D1 dopamine agonist effects assessed in vivo with [14C]-2-deoxyglucose autoradiography

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra, the 2-deoxyglucose (2-DG) autoradiographic method of measuring regional cerebral glucose utilization (RCGU) was used to assess the effects of three systemically administered dopamine agonists: bromocriptine, pergolide and (+)-4-propyl-9-hydroxynaphoxazine (PHNO). Pergolide increased RCGU in the substantia nigra pars reticulata (SNr) ipsilateral to the lesion in a dose-dependent manner (0.04 mg/kg, up 52%; 0.4 mg/kg, up 111%), resulting in asymmetric glucose utilization on the dopamine-denervated and intact sides of the brain. Pretreatment with a selective D1 antagonist (SCH 23390, 0.5 mg/kg) blocked completely the RCGU increase elicited by pergolide (0.4 mg/kg) whereas pretreatment with a selective D2 antagonist (eticlopride, 1.0 mg/kg) only mildly attenuated this increase. The effect of drug treatments on RCGU in the entopeduncular nucleus (EP) paralleled that in the SNr. These results demonstrate that the RCGU increase in the EP and SNr after pergolide administration is dependent primarily on D1 receptor stimulation. Administration of bromocriptine and PHNO minimally altered RCGU in the ipsilateral EP and SNr and did not result in significant left/right RCGU asymmetry. Considered in the context of prior studies of selective D1 and D2 agonists, the results suggest that, in this model, the magnitude of the RCGU increase in the EP and SNr elicited by a dopamine agonist, above the modest effects produced by selective D2 stimulation, represents a measure of D1 agonist effect in vivo. The results support a nonselective D1/D2 stimulatory effect of pergolide (0.04-0.4 mg/kg) and a selective D2 action of both bromocriptine and PHNO.