Exercise or saccharin during abstinence block estrus-induced increases in nicotine-seeking

Abstract

Recent evidence suggests that adolescent and young adult females may be particularly responsive to nicotine use interventions that include exercise or environmental enrichment. This possibility was addressed in the current study by comparing the efficacy of exercise versus non-exercise environmental enrichment (saccharin) during abstinence at reducing subsequent nicotine-seeking/relapse vulnerability in an adolescent-onset rat model. The efficacy of each intervention was examined as a function of estrous cycle phase given findings indicating that hormonal status influences relapse vulnerability and treatment outcome in females. Once adolescent female rats acquired nicotine self-administration, they were given 23-h/day access to nicotine (0.01mg/kg/infusion) for 10days. Following the last self-administration session, rats began a 10-day forced abstinence period with 2-h/day access to an unlocked wheel (exercise, n=15), a bottle containing a saccharin-sweetened solution (0.25%; saccharin, n=19), or without access to a wheel or saccharin (control, n=20). Nicotine-seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 11 of abstinence. Levels of nicotine-seeking were highest in females tested during estrus as compared to females tested during non-estrus phases. Exercise or saccharin during abstinence reduced nicotine-seeking in females tested during estrus, but neither affected the low levels of nicotine-seeking observed in females tested during non-estrus phases, presumably due to a floor effect. These results demonstrate that exercise or saccharin during abstinence decrease nicotine-seeking, and suggest that either would be effective as an early intervention for nicotine use and addiction in females.

Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine‐seeking following extended access self‐administration

“…Another objective of the present study was to examine the effects of exercise, a potential intervention for nicotine addiction, on markers associated with the incubation of nicotine‐seeking. Exercise has been reported to reduce craving and smoking in humans (Abrantes et al., ; Haasova et al., ; Roberts, Maddison, Simpson, Bullen, & Prapavessis, ; Taylor, Ussher, & Faulkner, ), and we demonstrated that when animals are allowed to exercise during abstinence from nicotine self‐administration they show markedly reduced levels of subsequent nicotine‐seeking (Lynch, Tan, Narmeen, Beiter, & Brunzell, ; Sanchez, Moore, Brunzell, & Lynch, , ). Exercise has also been reported to impact dendrite length and spine density within numerous brain regions, including the NAc (Eadie, Redila, & Christie, ; Eddy & Green, ; Redila & Christie, ; Ruegsegger, Toedebusch, Childs, Grigsby, & Booth, ; Stranahan, Khalil, & Gould, ).…”

“…The effects of exercise on structural plasticity also appear to be more robust in adolescents as compared to adults (Eddy & Green, ). Nicotine‐seeking was assessed under a within‐session extinction/cue‐induced reinstatement procedure in rats that had 2‐hr/day access to a locked (sedentary) or unlocked (exercise) running wheel during abstinence, a treatment that has been shown to block abstinence‐induced increases in nicotine‐seeking (Lynch et al., ; Sanchez et al., , ). To assess changes in synaptic organization and connectivity associated with nicotine‐seeking and its modulation by exercise, we performed an ultrastructural examination of asymmetric (excitatory) and symmetric (inhibitory) synapses and their postsynaptic profiles (i.e., location on dendritic shafts or spines) within the NAc core and shell using electron microscopy (Harris & Weinberg, ).…”

Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration

“…In order to track the pattern of the estrous cycle leading up to relapse testing and to habituate rats to the procedure, the phase of the estrous cycle was determined daily over a 5-day period beginning 3 days prior to extinction/reinstatement testing. The swabs of the vaginal epithelium cells were collected between 11 a.m. and 12 p.m.; male rats underwent similar handling by brushing their rear end with the cotton swab as described previously ( Lynch et al, 2019 ). The phase of the estrous cycle was determined based on the proportion of three vaginal cell types: leukocytes, nucleated epithelial cells, and cornified epithelial cells.…”

A buprenorphine-validated rat model of opioid use disorder optimized to study sex differences in vulnerability to relapse

“…Estrous cycle phase was determined over a 5-day period beginning 3 days prior to extinction/reinstatement testing, in order to habituate them to the procedure, and then continuing until the day after testing so that we could track their cycles leading up to and following relapse testing. Swabs were conducted between 11:30 am and 12 pm as described previously (Lynch et al 2019 ), and estrous cycle phase was determined based on previously published criteria (Feder 1981 ). In order to determine associations with estrous cycle phase and responding during extinction and reinstatement testing, swabs obtained on the day of extinction/reinstatement test were further categorized as either estrus ( n = 12 for buprenorphine and n = 11 for control) or non-estrus ( n = 15 for buprenorphine and n = 16 for control); this strategy has been used previously by our group (Peterson et al 2014 ; Lynch et al 2019 ) and others (Kerstetter et al 2008 ) and is based on findings showing that drug-seeking, including opioid-seeking, is higher during estrus as compared to non-estrus phases, and does not differ between metestrus, diestrus, and proestrus phases (Lynch et al 2019 ; Lacy et al 2020 ).…”