PAPERS
Repeated toluene inhalation in male and female adolescent rats induces persistent drug preference and impairs cognitive and social behavior
Joannes Luke B. Asis, Ajina C. Carampel, Jariel Naomi B. Bacar, Johanna C. Munar, Cynthia Grace C. Gregorio, Paul Mark B. Medina, Leslie Michelle M. Dalmacio, Jesus Emmanuel A. D. Sevilleja, Gregory J. Quirk & Rohani Cena-Navarro…
ABSTRACTS
Exercise reverses the effects of repeated toluene exposure in rats
Society for Neuroscience 2024 – October 5-9 at McCormick Place Convention Center, in Chicago, Illinois
A. Carampel, J. C. Munar, J. Asis, C. Gregorio, P. Medina, G. J. Quirk, R. Cena-Navarro
Inhalant (toluene) use disorder (IUD) mainly affects adolescents and is especially prevalent among Filipino street children. Currently, there are no approved pharmacological treatments for IUD. N-acetylcysteine (NAC) and melatonin are two affordable, over-the-counter medications that have been shown to decrease drug-seeking in other substance use disorders, but have never been tried with toluene. Last year, we reported that repeated inhalation of 3000 ppm toluene increased conditioned place preference (CPP) and impaired social novelty preference during abstinence. Toluene also increased locomotion in males, but not in females (Carampel et al., SfN 2023; Asis et al., SfN 2023). Here, we report that daily NAC injections (100 mg/kg I.P.) during abstinence (D1 to D8) significantly reduced CPP (two-way RM ANOVA: significant main effect of time p < 0.001 and time x group interaction p = 0.018; CPP score: D1 – 0.54, D8 – 0.39, p < 0.001). However, in females (but not in males), a similar effect was observed with saline injections (two-way RM ANOVA: significant main effect of time p < 0.001; CPP score: D1 – 0.56, D8 – 0.42, p < 0.001). NAC also restored social novelty preference (social novelty score: Tol-Sal – 0.59, Tol-NAC – 0.67; one-sample t-test vs. 0.5 with Bonferroni correction: Tol-Sal p = 0.026, Tol-NAC – p < 0.001). Lastly, NAC decreased locomotion in males (one-way ANOVA: p = 0.011; distance traveled: Air-Sal – 62 m, Tol-NAC – 46 m, p =0.012). Melatonin had no effect on any of these behaviors. Overall, NAC treatment (and also exercise, see Asis et al., this conference) during the abstinence period can reverse persistent toluene-induced behavioral deficits. We are now performing cFos immunofluorescence and transcriptomic analysis to determine the extent to which NAC can return brain functioning to its pre-addiction state.
Cognitive and social behaviors during abstinence from chronic toluene inhalation in adolescent rats
Society for Neuroscience 2023 – November 11-15 at Walter E. Washington Convention Center, in Washington, D.C.
A.C. Carampel, J.N. Bacar, J.B. Asis, J.C. Munar, S.K. Ko, K.A. Ladines, C.C. Gregorio, G.J. Quirk, R. Cena-Navarro
Abuse of inhaled solvents (toluene) is a significant public health issue worldwide and is especially prevalent among Filipino street children. Both male and female adolescents use inhalants, but prior animal studies have focused on males only. Indeed, toluene-induced effects on conditioned place preference (CPP) and anxiety-like behavior have not been reported in female rats. Accordingly, adolescent male (n=38) and female (n=42) Sprague Dawley rats were chronically exposed to either clean air, 1500 ppm, or 3000 ppm of toluene for 6 days, and were evaluated for drug-seeking behavior during abstinence with the CPP task. Rats exposed to 3000 ppm of toluene (but not 1500 ppm) showed significant CPP on days I and 8 (DI, D8) of abstinence, as evidenced by more time spent in the drug-associated chamber compared to controls (ANOVA main effect of treatment: p=0.001I; control vs. 3000 on DI: p=0.0014; control vs. 3000 on D8, p=0.0093). This significant CPP in toluene-exposed rats was no longer observed on day 22 (D22) of abstinence (control vs. 3000 on D22: p=0.1989). There was no significant effect of sex in the 3—way ANOVA (p=0.4069), but when males and females were analyzed separately, females showed significant CPP on both D8 and D22 of abstinence (main effect: p=0.0046; control vs. 3000 on D8, p=0.002 7; control vs. 3000 on D22: p=0.03 59), whereas males did not reach significance at either timepoint (main effect: p=0.1977). This apparent sex-difference in CPP was not due to differences in toluene intake or metabolism, as headspace gas chromatography showed similar blood levels of toluene in adolescents of both sexes following inhalation on the first and last day of toluene exposure (ANOVA main effect of sex: p=0.65 73). Chronic toluene exposure did not increase anxiety—like behavior in the elevated plus maze (EPM) or open field tests, however, we observed a significant sex difference in control rats, with females showing significantly less anxiety in the EPM than males (p=0.0015; proportion of time in open arms of maIes=0.185 5; Proportion of time in open arms of femaIes=0.4261). Thus, following chronic exposure to toluene, female adolescent rats exhibit sustained CPP to a greater extent than males. Female adolescent inhalant users constitute an underreponed and understudied group, and warrant further investigation to develop sex—specific treatments for inhalant use disorder.