Electrophysiological evidence for a reciprocal interaction between amphetamine and cocaine-related drugs on rat midbrain dopaminergic neurons

To determine the functional interactions occurring between amphetamine and cocaine-like drugs on a single neuron, we used intracellular single-electro de voltage-clamp recordings from dopaminergic cells of the rat midbrain mai ntained in vitro. In the presence of cocaine (3-30 mu M), the outward curre nt caused by amphetamine (100 mu M) on cells held at about - 60 mV was atte nuated. The degree of attenuation of the amphetamine-induced response was a lmost the same for 3 and 30 mu M cocaine (44 and 51% of control, respective ly). This effect of cocaine was reversible. We also tested other DA-uptake inhibitors (nomifensine and 4-phenyltetrahydroisoquinoline) against the amp hetamine-induced outward current. Both drugs enhanced the effects of dopami ne (DA) while reducing the outward response caused by amphetamine. Pretreat ment of the animals with reserpine (12 mg/kg/i.p.), which irreversibly depl etes the vesicular DA stores, neither affected the amplitude of the current caused by amphetamine nor changed the cocaine-induced attenuation of the m embrane responses to amphetamine. Interestingly, when amphetamine (3 mu M) was superfused on the dopaminergic neurons prior and during the application of cocaine, the DA-uptake blocker was no longer able to potentiate the out ward response caused by the superfusion of DA. Taken together, these data s uggest that: (i) amphetamine and cocaine interact with the DA transporter t o produce distinct actions which under certain circumstances can compete wi th each other; (ii) the amphetamine-induced release of DA from the somata a nd dendrites of the dopaminergic cells is, at least in part, related to the reverse operation of the DA transporter and is not dependent on the integr ity of the vesicular content of the catecholamine.