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.

Dose-response functions of apomorphine, SKF 38393, LY 171555, haloperidol and clonidine on the self-stimulation evoked from lateral hypothalamus and ventral tegmentum.

The experimental animals were implanted with two bipolar electodes, one in the lateral hypothalamus including medial forebrain bundle (LH-MFB) and other in ipsilateral ventral tegmental area-substantia nigra (VTA-SN) and were trained to press a pedal for self-stimulation. This provided the scope to compare directly the effect of a given dose of a drug on the two reward regions in the same animal in the same testing situation. The current intensity was set to produce intracranial self-stimulation (ICSS) response rates of 50% less than the maximal shaping response rates for the respective animals (M60). Following systemic (intraperitoneal) administration of apomorphine (a dopamine receptor D1/D2 mixed agonist), SKF 38393 (D1 > D3 > D2 agonist), LY 17155 or quinpirole (D3 > D2 and D1) agonist), haloperidol (a DA-D2 antagonist), and clonidine (noradrenaline receptor alpha 2 agonist), the ICSS response rates evoked from LH-MFB and VTA-SN were compared with vehicle or saline-treated animals on the basis of dose-response functions. A dose-dependent inhibitory effect at M50 was observed with apomorphine (0.01-1.00 mg/kg) and haloperidol (0.05-0.30 mg/kg) for both the sites of stimulation. These doses of haloperidol did not produce any motor deficits like catalepsy and muscular rigidity. The dose-response and time-effect functions of SKF 38393 and LY 171555 at M50 showed the facilitation and suppression of ICSS of VTA-SN and LH-MFB respectively. Clonidine (0.05-0.25 mg/kg) also produced inhibitory effect on ICSS rates, but this suppression was of different magnitude with respect to the site of stimulation. These doses of clonidine were in the range that did not prevent active pedal pressing responses. ED50 (the dose required to reduce the ICSS response rate 50% of the rate after administration of vehicle) for LY 171555 was 0.8 and 4.4 mg/kg for the ICSS of VTA-SN and LH-MFB respectively and thus statistically different ED50 for apomorphine was 0.27 and 0.36 mg/kg; and for haloperidol was 0.75 and 0.90 mg/kg for LH-MFB and VTA-SN respectively and thus not different significantly. ED50 for clonidine was 0.25 and 0.08 mg/kg for VTA-SN and LH-MFB respectively and thus statistically different. The two-way analysis of variance (ANOVAR) of interaction of dose-response function of alpha 2 agonist with respect to LH-MFB and VTA-SN showed significant independence in their suppressive effects.