Amphetamine-induced rotation in the transplanted hemi-parkinsonian rat – Response to pharmacological modulation

The transplantation of dopamine rich foetal tissue into Parkinson's disease patients holds much promise as a therapeutic strategy. The functional efficiency of transplantation is often tested experimentally, by grafting rat derived embryonic ventral mesencephalon tissue suspensions into the denervated striatum of hemi-parkinsonian rats that were previously rendered dyskinetic with l-DOPA. The survival and integration of the grafts in rats can be assessed by a variety of behavioural tests, however amphetamine-induced rotations remain one of the most widely used and robust measures. In this test, dopamine released from the transplant typically drives net rotation in the contralateral direction, in contrast to the ipsilateral rotational bias seen post-lesion. It is unknown what contribution other neurotransmitter systems may make to this response. In this study we monitored amphetamine-induced rotation in transplanted rats that were co-administered a second pharmacological challenge with agents known to affect dopamine-mediated behavioural responses in this model. Both D1 and D2 receptor antagonism (by SCH23390 and raclopride respectively) reduced the rotational response. However the cannabinoid CB1 agonist WIN55,212-2 and α1 and α2 adrenergic receptor antagonist yohimbine had no effect on rotation. Interestingly, glutamatergic antagonists reduced (MTEP) or even reversed (MK-801) total net rotations. The serotoninergic 5-HT1A and 5-HT1B agonists (8-OH-DPAT and CP94253 respectively) altered the temporal profile of the rotational behaviour supporting a regulatory role. Although dopamine clearly drives the motor response, this data implicates both 5-HT and glutamate systems in its regulation.

► Injections of D1/D2 agonists, not D3, lessen amphetamine rotation in grafted rats.
► 5-HT drug turning changed with the presence of amphetamine induced dyskinesia.
► The glutamatergic drug MK-801 reversed amphetamine-induced rotation in grafted rats.