In laboratory animals there are sex differences in many aspects. When we study aggression males are used because they exhibit overt aggression as opposed to female mice.

There are sex differences in the development of and recovery from ethanol dependence. Female rats have decreased seizure threshold following withdrawal and have a more rapid return to the control level of seizure susceptibility [36]. Devaud and colleagues have found that ethanol administration affects GABA-A and NMDA receptor subtypes differently in male and female rat brain, and the direction of the sex difference varies among brain regions [35]. Whether the sex differences in the effects of alcohol and GABA-A and NMDA receptors mediate sex differences in the long-term consequences of alcohol dependence is not known. In mice, sex differences in seizure threshold during ethanol withdrawal is modulated to some extent by ovarian hormones, but there are also inherent sex differences independent of gonadal hormones [1]. It is difficult to characterized sex differences in acquisition of ethanol taking behavior, as rats and mice don't readily self-administer alcohol. Acquisition of ethanol consumption usually involves training animals to self-administer a saccharine sweetened mixture and then fading out the saccharine until animals are taking a pure ethanol solution. This process can take 30 days, making it difficult to parse out factors that influence acquisition. Further research in the clinical setting and the laboratory is needed to clarify the causes and extend our understanding of the nature of these sex differences in alcohol use and abuse.

Psychomotor Stimulants (Cocaine and AMPH) The acute behavioral response to psychomotor stimulants in rodents can reflect both the sex difference and the modulatory role of gonadal hormones in males and females (e.g., [7,14,17,27,38,39,41,42,50,56,58,65,82,114,128]. With repeated exposure to psychomotor stimulants there is an increase in the psychomotor activating effects of the drug, known as behavioral sensitization. Behavioral sensitization can be different in males and females, and can be differentially affected by gonadal steroid hormones, as we now discuss.

Sensitization of AMPH- or cocaine-induced psychomotor behavior can be defined as the absolute increase in the behavioral response exhibited when two tests are compared. Under such comparisons, intact females exhibit more robust sensitization than do intact males [24,25,46,106,107,127]. Following ovariectomy (OVX) of female rats the expression of sensitization to AMPH is attenuated [24,25,46,106,107] or suppressed all together [116,127]. Estradiol treatments in OVX rats enhance sensitization of locomotor activity induced by AMPH or cocaine [46,95]. These results demonstrate that the neurobiological response to stimulant drugs is sexually dimorphic, but they do not address how this biological difference impacts sex differences in the motivation to take drugs.

Sex Differences in Stimulant Self-Administration in Animals

The animal model of human drug taking behavior that has the most face validity is self-administration. In self-administration studies, animals are trained to bar-press or nose poke in order to receive access to a drug (usually by i.v. infusion). The animal's pattern of drug taking can be studied during acquisition, maintenance and relapse. It is also possible to manipulate the schedule of reinforcement in order to determine motivation to take a drug.

Sex differences have been reported during all phases of the addiction process as assessed using various self-administration paradigms (see [27,82,109]. When a low dose of drug is used, intact or ovariectomized (OVX) female rats acquire cocaine self-administration at a faster rate than do intact of castrated (CAST) males [28,62,78,80]. Estradiol treatment enhances acquisition of cocaine self-administration in OVX female rats [62,83], but not males [64] and the estradiol antagonist, tamoxifen, when given to intact females inhibits acquisition in intact females [78]. So, there are inherent sex differences independent of circulating gonadal hormones in the acquisition of cocaine self-administration, with females being more vulnerable than males. Furthermore, estradiol enhances acquisition in females, but not in males.

During maintenance conditions, when given a choice between two doses of cocaine, female rats in estrus preferred higher doses of cocaine compared with females in other phases of the estrous cycle or male rats [78,79]. A proposed animal model for the transitional process from use/abuse to addiction is a procedure similar to that developed by Roberts et al. [105]. In this model, known as the “discrete trial procedure”, animals are housed in self-administration chambers 24 hours a day, but they only have access to drug during limited times during the day. With this procedure, female rats ‘binge’ for a longer initial period of time, take more cocaine over a 7-day access period, and show a greater loss of diurnal control over cocaine intake than do males [84]. When the role of estradiol in ‘binge’ cocaine intake and subsequent motivational changes is examined, estradiol benzoate (EB) treatment increases the initial binge length and total amount of cocaine self-administered [85]. In one experiment, OVX female rats were tested with and without EB replacement using this procedure (4 trials/hr, 1.5 mg/kg/infusion) over a 7-day period. Results revealed that following a 1-day abstinence period, motivation to obtain cocaine was decreased in OVX rats treated with vehicle, but not in OVX rats treated with EB. In another experiment under extended access conditions, using the discrete trial procedure, OVX rats treated with estradiol consumed more cocaine than vehicle treated controls [78]. These results show that estradiol influences both cocaine self-administration under high access conditions and that there are subsequent motivational changes resulting from such access.

When responding for low doses of cocaine is assessed under a schedule in which the number of responses required in order to obtain a cocaine infusion progressively increases, motivation for access to a drug can be assessed. Under this ‘progressive ratio schedule’ intact female rats reach much higher final ratios than do males, indicating that females are more motivated to obtain cocaine [104]. Females also worked harder for access to cocaine during the phase of the estrous cycle when estradiol was elevated, suggesting that ovarian hormones modulate the motivation to obtain cocaine [104].

In a recent study from our lab we investigated the involvement of ovarian hormones in the motivation to obtain cocaine. We found that estradiol treatment given to OVX rats enhances responding on a progressive ratio schedule at some doses of cocaine (Figure 1). Compared with OIL treated controls, female rats who received 5 μg EB 30 min before the self-administration session worked harder for access to cocaine at 0.4 and 0.5 mg/kg/infusion, but not at 0.3 mg/kg/infusion (Fig. 1). Thus, there are sex differences in the motivation to take cocaine, and estradiol enhances the motivation to take cocaine.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2235192/

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