Dopamine D3 Receptor Antagonist SB-277011A Influences Cell Firing in the Rat Ventral Tegmental Area, Parallel Role with the Cannabinoid System in Addiction and Neuropsychiatry Disorders?

ABSTRACT

SB-277011A is a compound entering the brain with high affinity and selectivity for the dopamine (DA) D3 receptor. Recent electrophysiological study has shown that acute oral administration of SB-277011A significantly alters the spontaneous activity of DA neurons in the ventral tegmental area (VTA) but that intravenous administration has no effects. In that electrophysiological study hypotheses to explain this discrepancy involved either administration routedependent timing for the compound to reach its active site or the formation of an active metabolite following oral administration that would sustain the activity of SB-277011A on DA cell firing. In an attempt to assess whether formation of a metabolite may account for the activity of the parent compound we conducted electrophysiological multi-unit field recordings of DA neurons in the VTA of anaesthetised rats following treatment with SB-277011A either systemically or locally in the VTA. The local dose (2.5g) was selected based on brain exposure achieved following systemic i.p. administration of 10mg/kg. Results show that both administrations increased VTA neurons firing compared to vehicle administration. However, local injection of SB-277011A in the VTA induced a more rapid and higher increase of neuronal activity than systemic treatment. These results suggest that the increased VTA cell firing occurring following systemic administration of SB-277011A is likely due to the compound itself and not to a putative metabolite. Finally, since the growing evidence that cannabinoids (CBs) modulate DA release in the brain and in view of the fact that CB₁ receptors are widely distributed over DA neurons, the interplay between these two systems in the context of the current findings is discussed.

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