Serotonin involvement in cocaine sensitization: Clues from studies with cocaine analogs

Abstract

AbstractWhile the behavioral effects of cocaine are generally ascribed to its ability to inhibit the uptake of dopamine, there is evidence to indicate that some of the other pharmacological properties of cocaine may play a significant role in its actions. Behavioral, biochemical, and electrophysiological 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 benzoylecognine which is formed in vivo during concurrent ingestion of cocaine and 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 cocaethylene on rat locomotor activity in an attempt to determine the serotonin component in this behavior. Acute dose‐response studies revealed that at higher doses (20 mg/kg ip) cocaethylene produced less stimulation of locomotor activity than cocaine. Prior exposure to cocaine resulted in an augmented response to a subsequent challenge dose of either cocaine (sensitization) or cocaethylene (cross‐sensitization). However, previous treatment with cocaethylene did not significantly affect the locomotor activity produced by challenges with cocaethylene or cocaine. The involvement of serotonergic systems in the development of cocaine‐induced sensitization is one intriguing possible explanation of these data. Biochemical studies have shown that other cocaine analogs possess even more selectivity for the dopamine uptake site than cocaethylene. In terms of comparative potency as inhibitors of dopamine, serotonin, and norepinephrine uptake, isopropylcocaine (isopropyl ester of benzoylecognine) is more selective than even cocaethylene. A metabolically resistant analog of cocaine, β‐CIT (2β‐carbomethoxy‐3β‐(4‐iodophenyl)tropane), was shown to be extraordinarily long‐acting, stimulating locomotor activity for 10 h following a dose of 0.1 mg/kg ip. Furthermore, β‐CIT was extremely potent, inhibiting dopamine or serotonin uptake in vitro at a concentration 100 times lower than is required for cocaine. Thus, isopropyl or other substitutions at the carbomethoxy position of the cocaine or β‐CIT structures may provide useful tools for the analysis of the serotonin or norepinephrine components in cocaine's actions and as selective probes of central dopamine systems in imaging studies. © 1993 wiley‐Liss, Inc.