SEROTONIN INVOLVEMENT IN COCAINE SENSITIZATION - CLUES FROM STUDIES WITH COCAINE ANALOGS

While the behavioral effects of cocaine are generally ascribed to its ability to inhibit the uptake of dopamine, there is evidence to indica te that some of the other pharmacological properties of cocaine may pl ay a significant role in its actions. Behavioral, biochemical, and ele ctrophysiological data suggest that the potent inhibition of serotonin uptake elicited by cocaine is a mechanism that may contribute to its overall effects in vivo. Cocaethylene is the ethyl ester of benzoyleco gnine which is formed in vivo during concurrent ingestion of cocaine a nd ethanol. Cocaethylene is equipotent with cocaine as an inhibitor of dopamine uptake, but less potent as an inhibitor of serotonin uptake. We have compared the effects of acute and chronic cocaine and cocaeth ylene on rat locomotor activity in an attempt to determine the seroton in component in this behavior. Acute dose-response studies revealed th at at higher doses (20 mg/kg ip) cocaethylene produced less stimulatio n of locomotor activity than cocaine. Prior exposure to cocaine result ed in an augmented response to a subsequent challenge dose of either c ocaine (sensitization) or cocaethylene (cross-sensitization). However, previous treatment with cocaethylene did not significantly affect the locomotor activity produced by challenges with cocaethylene or cocain e. The involvement of serotonergic systems in the development of cocai ne-induced sensitization is one intriguing possible explanation of the se data. Biochemical studies have shown that other cocaine analogs pos sess even more selectivity for the dopamine uptake site than cocaethyl ene. In terms of comparative potency as inhibitors of dopamine, seroto nin, and norepinephrine uptake, isopropylcocaine (isopropyl ester of b enzoylecognine) is more selective than even cocaethylene. A metabolica lly resistant analog of cocaine, beta-CIT (2 beta-carbomethoxy-3 beta- (4-iodophenyl)tropane) was shown to be extraordinarily long-acting, st imulating locomotor activity for 10 h following a dose of 0.1 mg/kg ip . Furthermore, beta-CIT was extremely potent, inhibiting dopamine or s erotonin uptake in vitro at a concentration 100 times lower than is re quired for cocaine. Thus, isopropyl or other substitutions at the carb omethoxy position of the cocaine or beta-CIT structures may provide us eful tools for the analysis of the serotonin or norepinephrine compone nts in cocaine's actions and as selective probes of central dopamine s ystems in imaging studies. (C) 1993 Wiley-Liss, Inc.