Abstract
While cocaine's interaction with the dopamine (DA) transporter and subsequent increase in DA transmission are usually considered key factors responsible for its locomotor stimulatory and reinforcing properties, many centrally mediated physiological and psychoemotional effects of cocaine are resistant to DA receptor blockade, suggesting the importance of other non-DA mechanisms. To explore the role of cocaine's interaction with Na+ channels, rats were used to compare locomotor stimulatory and temperature (NAcc, temporal muscle and skin) effects of repeated iv injections of cocaine (1 mg/kg) with those induced by procaine (PRO 5 mg/kg), a short-acting local anesthetic with negligible effect on the DA transporter, and cocaine methiodide (COC-MET 1.31 mg/kg), a quaternary cocaine derivative that is unable to cross the blood-brain barrier. While PRO, unlike cocaine, did not induce locomotor activation, it mimicked cocaine in its ability to increase brain temperature following the initial injection and to induce biphasic, down-up fluctuations following repeated injections. This similarity suggests that both these effects of cocaine may be driven by its action on Na+ channels, a common action of both drugs. While COC-MET also did not affect locomotor activity, it shared with cocaine and PRO their ability to increase brain temperature but failed to induce temperature decreases after repeated injections. These findings point toward activation of peripheral Na+ channels as the primary mechanism of rapid excitatory effects of cocaine and inhibition of centrally located Na+ channels as the primary mechanism for transient inhibitory effects of cocaine. DA receptor blockade (SCH23390+eticlopride) fully eliminated locomotor stimulatory and temperature-increasing effects of cocaine, but its temperature-decreasing effects remained intact. Surprisingly, DA receptor blockade also altered the temperature fluctuations caused by PRO and COC-MET, suggesting that some of the central effects triggered via Na+ channels are in fact DA-dependent. Finally, repeated administration of PRO to animals that had previous cocaine experience led to conditioned locomotion and potentiated temperature-increasing effects of this drug. It appears, therefore, that, in addition to the central effects of cocaine mediated via interaction with the DA transporter and potentiation of DA uptake, interaction with peripheral and central Na+ channels is important for the initial physiological and, perhaps, affective effects of cocaine, likely contributing to the unique abuse potential of this drug.