Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats:: a parallel neurochemical and behavioural analysis

Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D-3 versus D-2 receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D3 receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D-2 receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+) S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D-3 receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D-3 receptors as a target for treatment of disorders in which cognitive function is compromised.