Gender differences in cocaine‐induced hyperactivity and dopamine transporter trafficking to the plasma membrane

Abstract

As well known, cocaine induces stimulant effects and dopamine transporter (DAT) trafficking to the plasma membrane of dopaminergic neurons. In the present study, we examined cocaine‐induced hyperactivity along with cocaine‐induced DAT trafficking and the recovery rate of the dopaminergic system in female rats in comparison with male rats, demonstrating interesting gender differences. Female rats are initially more sensitive to cocaine than male rats in terms of both the DAT trafficking and hyperactivity induced by cocaine. Particularly, intraperitoneal (i.p.) administration of 5 mg/kg cocaine induced significant hyperactivity and DAT trafficking in female rats but not in male rats. After repeated cocaine exposures (i.e., i.p. administration of 20 mg/kg cocaine every other day from Day 0 to Day 32), cocaine‐induced hyperactivity in female rats gradually became a clear pattern of two phases, with the first phase of the hyperactivity lasting for only a few minutes and the second phase lasting for over an hour beginning at ~30 min, which is clearly different from that of male rats. It has also been demonstrated that the striatal DAT distribution of female rats may recover faster than that of male rats after multiple cocaine exposures. Nevertheless, despite the remarkable gender differences, our recently developed long‐acting cocaine hydrolase, known as CocH5‐Fc(M6), can similarly and effectively block cocaine‐induced DAT trafficking and hyperactivity in both male and female rats.

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

“…in rats) 61 . It was also demonstrated that CocH5-Fc(M6) effectively blocked cocaine-induced dopamine transporter (DAT) trafficking (associated with cocaine dependence) with repeated cocaine exposures by maintaining a plasma CocH5-Fc(M6) concentration ≥ 58.7 ± 2.9 nM in rats 62 , 63 . Through protecting the dopaminergic system and allowing the system to recover from cocaine-induced DAT trafficking, CocH5-Fc(M6) has become a promising therapeutic candidate, suitable for treatment of cocaine dependence 60 , 62 – 64 .…”

Kinetic characterization of an efficient cocaine hydrolase against toxic metabolites of cocaine

“…4,5 Unfortunately, cocaine interacts with many human proteins, including multiple receptors and transporters in the brain. 3,[6][7][8][9][10][11] It would be extremely challenging to directly antagonize the physiological effects of cocaine without impairing the brain's normal functions because all the neuronal receptors and transporters have their own normal physiological functions. Hence, there is still no FDA-approved pharmacotherapy specific for cocaine addiction or overdose.…”

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors

“…Several preclinical studies have explored DAT quantity and function following psychostimulant administration (reviewed in [ 125 ]). Deng et al showed that in response to cocaine administration, female mice showed augmented DAT trafficking to the membrane when compared to male mice [ 126 ]. With repeated cocaine self-administration in rats, researchers have observed, in ex vivo slice preparations, reduced rates of DA uptake in striatal areas, a reduced potency of cocaine to block DAT after local infusion, and a priming towards reinstatement even after 60 days of abstinence [ 127 , 128 , 129 , 130 , 131 ].…”