate central sympathetic outflow to the heart. To test this hypothesis, we investigated whether pretreatment with isoproterenol, known to induce cardiac beta-adrenoceptor desensitization, could reduce bromocriptine-induced tachycardia. A 5 day pretreatment with isoproterenol (5 mg/Kg/day) induced a 21 per cent increase in the ratio of ventricular dry weight to body weight, compared with saline-pretreated rats. In isolated perfused heart preparations from isoproterenol-pretreated rats, the isoproterenol-induced increase in left ventricular systolic pressure and heart rate was significantly reduced, compared with saline-pretreated rats (the isoproterenol concentration producing 50 per cent of the maximal positive inotropic and chronotropic responses was increased ~5-and 4- fold, respectively). In conscious control rats, intravenous injection of bromocriptine (50, 150 and 250 mug/Kg) decreased mean aortic pressure and increased heart rate in a dose-related manner. Pretreatment with isoproterenol for 5 days reduced bromocriptine-induced tachycardia without affecting hypotension. Cardiac autonomic tone remained of the same order of magnitude irrespective of whether the animal was pretreated with isoproterenol. These results indicate that isoproterenol pretreatment reduces bromocriptine-induced tachycardia mainly through desensitization of cardiac beta-adrenoceptors rather than via an impairment of autonomic regulation of the heart. This support the hypothesis that bromocriptine-induced activation of central dopamine D2 receptors increases heart rate via activation of central sympathetic outflow to the heart.