Dopamine D1 receptor‐expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine

Dopamine D1 receptors play an important role in the effects of cocaine. Here, we investigated the role of neurons which express these receptors (D1‐neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug, using the previously established two‐injection protocol of sensitization. We inhibited D1‐neurons using double transgenic mice conditionally expressing the inhibitory Gi‐coupled designer receptor exclusively activated by designer drugs (Gi‐DREADD) in D1‐neurons. Chemogenetic inhibition of D1‐neurons by a low dose of clozapine (0.1 mg/kg) decreased the cocaine‐induced expression of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper‐locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in wild‐type mice. Inhibition of D1‐neurons during the first cocaine administration prevented the sensitization of the locomotor response in response to a second cocaine administration 10 days later. On Day 11, inhibition of D1‐neurons by clozapine stimulation of Gi‐DREADD blocked cocaine‐induced locomotion including in sensitized mice, whereas on Day 12, in the absence of clozapine and D1‐neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1‐neurons decreases spontaneous and cocaine‐induced locomotor activity. It prevents sensitization induction and blocks sensitized locomotion in a two‐injection protocol of sensitization but does not reverse established sensitization. Our study further supports the central role of D1‐neurons in mediating the acute locomotor effects of cocaine and its sensitization. Striatal neurons that express dopamine D1 receptors are known to be important for cocaine effects. We use chemogenetics to inhibit the activity of all D1‐neurons and show it suppresses Fos induction in striatal neurons as well as basal and cocaine‐induced locomotor activity. Inhibition of D1‐neurons also prevents locomotor sensitization to cocaine as evaluated in a two‐injection protocol of sensitization.