The Role of Serotonin Availability in the Rat Insular Cortex on Conditioned Disgust and Conditioned Taste Avoidance
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.