Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats

Abstract

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8mg/kg), cotinine (0.5-5.0mg/kg), anatabine (0.5-5.0mg/kg), and myosmine (5.0-20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated.

Keywords: Anatabine; Conditioned place preference; Cotinine; Microdialysis; Myosmine; Nicotine.

Figure 1.

Mean (± S.E.M.) dopamine concentration in NAc dialysate in adults (panel A) and adolescents (panel B) as a percent of baseline for each time point following administration of saline or nicotine (n=13/group except adult saline n=11 and adolescent saline n=12). Arrow indicates time of injection. Dashed line represents baseline, expressed as 100%. Panel C shows area under the curve (AUC) following nicotine administration for each group expressed as a change from saline. * indicates significant difference from saline control.

Figure 2:

Mean (± S.E.M.) dopamine concentration in NAc dialysate in adults (panel A) and adolescents (panel B) as a percent of baseline for each time point following administration of saline or anatabine (ANA) (n=10/group except adult saline n=11 and adolescent saline n=12). Arrow indicates time of injection. Dashed line represents baseline, expressed as 100%. Panels C and D show mean (± S.E.M.) area under the curve (AUC) in adults (panel C) and adolescents (panel D) following anatabine administration expressed as a change from saline. Dashed lines represent S.E.M. for saline. * indicates significant difference from saline control.

Figure 3:

Mean (± S.E.M.) dopamine concentration in NAc dialysate in adults (panel A) and adolescents (panel B) as a percent of baseline for each time point following administration of saline or myosmine (MYO) (n=10/group except adult saline n=11 and adolescent saline n=12). Arrow indicates time of injection. Dashed line represents baseline, expressed as 100%. Panels C and D show mean (± S.E.M.) area under the curve (AUC) in adults (panel C) and adolescents (panel D) following myosmine administration expressed as a change from saline. Dashed lines represent S.E.M. for saline. * indicates significant difference from saline control.

Figure 4.

Preference for each tobacco constituent, calculated as time spent in drug side minus time spent in vehicle side during the post-conditioning test (n=10/group except adolescent 0.2 nicotine n=14). Values below the horizontal line indicate aversion whereas values above the horizontal line indicate preference. # indicates significant main effect of age compared to adult; $ indicates significant main effect of dose compared to vehicle. Sal stands for saline vehicle.

Figure 5.

Effects of nicotine and cotinine on locomotor activity during conditioning sessions. Data from adults are shown in panels A-B, and data from adolescents are shown in panels C-D (n=10/group except adolescent 0.2 nicotine n=14). * indicates a significant difference from the saline group (dose × session interaction), and # indicates a significant difference from the first session for the same dose group (dose × session interaction). Numbers in parenthesis highlight doses with significant effects. Pre stands for pre-conditioning and post stands for post-conditioning.

Figure 6.

Effects of anatabine and myosmine on locomotor activity during each conditioning session. Data from adults are shown in panels A-B, and data from adolescents are shown in panels C-D (n=10/group). * indicates a significant difference from the saline group (dose × session interaction), and # indicates a significant difference from the first session for the same dose group (dose × session interaction). $ indicates a significant main effect of dose or session as shown in the legend and x axis, respectively. Numbers in parenthesis highlight doses with significant effects.

Figure 7.

Panel A shows preference for methamphetamine calculated as time spent in drug side minus time spent in vehicle side during the post-conditioning test. Panels B and C show effects of methamphetamine on locomotor activity during conditioning sessions for adults and adolescents, respectively (n=8/group except that sal n=10/group). $ indicates a significant difference from saline (main effect of dose). # indicates a significant difference from the first session for the same dose group (dose × session interaction).