Although the neural mechanisms regulating vomiting are well understood, the neurobiology of nausea is not. Unlike conditioned taste avoidance (CTA), conditioned disgust (indicated by orofacial gaping reactions) is a model of nausea-induced behaviour in rats because it is selectively produced by emetic drugs and anti-emetics attenuate it. Treatments that reduce serotonin (5-HT) availability selectively interfere with conditioned gaping (Limebeer and Parker, 2000; 2003) and forebrain serotonin is critical for the production of disgust reactions (Grill and Norgren, 1978b; Limebeer et al., 2004). The insular cortex (IC) is a site of taste-illness associations and is involved in the sensation of nausea and vomiting in humans (Penfield and Faulk, 1955; Fiol et al., 1988; Catenoix et al., 2008) and other animals (Kaada, 1951; Contreras et al., 2007). Therefore, we investigated the relationship between serotonin, conditioned gaping and CTA in the insular cortex. Systemic pretreatment with the classic anti-emetic ondansetron (OND) reduced both LiCl-induced unconditioned malaise (assessed by lying on belly) and conditioned gaping reactions, without modifying CTA. These experiments demonstrate that decreases in serotonin availability interfere with conditioned gaping and unconditioned malaise as well as provide further evidence of the validity of the conditioned gaping model. Rats with bilateral NMDA lesions of the agranular IC showed attenuated CTA learning but conditioned gaping reactions were unaffected. This finding suggests that the agranular IC, a site of gustatory input, may be required for CTA learning. Partial serotonergic depletion of the IC attenuated conditioned gaping reactions, suggesting that serotonin in the IC is required to establish conditioned gaping. A double dissociation in the regulation of disgust and taste avoidance, by selective 5-HT3 receptor antagonism/agonism in the visceral (granular) IC and the gustatory (agranular) IC was observed. Infusion of OND into the visceral IC attenuated conditioned gaping but spared CTA. Additionally, administration of the 5-HT3 receptor agonist m-chlorophenylbiguanide (mCPBG) enhanced LiCl-induced conditioned gaping reactions (which was prevented by intracranial administration of OND), but spared CTA. In contrast, intracranial OND pretreatment in the gustatory IC attenuated CTA and mCPBG infusions produced CTA, but neither affected the nausea-induced behaviour of conditioned gaping. Together, these studies shed light on the neurobiology of nausea. These results suggest that 5-HT activity (at the 5-HT3 receptor) in the visceral IC may selectively produce the nausea-induced reactions of conditioned disgust, while activity in the gustatory IC may be involved in the production of CTA learning. / This research was supported by a Natural Sciences and Engineering Research Council (NSERC) operating grant (92057) to L.A. Parker and a NSERC CGS-D scholarship to K.J. Tuerke. This work was also supported by an Ontario Graduate Scholarship to K.J. Tuerke.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.