Cocaine and cocaethylene: microdialysis comparison of brain drug levels and effects on dopamine and serotonin.
Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 mumol/kg) and intraperitoneal (44 mumol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to approximately 400% of preinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds.
Bradberry
C W
CW
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Nobiletti
J B
JB
Elsworth
J D
JD
Murphy
B
B
Jatlow
P
P
Roth
R H
RH
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D007275:Injections, Intravenous; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010537:Peritoneum; D051381:Rats; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin; C066444:cocaethylene; D003042:Cocaine; D004298:Dopamine