Nearly 90% of smokers start smoking by the age of 18 and tobacco use is strongly predictive of pathological alcohol consumption. This association is thought to originate in adolescence, with early tobacco exposure acting as a gateway for subsequent alcohol use and abuse.
Adolescence is a neurodevelopmental window marked by major reorganization of limbic brain regions important for reward processing. Nicotine exposure may, therefore, alter brain development to promote pathological drug use later in life.
Evidence from rodent models shows that exposure to nicotine during adolescence, but not post-adolescence, is associated with enhanced drug reinforcement in adulthood. Although long-term alterations in brain function have been reported following adolescent nicotine exposure, the specific neuroadaptations that give rise to excessive alcohol consumption in adulthood remain unknown.
Previous work by the authors suggested that nicotine-ethanol interactions could arise via altered GABAA receptor (GABAAR) signaling within the ventral tegmental area (VTA). GABAARs are positively modulated by ethanol and are implicated in ethanol reinforcement. The strength and polarity of GABAAR signaling are predominantly dictated by cellular chloride (Cl) gradients and maintained by the K+ , Cl transporter, KCC2.
Impaired KCC2 function and intracellular Cl accumulation leads to depolarizing shifts in the Cl reversal potential (EGABA) and compromised GABAAR-mediated inhibition. Within VTA GABA neurons, functional KCC2 downregulation and the consequent decreased GABAAR-mediated inhibition are thought to promote alcohol self-administration following glucocorticoid receptor activation.
To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. Authors found that rats treated with nicotine as adolescents, but not those treated as adults, showed elevated ethanol self-administration and excitatory shifts in GABAAR signaling a month later that were dependent on glucocorticoid receptor activation. Adolescent nicotine exposure impaired Cl extrusion via KCC2 downregulation and altered mesolimbic responses to ethanol.
Enhancing Cl extrusion in adolescent nicotinetreated rats returned GABAergic inhibitory signaling to normal and returned alcohol consumption to control levels. These results indicate that adolescent nicotine exposure produces long-lasting alterations in Cl homeostasis and GABAAR signaling and contributes to elevated ethanol self-administration in adulthood.
http://www.cell.com/cell-reports/fulltext/S2211-1247(18)30372-3
How adolescent smoking linked to pathological drinking later in life
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