Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine

Abstract

The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT2A receptors (5-HT2AR) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT2AR in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT2AR linked to a synthetic marker peptide (Flag) was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT2AR-Flag). This viral vector (2 μl; 109–10 transducing units/ml) was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer’s solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip), both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p < 0.05). Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT2AR protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT2AR in the VTA and suggest that the 5-HT2AR receptor in the VTA plays a role in regulation of responsiveness to cocaine.

Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

“…Nevertheless, a strictly causal relationship between 5-HT 2A R density and individual differences in motor impulsivity cannot be definitively deduced from these experiments. Genetic manipulation of 5-HT 2A R through virally mediated overexpression (Herin et al, 2013) or knockdown of the 5-HT 2A R in the mPFC will facilitate a more conclusive determination of causal directionality in the association between 5-HT 2A R density and phenotypic impulsive action.…”

Genetic Addiction Risk Score (GARS): Molecular Neurogenetic Evidence for Predisposition to Reward Deficiency Syndrome (RDS)

“…These results point to the possibility of a role for the T102C HTR2A polymorphism in development of alcohol dependence and even relapse [ 27 , 28 ]. Additionally, 5-HT2A, and 5-HT2C receptors that innervate the DA meso-accumbens pathway may play a prominent role in the behavioral effects of cocaine [ 29 ]. Smoking behavior is influenced by genetic factors affecting the dopaminergic system, and dopaminergic polymorphisms have been linked to smoking habits [ 30 ].…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Moreover, virally mediated overexpression of 5-HT 2A R in the VTA enhances the locomotorstimulant effects of cocaine (Herin et al, 2013). 5-HT 2A R antagonists also attenuate the discriminative stimulus effects of cocaine, shifting the dose-response curve to the right (Filip et al, 2006) and blocking both cocaineassociated cue-induced and cocaine-primed reinstatement in rats (Fletcher et al, 2002;Filip, 2005;Nic Dhonnchadha et al, 2009;Pockros et al, 2011) without attenuating reinstatement induced by cues associated with food reinforcement (Nic Dhonnchadha et al, 2009).…”