Serotonergic systems in the regulation of sexually dimorphic responses to cocaine

Sex differences in cocaine abuse have been consistently reported in humans. Similarly, rats show sexually dimorphic neuorochemical and behavioral effects after cocaine administration. This research aims to determine whether serotonin (5-HT) plays a significant role in cocaine-induced behavioral sex differences found after cocaine administration. We hypothesize that 5-HT (at the level of release, reuptake, and/or receptor activation) mediate sexual dimorphisms seen after cocaine administration. To this end, male and female rats were pretreated (i.p.) with WAY 100635 (a 5-HT1A antagonist; 0, 0.4, 0.8 & 1.6 mg/kg; 15 min pretreatment), GR 129735 (a 5-HT1B receptor antagonist; 0, 5, 10, 15 mg/kg; 30 min pretreatment), or Fluoxetine (0, 5, 10, 15 mg/kg; 1 hour) followed by an i.p. injections of saline or cocaine (20mg/kg); behavioral responses were then measured. Further, we assessed activation of the 5-HT1A receptor after saline or cocaine administration utilizing in vitro autoradiography of agonist stimulated [35S]GTPgammaS in mesocorticolimbic and nigrostriatal pathways which are involved in cocaine behavioral hyperactivation. Finally, sexual dimorphisms of the activation of the endocrine system by the co-administration of cocaine and the 5-HT 1A antagonist WAY 100635 was explored via radioimmunoassay. Increases in cocaine-induced behaviors were found in both male and female rats however, females demonstrated heightened responses. Sexual dimorphisms in the attenuation of cocaine-induced behaviors was found with administration of the 5-HT 1A antagonist WAY 100635 and the 5-HT1B antagonist GR 127935. Furthermore, we found differential activation of the 5-HT1A G-protein receptor which varied by sex and drug administered. Our findings suggest that intrinsic sex differences exist in the regulation of 5HT1A and 5-HT1B receptors and not by the serotonin transporter in cocaine-induced behaviors. Moreover, cocaine activated G-protein 5-HT1A receptors is sexually dimorphic and suggests a principal role in the modulation of sexually dimorphic aspects of cocaine-induced behaviors. Decreased corticosterone levels were only found in females after WAY 100635 and saline. As suggested in previous literature a possible anxiolytic effect of this antagonist could clarify this finding. The understanding how the serotonergic system contributes to sex differences in cocaine-induced behavioral activation will allow for more efficient pharmacological treatment of male and female cocaine abusers.