Decreased Motivation Following Cocaine Self-Administration Under Extended Access Conditions: Effects of Sex and Ovarian Hormones

Abstract

We have previously shown that following extended access to cocaine, females, but not males, show marked increases in motivation to obtain cocaine, and we have hypothesized that such changes may contribute to long-term compulsive aspects of addiction that result in a persistent vulnerability to relapse. Here, we investigate the effects of extended cocaine access on short-term motivational changes in both male and female rats. An additional goal was to determine whether estrogen modulates motivation to self-administer cocaine in female rats following extended access to cocaine. A discrete trial procedure was used that allowed rats 24-h access to cocaine infusions (1.5 mg/ kg) that were available in discrete trials (four, 10-min trials/h) for 7 consecutive days. Motivation to obtain cocaine was assessed by responding under a progressive ratio schedule, and preference for sucrose (1%) vs water was assessed using a two-bottle, 24-h test. Each was assessed prior to and immediately following discrete trial cocaine self-administration. Results showed that following discrete trial cocaine self-administration, both males and females showed a decrease in preference for sucrose, but only females showed a reduction in levels of responding for cocaine under the progressive ratio schedule, suggesting a sex difference in motivation that was specific to cocaine. Subsequent studies with ovariectomized rats showed that estrogen replacement blocked the decrease in motivation to obtain cocaine infusions. Together, these findings suggest that there is a dissociation between sex and the short-vs long-term alteration in motivation to use cocaine. The mechanisms that may underlie these observed sex differences, including the role of estrogen, are discussed. Neuropsychopharmacology (2005) 30, 927-935, advance online publication, 12 January 2005; doi:10.1038/sj.npp.1300656Keywords: sex differences; cocaine; self-administration; motivation; sucrose; withdrawal INTRODUCTIONCocaine addiction in humans is characterized by periods of heavy use, or binges, followed by periods of abstinence in which craving and motivation to use the drug progressively increase (Gawin and Kleber, 1986;Jentsch and Taylor, 1999). During active binge cycles, addicts report increasing difficulty in abstaining from cocaine use, despite the continually decreasing hedonic effects of cocaine with repeated use (Robinson and Berridge, 2001). During abstinence periods, motivation to use cocaine appears to be low during the initial withdrawal period (or the 'crash'), but to progressively increase over time. The initial withdrawal period is also associated with affective disturbances including lethargy, dysphoria, and anhedonia (eg American Psychiatric Association, 1994;Gawin and Kleber, 1986;Mulvaney et al, 1999;Kampman et al, 2002). These symptoms have been reported to develop within hours of abstinence and may persist weeks or even months (Gawin and Kleber, 1986).A similar time course and pattern of motivational changes have been observed in laboratory animals following c...

Effects of Estradiol on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys

“…For example, when drug-naïve ovariectomized rats were given access to high unit doses of cocaine (1.0-2.5 mg/kg/ inj. ), acquisition of cocaine self-administration did not differ significantly from gonadally intact females (Caine et al, 2004;Grimm and See, 1997) or from ovariectomized females with estrogen replacement (Lynch and Taylor, 2005). Moreover, there were no differences in the shape and position of the cocaine dose-effect curve (0.032-3.2 mg/kg/ inj.)…”

“…There were also no differences in the acquisition of cocaine self-administration (1.5 mg/kg/inj.) between ovariectomized females with and without estradiol replacement (Lynch and Taylor, 2005). Moreover, there were no differences in the shape and position of the cocaine self-administration dose-effect curve (0.032-3.2 mg/kg/inj.)…”

“…Findings in the present study are consistent with clinical studies in which estradiol failed to enhance responses to d-amphetamine (Justice and de Wit, 2000a, b). When cocaine unit doses that maintained consistent self-administration were available in rodents, the effects of estradiol often were not significant (Caine et al, 2004;Grimm and See, 1997;Lynch and Taylor, 2005). Taken together, these findings suggest that the effects of estradiol on the abuse-related effects of cocaine are subtle at best.…”

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

“…As the magnitude of active lever responding during reinstatement has been used as a measure of an animal's motivation to obtain cocaine (De Wit and Stewart, 1981;Self et al, 1996), another possibility is that activation of ERb by EB or DPN served to enhance the incentivemotivational state of the rat. Some support for this idea comes from one study that used a progressive ratio schedule of reinforcement to assess motivation and found that under certain conditions EB could enhance responding for cocaine under this schedule (Lynch and Taylor, 2005). However, more research is needed to specifically examine the effects of estrogen and the role of ERa and ERb on cocaineassociated motivational states.…”

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

“…Female rats exhibit enhanced responding to psychostimulants in multiple paradigms in a manner both dependent and independent of ovarian sex hormones (Hu et al 2004;Jackson et al 2006). In ovariectomized rats, E 2 enhances the sensitization of cocaine-induced locomotor behavior and CPP (Segarra et al 2010), self-administration of cocaine on both fixed and progressive ratio schedules of reinforcement (Lynch and Taylor 2005;Zhao and Becker 2010), and preference for cocaine over food reinforcement in a discrete trials procedure (Kerstetter and Kippin 2011), and lowers thresholds for electrical brain stimulation of the ventral tegmental area (Galankin et al 2010). Thus, E 2 -enhanced expression of CPP could be interpreted as further evidence in females of "enhanced abuse liability to cocaine," yet this interpretation is at odds with the finding that E 2 also enhanced extinction of drug seeking.…”