Adolescent rats are protected from the conditioned aversive properties of cocaine and lithium chloride

Abstract

In humans, most drug use is initiated during adolescence and adolescent users are more likely to become drug-dependent than adult users. Repeated, high levels of use are required for the transition from use to addiction. Individual levels of drug use are thought to result from a balance between the pleasant or rewarding and the unpleasant or aversive properties of the drug. Repeated high levels of drug use are required for the transition from drug use to dependence. We hypothesized that diminished aversive effects of drugs of abuse during adolescence might be one reason for higher rates of use and addiction during this phase. We therefore tested adolescent and adult CD rats in single-dose cocaine conditioned taste aversion (CTA) at a range of doses (10-40 mg/kg), and examined whether various behavioral markers of addiction vulnerability were correlated to outcome in cocaine CTA. We found that adolescents are indeed less susceptible to cocaine CTA. In fact, age was the predominant predictor of CTA outcome, predominating over measures of novelty-seeking, anxiety, and stress hormone levels, which are all known to be related to drug intake in other models. Furthermore, we found that adolescent rats are also less susceptible to conditioned taste aversion to a low dose of a non-addictive substance, lithium chloride. These results suggest that one explanation for elevated drug use and addiction among adolescents is reduced aversive or use-limiting effects of the drugs. This contributes to our understanding of why adolescence is a particularly vulnerable period for development of drug abuse.

Fig. 1

Time line for prescreen experiments. (See Methods.) To the left of the bar are the ages (in days) of adolescent and adult rats (adolescent/adult) at each phase of the experiment. To the right of the bar are the manipulations performed at those days.

Fig. 2

Cocaine-conditioned taste aversion. Percent saccharin choice (see Methods) for adult (65 days old) and adolescent (28 days old) rats treated with the indicated doses (mg/kg, i.p.) of cocaine. *, significantly different from adults at same dose, p<0.05. Number per group is indicated in parentheses above each bar.

Fig. 3

Lithium chloride-conditioned taste aversion. Percent saccharin choice for adult and adolescent rats at the indicated doses of lithium chloride (mg/kg, i.p.). *, significantly different from adults at same dose, p<0.05. Number per group is indicated in parentheses above each bar.

Fig. 4

Correlations between prescreened parameters and conditioned taste aversion outcome (expressed as the square root of the arcsine of the percent saccharin choice, see Methods). (a) Percent open arm time in the EPM is not significantly correlated with CTA outcome. (b) Basal corticosterone levels are not significantly correlated with CTA outcome. (c) Locomotor distance in a novel open field is not significantly correlated with CTA outcome. (d) Basal corticosterone is significantly correlated with percent open arm time in the EPM (R²=0.22, p<0.01). Solid lines and + symbols, adolescent rats (28 days old); dashed lines and open boxes, adult rats (65 days old). Lines represent the least-squares fit for each age. Age effect, p<0.01.

Fig. 5

Basal corticosterone is significantly correlated with cocaine-induced corticosterone levels. R²=0.16, p<0.01. Solid lines and + symbols, adolescent rats (28 days old); dashed lines and open boxes, adult rats (65 days old). Lines represent the least-squares fit for each age. Age effect, p<0.05.