People who start smoking during their teenage years are more likely to be heavy drinkers later in life, and a new study in rats has now shown how exposure to nicotine during adolescence, but not in adulthood, alters GABA signalling in the brain’s reward pathways. The findings, by researchers at the University of Pennsylvania, could also have implications for teenagers who vape, with studies already showing that adolescents who use electronic cigarettes are more likely to progress to regular cigarette smoking. “This work on adolescent rats is particularly important because in recent years nicotine vaping with electronic cigarettes has increased among high school and middle school students,” comments John Dani, Ph.D., chair of Neuroscience at the Mahoney Institute for Neurosciences, Perelman School of Medicine.
Dr. Dani’s team reports on the findings in Cell Reports, in a paper entitled, “Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration.”
The researchers cite U.S. Department of Health and Human Sciences figures estimating that nearly 90% of smokers start smoking by the time they reach 18 years of age. Prior studies have also found that tobacco use is strongly predictive of “pathological alcohol consumption,” the authors write. And while the biological basis for this association between tobacco use and alcohol consumption isn’t known, it is believed to originate in adolescence “with early tobacco exposure acting as a gateway for subsequent alcohol use and abuse.”
Adolescence also represents a neurodevelopmental window that is marked by “a major reorganization of limbic brain regions important for reward processing,” the researchers continue. Prior studies in rodents have shown that exposure to nicotine during adolescence, but not post-adolescence, is linked with increased drug reinforcement in adulthood, and Dr. Dani's team reasoned that nicotine exposure may alter brain development to promote pathological drug use later in life. However, the team acknowleges, “although long-term alterations in brain functions have been reported following adolescent nicotine exposure, the specific neuroadaptations that give rise to excessive alcohol consumption in adulthood remain unknown.”
To investigate the biochemical and neural basis of this link the team designed through which rats were given daily nicotine injections, starting either during either adolescence or during adulthood. A month later the researchers then started measuring how much alcohol the animals self administered. They found that rats exposed to nicotine during adolescence more frequently self-administered alcohol—by pushing a lever to obtain an alcohol drink—in adulthood than did the animals that were only exposed to nicotine during post adolescence. Further tests showed that adolescent, but not adult, nicotine exposure altered GABA signalling in the ventral tegmental area (VTA) of the midbrain, a collection of dopamine and GABA neurons that is involved in reward-related and addictive behaviors.
Their results showed that in response to teenage nicotine exposure, GABA signals in the VTA neurons that were normally inhibitory in response to alcohol were shifting toward excitatory. “We found that rats treated with nicotine as adolescents, but not those treated as adults, showed elevated ethanol self-administration and excitatory shifts in GABAAR [GABAA receptor] signaling a month later that were dependent on glucocorticoid receptor activation,” the authors write. “We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA.”
These long-term neuronal changes were associated with downreglation of the K–, Cl– cotransporter KCC2, leading to impaired chloride ion extrusion, and so impaired Cl– homeostasis. “Most importantly,” the team continues, using a KCC2 agonist known as CLP290 to improve chloride extrusion normalized GABA signalling in rats that had been exposed to nicotine during adolescence, and restored the animals' alcohol self-administration to control levels. “Taken together, these results reveal that adolescent nicotine exposure induces long-lasting alterations in mesolimbic responses to ethanol and promotes ethanol consumption in adulthood,” the team concludes. “Thus, adolescent tobacco use may increase the risk for excessive alcohol drinking in adulthood…These results suggest that chloride extrusion enhancers may serve as a therapeutic strategy to mitigate excessive alcohol consumption in smoking populations.”
