Assessment of cocaethylene lethality in Long-Evans female and male rats.

Cocaethylene, the metabolite of cocaine produced only in the presence of alcohol, produces a number of pharmacological, physiological, and behavioral effects. It also has a range of toxicological consequences, the most severe being lethality. Given that the assessments of cocaethylene lethality have been limited to mice, the present study assessed the lethality of cocaethylene in rats. Further, because of within-species sex differences with its parent compound, cocaine, cocaethylene lethality was also examined in both females and males. Specifically, female and male rats were injected IP with 75, 87, 100, 115, and 133 mg/kg cocaethylene and observed over a 24-h period. Deaths were dose dependent and occurred within 30 min for both females and males. For females, the LD50 was 96 mg/kg; for males, the LD50 was 70 mg/kg. The percentage of rats displaying severe effects (i.e., seizure and death) increased with dose across all postinjection times. Further, these effects occurred earlier as dose increased. Differences in the LD50 for rats and mice, as well as the greater sensitivity to cocaethylene in male rats, are discussed.

The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions.

In separate experiments, rats received either five intraperitoneal or five subcutaneous injections of cocaine (once daily or spaced every fourth day) prior to receiving repeated saccharin-cocaine pairings (during taste aversion conditioning). Both spaced and massed subcutaneous cocaine preexposure attenuated the subsequent acquisition of taste aversions induced by cocaine. Specifically, aversions in the preexposed subjects were acquired at a slower rate and/or to a lesser degree than those acquired by subjects preexposed to the cocaine vehicle and injected with cocaine during conditioning. Spaced and massed intraperitoneal cocaine preexposure had only a weak or no effect, respectively, on the subsequent acquisition of cocaine-induced taste aversions. Specifically, subjects receiving spaced intraperitoneal injections of cocaine during preexposure differed from nonpreexposed subjects on only a single conditioning trial, and subjects receiving massed intraperitoneal injections of cocaine during preexposure displayed aversions comparable to those of nonpreexposed subjects. Although the effects of subcutaneous cocaine preexposure were similar to those reported with other drugs within the aversion design, it is clear that the preexposure effect with cocaine is dependent upon the specific parameters of preexposure. Several possibilities for these differential effects of cocaine preexposure were discussed, including the influence of changing the route of administration from preexposure to conditioning (i.e., from i.p. to s.c.) and the differential masking of the aversive effects of cocaine during conditioning by differential sensitization to cocaine's reinforcing properties following s.c. and i.p. preexposure. Although the present series of experiments did not directly address the mechanism(s) underlying the attenuating effects of cocaine preexposure on aversion learning, several possibilities were noted, including adaptation or tolerance to the aversive effects of cocaine and sensitization to its rewarding effects.