Persistent effects of repetitive transcranial magnetic stimulation on reducing voluntary ethanol consumption in adult rats following adolescent drug exposure

Binge drinking is a widespread pattern of alcohol misuse, particularly during adolescence. This developmental stage represents a sensitive window for brain development, and early alcohol use has been linked to a greater risk of long-term alcohol-related issues and increased vulnerability to substance use disorders later in life. Previous work from our group demonstrated that adolescent alcohol exposure during adolescence leads to an increased voluntary consumption later in adulthood in both female and male rats. These findings highlight the urgent need to identify therapeutic strategies capable of counteracting the negative consequences of early alcohol exposure on ethanol abuse disorder and preventing the persistence of maladaptive drinking behaviours. Neuromodulation approaches have emerged as promising tools in the treatment of neuropsychiatric disorders. In this context, earlier studies have explored electroconvulsive seizures (ECS) as a potential therapeutic option. However, its efficacy in substance use disorder is still not well established. In this background, the present study aimed to evaluate a different neuromodulation technique – repetitive transcranial stimulation (rTMS), as a potential therapeutic approach to mitigate the long-term increase in ethanol consumption induced by adolescent drug exposure, while incorporating rats of both sexes and assessing sex-dependent responses. A total of 40 Sprague-Dawley rats were used (male-saline n=10, male-ethanol n=10; female-saline n=10, female-ethanol n=10). First, we assessed the impact of adolescent ethanol exposure (2 g/kg, i.p., on 2 consecutive days followed by a 48-hour withdrawal period, repeated over three cycles from postnatal days, PND, 29-38) on voluntary consumption in adulthood. After persistent forced abstinence, ethanol intake was evaluated in adulthood using a two-bottle choice paradigm (20% ethanol vs. water) over 3 consecutive days of ethanol access. Subsequently, all animals received rTMS once daily for 5 consecutive days (10 Hz, 100% of the motor threshold, 20 trains of 5 seconds, 1000 pulses/day). One week after the intervention, voluntary ethanol consumption was reassessed over a four-week period to evaluate the effects and persistence of rTMS’ efficacy on reducing ethanol intake. The findings validated that adolescent ethanol exposure led to increased voluntary ethanol intake and preference in adulthood; two-way ANOVAs revealed main effects of ethanol history similarly for both sexes (F1,36=56.34; ****p<0.0001 and F1,34=72.03; ****p<0.0001). Additionally, rTMS significantly reduced voluntary ethanol intake and preference in both male and female rats with an adolescent ethanol history (two-way ANOVAs no longer detected an ethanol history effect; F1, 36=2.60; p>0.05, n.s. and F1, 36=3.06; p>0.05, n.s.). This effect was maintained for up to three weeks following the intervention. However, by the fourth week post-treatment, a significant effect of adolescent ethanol exposure re-emerged across measures, indicating a gradual loss of rTMS efficacy over time and a partial return towards pre-treatment levels of consumption. These results underscored adolescent susceptibility to drug exposure and suggested that rTMS might be a promising intervention to reduce long-term alcohol-related issues in both sexes.

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