Sex differences in escalation of methamphetamine self-administration: cognitive and motivational consequences in rats

Abstract

Rationale Male rats escalate methamphetamine (meth) intake during long access meth self-administration, show enhanced reinstatement of meth seeking, and exhibit meth-induced memory impairments. However, the impact of long access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women. Objectives This study determined whether male and freely-cycling female rats: 1) escalate meth-intake in a 6-h daily access period relative to 1-h access; 2) show different sensitivity to meth primed reinstatement after short and long access conditions; and 3) show deficits in novel object and object in place recognition memory. Methods Male and female Long-Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21 days, meth access was discontinued and rats entered an abstinence period. On the 7th and 14th days of abstinence, rats were assessed for recognition memory using tests for: a) novel object recognition memory, and b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding. Results Female rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males. Conclusions Relative to males, females were equally susceptible to meth-induced memory deficits, but exhibited higher meth intake and greater relapse to meth-seeking.

Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats

“…What might account for our results showing no sex differences in methamphetamine selfadministration and relapse and the reported sex differences in the above-mentioned studies? Regarding methamphetamine self-administration, we suspect that the negative results in our study versus the positive results of sex differences in the previous studies (Reichel et al, 2012;Roth and Carroll, 2004) are due to the use of higher unit dose in our study than in these studies. Indeed, there is evidence that sex differences in cocaine and nicotine self-administration are more apparent when low drug doses are used (Carroll et al, 2001;Donny et al, 2000;Lynch and Carroll, 1999).…”

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats

“…The variation may be a result of inherent differences between males and females. Indeed, studies have identified meth self-administration differences between males and females (Reichel et al, 2012; Roth & Carroll, 2004). Future work programmatically examining possible sex differences in varenicline treatment of meth dependence would be needed to further elucidate the mechanism of these differences.…”

“…Indeed, varenicline has been shown to partially substitute for the discriminative-stimulus effects of meth (Desai & Bergman, 2014). Additionally, the level of responding evoked by meth in a reinstatement test is sensitive to the dose (Anggadiradja et al, 2004; Reichel et al, 2012). The finding that 3.0 mg/kg varenicline had no effect may reflect a summative meth-like dose (i.e., varenicline + meth) that is on the descending portion of the meth-prime reinstatement curve.…”

Perirhinal Cortex mGlu5 Receptor Activation Reduces Relapse to Methamphetamine Seeking by Restoring Novelty Salience

“…Novel object recognition testing was performed as previously described (Reichel et al, 2012a). On abstinence day 7 or 14 (see Experimental Procedures), rats explored two identical objects for 3 min.…”

“…We hypothesized that such a model would engage the perirhinal cortex, which to date has not been implicated in relapse, despite its extensive interconnectivity with other brain regions, including the prefrontal cortex, nucleus accumbens, and amygdala (Kealy and Commins, 2011), all known to mediate relapse (Nawata et al, 2012;Rocha and Kalivas, 2010). Given that short-access meth rats do not exhibit deficits in novelty recognition (Reichel et al, 2012a;Rogers et al, 2008), and animals have an innate propensity to explore and interact with novel objects (Ennaceur and Delacour, 1988), we hypothesized that a novel cue would invigorate responding as well as a meth cue in short-access rats. In long-access rats, however, we anticipated that their deficits in novelty detection would bias them toward greater responding for the meth cue.…”