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 D3 versus D2 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 D2 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 D3 receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D3 receptors as a target for treatment of disorders in which cognitive function is compromised.