Nicotine sensitization and loss of inhibitory control. Role of serotonin

Abstract: Drug dependence is a devastating disorder present in all parts of the world. It is manifested by craving and a general loss of control over the drug intake and the life situation, ultimately leading to compulsive use of the addictive drug at the expense of normal behavioral patterns. This condition is associated with a marked risk for relapse, even after extended periods of drug abstinence. These behavioral impairments have been ascribed the dependence-producing effects of the addictive drugs. The aim of the present thesis was to investigate the effects of subchonic nicotine exposure on animal (rat) behaviors proposed to correlate to craving and drug-taking (i.e. locomotor sensitization) and on brain mechanisms involved in the inhibitory control of such inappropriate motivational impulses and behaviors (i.e. behavioral inhibition). The present experiments demonstrate that repeated treatment with nicotine or amphetamine for 15 consecutive days results in, at least, two distinct behavioral effects: locomotor sensitization and behavioral disinhibition. The expression, but not the induction, of the nicotine-induced behavioral alterations was counteracted by pharmacological manipulations that enhance brain 5-HT neurotransmission. In amphetamine-treated rats, however, these manipulations only antagonized the expression of behavioral disinhibition, and not locomotor sensitization. On the contrary, manipulations that decrease brain 5-HT activity, causing behavioral disinhibition, tended to augment the expression of locomotor sensitization. Behavioral and neurochemical evidence was also obtained indicating that the effects of 5-HT acting drugs on locomotor sensitization and behavioral disinhibition are mediated via distinct neurochemical mechanisms, in which the 5-HT1A and 5-HT2 receptors are differentially involved. Finally, the present experiments demonstrated a strong positive correlation between nicotine-induced behavioral disinhibition and high voluntary ethanol consumption, suggesting that the drug-induced reduction of inhibitory control may have implications for the intake of addictive drugs. Taken together, the findings presented in this thesis indicate that repeated exposure to drugs of abuse concurrently augments the incentive motivational impulse to use the drug and impairs the brain functions involved in inhibitory control of behavior. It is suggested that these drug-induced behavioral changes reflect critical components of the drug-induced neuroadaptive processes which ultimately lead to compulsive drug use, and the pharmacological treatments which antagonized the expression of these behavioral impairments may have beneficial effects in the treatment of drug abuse.