1 Electrophysiological recordings were made from presumed dopaminergic neurones in the substantia nigra pars compacta and ventral tegmental area of rat brain slices. The ability of selective dopamine receptor agonists to hyperpolarize neurones and inhibit cell firing, as well as the ability of dopamine receptor antagonists to block responses to quinpirole were compared. 2 Six dopamine receptor agonists were examined for their ability to hyperpolarize neurones within the substantia nigra pars compacta. Of these, the most potent ligand tested was naxagolide with an ECH, value of 20 nM and estimated maximum of 10 mV. The rank order of agonist potency was naxagolide>quinpirole>apomorphine>dopamine. 3 Quinpirole was more potent at inhibiting cell firing in the substantia nigra pars compacta (pIC(50) = 7.65 +/- 0.06, n = 35) than in the ventral tegmental area (pIC(50) = 7.24 +/- 0.06, n = 32; P<0.01, Student's t test). 7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), a putative D-3 selective agonist, had a comparable potency to quinpirole in both the ventral tegmental area (pIC(50) = 7.39 +/- 0.26, n = 4), and substantia nigra pars compacta (pIC(50) = 7.71 +/- 0.20; n = 4). 4 The inhibition of cell firing by quinpirole was antagonized by haloperidol, S(-)-sulpiride, clozapine, and ritanserin. S(-)-sulpiride and haloperidol had the highest estimated affinities in the substantia nigra, with pA(2) values of 8.97 (slope = 0.85) and 8.20 (slope = 2.09) respectively. The pA(2) values for S(-)sulpiride and haloperidol in the ventral tegmental area were 8.07 (slope = 0.87) and 8.11 (slope = 1.48) respectively. Clozapine had a lower functional affinity than S(-)-sulpiride and haloperidol in both the substantia nigra (pA(2) = 6.47, slope = 1.19) and ventral tegmental area (pA(2) = 6.53, slope 0.87). Ritanserin, a 5-HT2 receptor antagonist that also binds to D-2-like dopamine receptors, caused a slight but significant shift in the concentration-effect curve to quinpirole with an estimated pK(A) of 6.97 +/- 0.13 (n = 4) in the substantia nigra and pK(A) of 7.12 +/- 0.22 (n = 4) in the ventral tegmental area. 5 Comparison of these data with the binding affinity for cloned dopamine receptors demonstrates that the responses to quinpirole on dopaminergic neurones in both the A9 (substantia nigra) and A10 (ventral tegmental area) brain areas are consistent with the activation of predominantly D-2, and not D-3 or D-4 dopamine receptors. Furthermore, the similarity in functional affinity of antagonists for these receptors suggest that the mesolimbic selectivity of atypical neuroleptics, like clozapine, may be a consequence of their actions on other receptors or their effects elsewhere in the brain.
