Effects of neonatal dopaminergic lesion on oral cocaine self-administration in rats: Higher female vulnerability to cocaine consumption

Abstract

The dopaminergic system is associated with cocaine-seeking behaviors, being influenced by other neurotransmitters such as GABA and deregulated by chronic cocaine self-administration. Administration of 6-hydroxydopamine (6-OHDA) to neonatal rats produces a depletion of brain dopamine, mainly, that results in behavioral alterations in adulthood. This model can be applied to better understanding of the role of the dopaminergic system in cocaine use and how its behavioral effects can modulate drug intake. Though there are well-established sex differences in the pattern of drug use, there are no published studies investigating sex-dependent effects of neonatal lesions with 6-OHDA on cocaine self-administration nor regarding GABAA receptor (GABAAR) subunits expression. Herein, neurotoxic lesion was induced in male and female neonatal rats by intracisternal injection of 6-OHDA at PND 4, and locomotion was evaluated before and after cocaine self-administration. Cocaine was diluted in a sweet solution (sucrose 1.5%) and offered for 27 consecutive 3-h daily sessions via a dispenser for oral intake, in an operant chamber under a fixed-ratio 1 (FR1) schedule. The 6-OHDA lesion reduced oral cocaine self-administration in male and female rats. Female rats, independent of dopaminergic condition, consumed more cocaine-containing solution than sucrose-only solution. Furthermore, as expected, 6-OHDA-lesioned animals presented a higher basal locomotor activity when compared to sham rats. We evaluated GABAAR subunit expression and found no statistically significant differences between rats that self-administered a sucrose-only solution and those that self-administered a cocaine-containing solution. Even when the reward system is depleted, some behavioral differences remain in females, providing more data that highlight the female vulnerability to cocaine consumption.