Gender differences in zebrafish responses to cocaine withdrawal

The acute responses to cocaine and its withdrawal contribute to cocaine dependence and potentiate relapse, with gender being one of the genetic factors affecting the outcome. Here we report that in both male and female zebrafish (Danio rerio, AB strain), an initial low-dose cocaine treatment (1.5 μM, immersion) does not acutely change their behavior. The cocaine withdrawal, however, is associated with an anxiety-like state that develops earlier in female zebrafish but is more robust and persistent in males, and can be acutely attenuated by cocaine administration. This is not a result of gender differences in the expression of anxiety-like state, since behavioral responses to an anxiogenic drug, FG-7142, are similar in male and female zebrafish. The basal brain dopamine (DA) levels and the expression of dopamine transporter mRNA (zDAT) show no significant sexual dimorphism. Acute cocaine exposure does not significantly change DA or zDAT. Withdrawal from repeated cocaine administration results in an overall reduction in zDAT, as well as an increase in DA levels. Neither treatment leads to significant gender differences in brain DA or zDAT. The common and gender-specific effects of cocaine on zebrafish, a well-characterized model of vertebrate development and genetics, should help in understanding the mechanisms involved in the anxiety associated with cocaine withdrawal and provide new opportunities in search for therapeutic solutions.