Heteromers of μ opioid and dopamine D 1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner

Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear. Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization. The dopamine D receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of μ opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D receptor knockout (KO) mice, suggesting that SCH23390 modified μ receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of μ receptor-D receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D or μ receptor KO mice and thus unable to form μ receptor-D receptor heterodimers, failed to show locomotor sensitization to morphine. Our results suggest that μ receptor-D receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.