Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Cocaine Potently Blocks Neuronal α3β4 Nicotinic Acetylcholine Receptors In Sh-Sy5Y Cells

Cocaine is one of the most abused illicit drugs worldwide. It is well known that the dopamine (DA) transporter is its major target; but cocaine also acts on other targets including nicotinic acetylcholine receptors (nAChRs). In this study, we investigated the effects of cocaine on a special subtype of neuronal nAChR, α3β4-nAChR expressed in native SH-SY5Y cells. α3β4-nAChR-mediated currents were recorded using whole-cell recordings. Drugs were applied using a computer-controlled U-tube drug perfusion system. We showed that bath application of nicotine induced inward currents in a concentration-dependent manner with an EC50 value of 20 µM. Pre-treatment with cocaine concentration-dependently inhibited nicotine-induced current with an IC50 of 1.5 μM. Kinetic analysis showed that cocaine accelerated α3β4-nAChR desensitization, which caused a reduction of the amplitude of nicotine-induced currents. Co-application of nicotine and cocaine (1.5 μM) depressed the maximum response on the nicotine concentration-response curve without changing the EC50 value, suggesting a non-competitive mechanism. The cocaine-induced inhibition of nicotine response exhibited both voltage- and use-dependence, suggesting an open-channel blocking mechanism. Furthermore, intracellular application of GDP-βS (via recording electrode) did not affect cocaine-induced inhibition, suggesting that cocaine did not alter receptor internalization. Moreover, intracellular application of cocaine (30 µM) failed to alter the nicotine response. Finally, cocaine (1.5 μM) was unable to inhibit the nicotine-induced inward current in heterologous expressed α6/α3β2β3-nAChRs and α4β2-nAChRs expressed in human SH-EP1 cells. Collectively, our results suggest that cocaine is a potent blocker for native α3β4-nAChRs expressed in SH-SY5Y cells

Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions

Ethanol and nicotine can modulate the activity of several neurotransmitter systems and signalling pathways. Interactions between ethanol and nicotine can also occur via common molecular targets including nicotinic acetylcholine receptors (nAChRs). These effects can induce molecular and synaptic adaptations that over time, are consolidated in brain circuits that reinforce drug-seeking behavior, contribute to the development of withdrawal symptoms during abstinence and increase the susceptibility to relapse. This chapter will discuss the acute and chronic effects of ethanol and nicotine within the mesolimbic reward pathway and brain circuits involved in learning, memory, and withdrawal. Individual and common molecular targets of ethanol and nicotine within these circuits are also discussed. Finally, we review studies that have identified potential molecular and neuronal processes underlying the high incidence of ethanol and nicotine co-use that may contribute to the development of ethanol and nicotine co-addiction