Role of endogenous neurotensin in the behavioral and neuroendocrine effects of cocaine

Abstract

The present experiments were designed to assess the role of endogenous neurotensin (NT) in the behavioral response to acute and daily cocaine, after administration of the NT receptor antagonist, SR 48692. Given that glucocorticoids increase the sensitivity to the psychomotor effects of drugs of abuse, we also investigated the effects of SR 48692 on basal and cocaine-induced corticosterone secretion. Acute administration of SR 48692 (1 mg/kg i.p.) reduced the number of rearings induced by cocaine (15 mg/kg i.p.), without modifying horizontal activity. Repeated pretreatment with SR 48692 (1 mg/kg x 5 days) markedly reduced locomotion and rearings after an acute cocaine challenge (day 1), whereas the lower dose of SR 48692 (0.1 mg/kg) had no effect. SR 48692 (1 mg/kg), given daily before cocaine, also decreased cocaine-induced rearing on day 2, but had no effect on the following drug challenges (days 3-10). One week after discontinuing repeated cocaine injections, SR 48692 blocked vertical, but not horizontal, activity induced by an acute cocaine challenge. Rats treated repeatedly with cocaine showed an enhanced behavioral response characterized by the development of stereotypes, which were unaffected by SR 48692. Finally, treatment with SR 48692 did not alter corticosterone circadian secretion nor cocaine-stimulated corticosterone levels, indicating that the attenuation of the behavioral effects of cocaine after NT receptor blockade is not associated with blunted glucocorticoid secretion. These results indicate that administration of SR 48692 attenuates the locomotion and rearing response to cocaine but fails to modify stereotyped behavior, suggesting that SR 48692 modulates the behavioral effects of psychostimulant drugs by acting selectively on the mesolimbic dopaminergic system.

Figure 1

Experiment 1. Effect of an acute injection of SR 48692 on cocaine-induced horizontal and vertical activity. Data are shown as mean ± SEM. SR 48692 (1 mg/kg IP), injected 1 h before cocaine (15 mg/kg IP), decreased the number of rearings induced by the psychostimulant (ANOVA, p < .05), without affecting locomotion.

Figure 2

Experiment 2. Effect of repeated SR 48692 administration on horizontal locomotion during daily cocaine challenges. Data are shown as mean ± SEM. The top and middle panels show the time course of horizontal activity on the first (day 1) and the last cocaine challenge (day 18), performed 8 days after cocaine withdrawal. The bottom panel shows the cumulative distance moved on the first 120 min after cocaine administration on each daily cocaine test. Pretreatment with SR 48692 (1 mg/kg) reduced the horizontal activity elicited by cocaine on day 1 (ANOVA, p < .03), but did not modify cocaine-induced locomotion on the following cocaine challenges (days 2–10 and 18). Repeated cocaine administration did not induce a progressive increase in horizontal activity. *p < .05, comparing SR 48692- to vehicle-treated subjects on each cocaine challenge (ANOVA).

Figure 3

Experiment 2. Effect of repeated SR 48692 administration on vertical activity during daily cocaine challenges. These data were obtained simultaneously with those shown in Figure 2 and correspond to the number of rearings (mean ± SEM). The top and middle panels show the time course of vertical activity on the first (day 1) and the last cocaine challenges (day 18). Bottom panel: Cumulative number of rearings on the first 120 min after cocaine administration on daily cocaine challenges. On day 1, pretreatment with SR 48692 (1 mg/kg) reduced the vertical activity elicited by a novel environment (ANOVA, p < .03) and by cocaine (p < .05). SR 48692 (1 mg/kg) also decreased rearing in response to cocaine on day 2 (p < .03) but had no effect on subsequent cocaine challenges (days 3–10). On day 18 (8 days after cocaine withdrawal), rearing behavior elicited by cocaine was reduced after treatment with SR 48692 1 mg/kg (p < .01) and 0.1 mg/kg (p < .06). Repeated cocaine administration did not induce a progressive increase in rearing behavior. *p < .05, **p < .01, comparing SR 48692- to vehicle-treated subjects on each cocaine challenge (ANOVA).

Figure 4

Experiment 2. Effect of repeated treatment with SR 48692 on the behavioral rating after the first cocaine injection (day 1) and after the last cocaine challenge, performed 8 days after discontinuing daily cocaine injections (day 18). The data are shown as the mean ± SEM. On day 1, the low behavioral rating indicated an increase in locomotion and rearing after acute cocaine, which were inhibited by treatment with SR 48692 1 mg/kg (ANOVA, p < .01), and no stereotypies were observed. On day 18, there was a clear increase in the behavioral rating (behavioral sensitization) as compared to day 1 (ANOVA, day effect, p < .001), indicating the development of stereotypies, which were not affected by treatment with the NT antagonist.

Figure 5

Experiment 3. Effect of SR 48692 pre-exposure and cotreatment on basal and cocaine-stimulated plasma corticosterone levels. Top panel shows the effects of 1 and 5 daily injections of SR 48692 (0.1 or 1 mg/kg IP) or vehicle on the circadian fluctuation of corticosterone plasma levels, on blood samples obtained in the morning (am) and in the evening (pm). Bottom panel shows the corticosterone response to a cocaine challenge (15 mg/kg IP) in rats pretreated with SR 48692 or vehicle for 5 days. Results are expressed as mean ± SEM of plasma corticosterone levels (mg/dl). SR 48692 did not modify the circadian secretion of corticosterone, nor the cocaine-induced release of the hormone. *p < .05, **p < .01, compared to basal levels within the same treatment group, using ANOVA followed by Tukey test.