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

Abstract

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 D 3 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.

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D3versus D2Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

“…Fourth, long-term administration of D 3 receptor antagonists reduces the spontaneous activity of mesolimbic but not nigrostriatal dopaminergic pathways (Ashby et al, 2000). Fifth, selective blockade of D 3 versus D 2 receptors improves cognitive performance and enhances frontocortical cholinergic transmission (Laszy et al, 2005;Millan et al, 2007a). Furthermore, consistent with an improvement in negative symptoms, pharmacological or genetic deletion of D 3 receptors enhances social interaction in rodents (Millan, 2003).…”

S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects

“…Its distinctive preference for D 3 versus D 2 receptors is also of importance because D 3 receptor blockade improves cognitive function. In contrast, D 2 receptor blockade exerts a negative influence (Laszy et al, 2005;Millan et al, 2007). For example, selective D 3 and D 2 receptor antagonists, respectively, enhance and disrupt social cognition in rats , a model selected for detailed evaluation of the cognitive actions of S33138.…”

Social memories in rodents: Methods, mechanisms and modulation by stress

“…Acetylcholine has been shown to play a key role in social recognition. Systemic administration of the partial muscarinic cholinergic agonist arecoline or the antagonist scopolamine has been shown to decrease or increase social recognition, respectively (Letty et al, 1997;Millan et al, 2007;Loiseau et al, 2008). Much less is known about the specific involvement of norepinephrine (NE) and, notably, dopamine (DA) and serotonin (5-HT) in social memory.…”

“…For example, stimulation of the D1 receptor in the frontal cortex and hippocampus or blockage of the D3 receptor in the frontal cortex was shown to stimulate local cholinergic neurotransmission and subsequent social recognition Millan et al, 2007). Examining the interactions among the various neurotransmitter systems that are committed to social recognition is the next step required to lead to a deeper understanding of their contribution to social memory formation.…”