Sex Differences in Neurochemical Effects of Dopaminergic Drugs in Rat Striatum

Abstract

Previous data indicate that dopamine neurotransmission is differently regulated in male and female rats. The purpose of the present study was to investigate the dopamine transporter and autoreceptor as potential loci responsible for this sex difference. Fast cyclic voltammetry at carbon-fiber microelectrodes was used to monitor changes in electrically evoked levels of extracellular dopamine in the striata of anesthetized male and female rats before and after administration of an uptake inhibitor, a dopamine D 2 antagonist, or a D 3 /D 2 agonist. Administration of 40 mg/kg cocaine ip increased electrically-evoked extracellular dopamine concentrations in both sexes, but to a significantly greater extent in female striatum at the higher stimulation frequencies. The typical antipsychotic, haloperidol, increased dopamine efflux in both sexes but the effect was twice as large in the female striatum. The D 3 /D 2 agonist quinpirole induced an unexpected, transient increase in dopamine efflux following high-frequency stimulation only in females, and evoked dopamine was higher in females across this entire time course. More detailed analysis of cocaine effects revealed no fundamental sex differences in the interaction of cocaine with DAT in vivo or in synaptosomes. These results indicate that nigrostriatal dopamine neurotransmission in the female rat is more tightly regulated by autoreceptor and transporter mechanisms, perhaps related by greater autoreceptor control of DAT activity. Thus, baseline sex differences in striatal dopamine regulation induce different pharmacologic responses. These results contribute to understanding sex differences in stimulant-induced locomotor activity in rats and may have broader implications for neurologic disorders and their pharmacotherapies in humans.

Cocaine increases stimulated dopamine release more in periadolescent than adult rats

“…The mean age and range on the day of the experiment was 28 (27)(28)(29)(30) and 68 (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77) for the PN28 and PN65 groups, respectively. Varying the frequency of electrical stimulation evokes steady-state responses at low frequencies (20 Hz) as uptake and release are balanced, and linear increases at high frequencies (60 Hz) as release overwhelms uptake.…”

“…Voltammetry procedures were similar to our previously published methods [72,73]. Fast-scan cyclic voltammetry [46] was conducted with an EI-400 potentiostat (Ensman Instrumentation, Bloomington, IN, U.S.A.) with hardware modifications as described by Michael et al [45].…”

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

“…A large literature suggests that both genomic and nongenomic effects of estrogen contribute to this response. Estrogen augments dopaminergic function both presynaptically and postsynaptically (Becker 1999;Becker and Beer 1986;Lynch et al 2002;Walker et al 2006). Estrogen enhances stimulant-induced dopamine release and dopamine receptor sensitivity (Becker 1999).…”

“…Female rats may also initiate cocaine self-administration more rapidly and achieve higher break point values than males when provided with equal access to drug although contradictory results also exist (Caine et al 2004; reviewed in Roth et al 2004). Sex differences in dopaminergic function have been identified and likely contribute to these effects (Walker et al 2000;2006). Numerous reports suggest that gonadal hormones modulate behavioral responsiveness to cocaine.…”

Sex differences in drug abuse

“…Following OVX, the AMPH-induced increase in striatal DA release is significantly less than the response of tissue from CAST [9,17]. On the other hand, in experiments with in vivo voltammetry, cocaine or haloperidol induce a greater increase in electrical stimulation evoked extracellular DA in females than in males, possibly due to greater autoreceptor control of the dopamine transporter (DAT) [133,134]. So, there are more D1 DA receptors in striatum of males compared with females, and if there is a sex difference in D2 DA receptors there are more in males than in females, while AMPH-stimulated DA release is comparable in intact males and females during estrus, even though females show a greater behavioral response to AMPH.…”