Voluntary exercise attenuates toluene conditioned place preference and restores reward neurocircuitry in rats
J.L. Asis1,2, A. Carampel1,2, J. Munar2, C.G. Gregorio3, L.M. Dalmacio4,1, G. Quirk2, R. Cena-Navarro2
1University of the Philippines Manila, College of Medicine, Manila, Philippines, 2National Institutes of Health - University of the Philippines Manila, Behavioral Neuroscience Laboratory, Institute of Molecular Biology and Biotechnology, Manila, Philippines, 3University of the Philippines Diliman, Institute of Chemistry, Quezon City, Philippines, 4University of the Philippines Manila, Department of Biochemistry and Molecular Biology, College of Medicine, Manila, Philippines
Background: Chronic use of inhalants in adolescents can cause persistent behavioral impairments, highlighting the urgent need for accessible, low-cost treatments. We recently reported that repeated inhalation of 3000 ppm toluene increased conditioned place preference (CPP) (Asis et al., 2024).
Aims & Objectives: Our aim is to assess whether voluntary exercise could decrease toluene CPP and restore the brain to its pre-addiction state.
Method: We exposed male (n = 27) and female (n = 27) adolescent SD rats to 3000 ppm toluene vapor over a 12-day period. They were then assigned to either an exercise group (Tol-Run) or a sedentary group (Tol-Sed). During the abstinence period (Day 1 to Day 7), rats in the exercise group had daily access to a movable running wheel (4 h/day), while sedentary rats were provided a fixed wheel. CPP was performed on Day 8, and brains were collected the same day for cFos immunohistochemistry.
Results: In toluene-exposed rats, females spent much more time running than males (t29 = 7.43, p < 0.001). On D8 of abstinence, the total distance run by the females was negatively correlated with the CPP score (p = 0.007). Exercise also prevented the incubation of CPP from D1 to D8 in females (unpaired t-test: p = 0.036), but not in males (p = 0.241). We then performed cFos immunofluorescence and found that toluene significantly increased cFos density in the nucleus accumbens core (p = 0.015), dorsal CA1 (p = 0.036), and hilus (p = 0.011) in females, but not in males. These effects were reversed by exercise (nucleus accumbens core: p = 0.007, dorsal CA1: p = 0.055, hilus: p = 0.025). In males, exercise significantly decreased cFos density in the prelimbic (p = 0.024) and infralimbic prefrontal cortices (p = 0.016).
Discussion & Conclusions: Exercise may be a promising intervention for preventing relapse in inhalant use disorder, especially in females.
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