Ventral tegmental area neurons are either excited or inhibited by cocaine's actions in the peripheral nervous system

Cocaine's multiple pharmacological substrates are ubiquitously present in the peripheral and central nervous system. Thus, upon its administration, cocaine acts in the periphery before directly acting in the brain. We determined whether cocaine alters ventral tegmental area (VTA) neuronal activity via its peripheral actions. In urethane-anesthetized rats, we recorded VTA neuron's responses to intravenous injections of two cocaine analogs: cocaine-hydrochloride (HCl, 0.25 mg/kg), which readily cross the blood-brain barrier (BBB), and cocaine-methiodide (MI, 0.33 mg/kg), which does not cross the BBB. Both cocaine analogs produced sustained changes in discharge rates that began 5 s after the initiation of a 10-s drug infusion. Within the first 90 s post-injection, the magnitudes of neuronal responsiveness of both cocaine analogs were comparable, but later the effects of cocaine-HCl were stronger and persisted longer than those of cocaine-MI. The proportion of neurons responsive to cocaine-HCl was twice that of cocaine-MI (74% and 35%, respectively). Both analogs also differed in their response onsets. Cocaine-MI rarely evoked responses after 1 min, whereas cocaine-HCl continued to evoke responses within 3 min post-injection. VTA neurons were either excited or inhibited by both cocaine analogs. Most units responsive to cocaine-MI, regardless of whether they were excited or inhibited, had electrophysiological characteristics of putative dopamine (DA) neurons. Units inhibited by cocaine-HCl also had characteristics of DA neurons, whereas excited neurons had widely varying action potential durations and discharge rates. Cocaine-MI and cocaine-HCl each produced changes in VTA neuron activity under full DA receptor blockade. However, the duration of inhibition was shortened and the number of excitations increased, and they occurred with an earlier onset during DA receptor blockade. These findings indicate that cocaine acts peripherally with a short latency and alters the activity of VTA neurons before its well-known direct actions in the brain.