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Rationale-Exercise shows promise as a treatment option for addiction, but in order to prevent relapse, it may need to be introduced early in the course of treatment. Objective-We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse. Methods-We compared the effects of exercise (wheel-running, 2-hr/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaineseeking and gene expression in the dmPFC and NAc core of male rats tested following 24-hr/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days). Based on these data, we then used site-specific manipulation to determine whether dmPFC metabotropic glutamate receptor-5 (mGlu5) underlies the efficacy of exercise. Results-Exercise initiated during early, but not late abstinence, reduced cocaine-seeking; this effect was strongly associated with dmPFC Grm5 expression (gene encoding mGlu5), and modestly associated with dmPFC Grin1 and Bdnf-IV expression. Activation of mGlu5 in the dmPFC during early abstinence mimicked the efficacy of early-initiated exercise; however, inhibition of these receptors prior to the exercise sessions did not block its efficacy indicating that there may be redundancy in the mechanisms through which exercise reduces cocaine-seeking. Conclusion-These findings indicate that addiction treatments, including exercise, should be tailored for early versus late phases of abstinence since their effectiveness will vary over abstinence due to the dynamic nature of the underlying neuroadaptations.

Rationale: Epidemiological data suggest that menthol may increase vulnerability to cigarette/ nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine.Objective: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure.Methods: Following acquisition, adolescent rats were given 23-hr/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10-days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive-ratio responding for nicotine (0.01 mg/kg/infusion).Results: Menthol decreased PR responding for nicotine, but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas, the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish. Conclusions:Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals.

Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear. Thus, the goal of this study was to determine the role of estradiol in the development of an addiction-like phenotype in ovaryintact females treated chronically with the selective estrogen receptor (ER) modulator tamoxifen. We hypothesized that tamoxifen, by antagonizing ERs, would block the development of an addiction-like phenotype as defined by an enhanced motivation for cocaine (assessed under a progressive-ratio schedule), and a heightened vulnerability to relapse (assessed under an extinction/cue-induced reinstatement procedure). Effects were examined following extended access cocaine self-administration (24-h/day; 4discrete trials/h; 1.5 mg/kg/infusion) and 14-days of abstinence, conditions optimized for inducing an addiction-like phenotype. As predicted, motivation for cocaine was increased following extended-access self-administration and protracted abstinence in the vehicle (sesame oil) and no-injection control groups, but not in the tamoxifen group indicating that ER signaling is critical for the development of this feature of an addiction-like phenotype. Surprisingly, the increase in motivation for cocaine following abstinence was also attenuated in the vehicle group as compared to no-injection controls suggesting that oil/injections also affected its development. Contrary to our hypothesis, tamoxifen did not decrease vulnerability to relapse as this group responded at similar levels during initial extinction sessions and cue-induced reinstatement testing as compared to controls. Tamoxifen did, however, impair extinction learning as this group took longer to extinguish as compared to controls. Taken together, these findings indicate that estradiol is critical for the extinction of drug-associated cues and the development of motivational features of addiction.

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IntroductionWomen have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).MethodsCocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.ResultsIn males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.DiscussionThese findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

Nicotine‐craving progressively increases, or incubates, over abstinence following extended access self‐administration. While not yet examined for nicotine, the incubation of cocaine‐seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine‐seeking following extended access self‐administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes. Given that in humans, tobacco/nicotine use begins during adolescence, we used an adolescent‐onset model. Nicotine‐seeking was assessed in male rats following extended access nicotine or saline self‐administration (23‐hr/day, 10 days) and 10 days of abstinence, conditions known to induce the incubation of nicotine‐seeking, using a within‐session extinction/cue‐induced reinstatement procedure. A subset of rats had 2‐hr/day access to a running wheel during abstinence. Ultrastructural alterations of synapses in the nucleus accumbens core and shell were examined using electron microscopy. Nicotine‐seeking was elevated following extended access self‐administration and abstinence (in sedentary group), and levels of seeking were associated with an increase in the density of asymmetric (excitatory) and symmetric (inhibitory) synapses onto dendrites in the core, as well as longer asymmetric synapses onto spines, a marker of synaptic potentiation, in both the core and shell. Exercise normalized each of these changes; however, in the shell, exercise and nicotine similarly increased the synapse length. Together, these findings indicate an association between nicotine‐seeking and synaptic plasticity in the nucleus accumbens, particularly the core, and indicate that the efficacy of exercise to reduce nicotine‐seeking may be mediated by reversing these adaptations.