RESUMO
Adolescence marks a sensitive period for neurodevelopment wherein exposure to drugs of abuse may disrupt maturation and induce persistent changes in neurophysiology which may exacerbate the risk for developing substance use disorders in adulthood. Adolescent nicotine exposure (ANE) enhances motivation to obtain drugs of abuse, particularly opioids, and increases vulnerability for the development of opioid use disorder (OUD). Here, we characterized ANE effects on learning about the adverse consequences of opioid consumption in adulthood in the absence of further nicotine administration. First, we show that ANE engenders punishment resistant fentanyl self-administration in a heterogenous seeking-taking chain schedule of reinforcement at least at the tested dose of fentanyl (0.75 µg/kg). We found that ANE rats consumed significantly more fentanyl and contingent foot shock punishment was less efficacious in limiting fentanyl seeking in ANE rats, relative to nicotine-naïve controls. Next, we demonstrated that ANE limits learning about the deleterious consequences of acute opioid intoxication in adulthood. In a combined conditioned taste avoidance and place preference paradigm we found that ANE resulted in significant reductions in the strength of morphine-induced CTA, and a simultaneous enhancement of CPP at a higher dose that was less capable of driving reinforcement in naïve controls. Finally, we examined the expression of perineuronal nets (PNNs) within insular cortex (IC) and found ANE rats to have increased density of PNNs across the anterior IC and significantly more parvalbumin-labeled IC cells relative to naïve controls. Together, these data lay the framework for a mechanistic explanation of the extreme comorbidity between nicotine use and development of OUDs.
RESUMO
Approximately 90 % of individuals undergoing treatment for opioid use disorder (OUD) report comorbid use of nicotine. As such, further investigation into underlying mechanisms contributing to the extreme comorbidity between nicotine and opioid use are warranted. Nicotine administration significantly escalates self-administration of opioids and this increase in motivational efficacy persists despite contingent punishment of opioid consumption. Additionally, both systemic and intra-insular administration of nicotine produces a rightward shift in the dose-response function in both morphine-induced conditioned place preference and taste avoidance paradigms, particularly at higher doses (5-20 mg/kg). Two possible interpretations arise from these outcomes. One is that nicotine may specifically affect learning about the malaise-inducing effects of morphine thus facilitating acceptance of higher doses of morphine. Another interpretation is that it more generally reduces sensitivity to the interoceptive effects of morphine such that higher doses are needed to produce comparable effects in nicotine-treated, relative to control, rats. To further address these possibilities, we asked whether nicotine administration interfered with the ability to discriminate the morphine interoceptive state, irrespective of its hedonic evaluation, at a dose that is impacted by nicotine in avoidance conditioning paradigms. First, we demonstrated that systemic nicotine pretreatment significantly attenuates taste avoidance induced by a low dose of morphine (3 mg/kg). Next, we used an occasion setting paradigm with this same dose of morphine to test whether systemic nicotine pretreatment interferes with the ability to discriminate between saline- and morphine-induced interoceptive states. Within this task, nicotine had no effect on the ability to effectively discriminate between the interoceptive effects of morphine and saline. Collectively, these data suggest that nicotine may be specifically altering the overall hedonic assessment of morphine perhaps by interfering with learning about its deleterious consequences.
