Fluoxetine exposure during adolescence increases preference for cocaine in adulthood

Abstract

Currently, there is a high prevalence of antidepressant prescription rates within juvenile populations, yet little is known about the potential long-lasting consequences of such treatments, particularly on subsequent responses to drugs of abuse. To address this issue at the preclinical level, we examined whether adolescent exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, results in changes to the sensitivity of the rewarding properties of cocaine in adulthood. Separate groups of male c57bl/6 mice were exposed to FLX (0 or 20 mg/kg) for 15 consecutive days either during adolescence (postnatal days [PD] 35-49) or adulthood (PD 65-79). Twenty-one days after FLX treatment, behavioral responsivity to cocaine (0, 2.5, 5, 10, or 20 mg/kg) conditioned place preference was assessed. Our data shows that mice pretreated with FLX during adolescence, but not during adulthood, display an enhanced dose-dependent preference to the environment paired with cocaine (5 or 10 mg/kg) when compared to age-matched saline pretreated controls. Taken together, our findings suggest that adolescent exposure to FLX increases sensitivity to the rewarding properties of cocaine, later in life.

Figure 1. Enduring effects of fluoxetine (FLX; 20 mg/kg) exposure on cocaine-induced place conditioning.

(a) Three-weeks after adolescent antidepressant exposure (postnatal day [PD]-75), FLX-pretreated mice displayed enhanced sensitivity to 5 and 10 mg/kg cocaine, when compared to vehicle (VEH)-pretreated mice (n = 8–11 per group; *p < 0.05). (b) Conversely, adult FLX-pretreatment did not influence preference for the cocaine-paired side, three-weeks after antidepressant exposure (PD 105; n = 7–10 per group; p > 0.05). Regardless of age, VEH-and FLX-pretreated mice displayed reliable conditioning to cocaine (^αp < 0.05). *Within cocaine group comparison (p < 0.05). ^αSignificantly different when compared to age-matched controls conditioned to saline (p < 0.05).

Figure 2. Timeline of developmental fluoxetine (FLX) treatment and cocaine place conditioning procedures.

Separate groups of adolescent (postnatal day [PD]-35) and adult (PD 65) male c57bl/6 mice received vehicle (VEH) or fluoxetine (FLX; 20 mg/kg) for 15 consecutive days. Twenty-one days after the last exposure to FLX, mice were screened for side-preference bias (preconditioning), and were randomly assigned to receive cocaine (0, 2.5, 5, 10, or 20 mg/kg) for four consecutive days (conditioning). During the conditioning trials, mice were initially administered with saline and confined to the preferred compartment for 25 min. Three h later, mice were administered with cocaine, and confined to the opposite side of the chamber (25 min). On test day (preference), mice were given access to the entire apparatus (25 min), and the time spent in each compartment of the testing chamber was recorded.