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Background Nicotine is commonly abused in adolescence and is believed to be a “gateway” to other drugs of abuse [e.g., methamphetamine (METH)]. The relationship between early nicotine exposure and later METH use is complicated because the majority of juvenile smokers continue to use cigarettes into adulthood. Thus, the present investigation examined the individual and combined contribution of adolescent and adult nicotine exposure on METH self administration. Methods Forty-three male rats were pretreated with saline or nicotine (0.16 or 0.64 mg/kg, SC) from postnatal day (PD) 35–50. On PD 51, subjects were split into the following groups: 0.16/0.16, 0.16/SAL, 0.64/0.64, and 0.64/SAL. Rats were then trained to lever press for METH (0.05 mg/kg) for seven days on an FR1 and seven days on an FR3 reinforcement schedule. After acquisition training, rats underwent 14 days of extinction and were then tested for METH-induced primed reinstatement (1.0 mg/kg, IP). Results Data showed that rats receiving continuous injections of the low dose of nicotine (0.16/0.16) obtained more METH infusions versus the control group (SAL/SAL) on an FR1 and FR3 schedule. In addition, rats on the FR3 schedule that received a low dose of nicotine during the adolescent period only (0.16/SAL) had more METH intake than the control group (SAL/SAL). Interestingly, the high dose of nicotine exposure had no effect on METH intake and neither nicotine dose altered METH seeking behavior. Conclusions Low dose exposure to nicotine during adolescence enhances the reinforcing effects of METH, while heavier exposure has no effect on METH intake.

Addiction is a chronically relapsing neuropsychiatric disease that occurs in some, but not all, individuals who use substances of abuse. Relatively little is known about the mechanisms which contribute to individual differences in susceptibility to addiction. Neural gene expression regulation underlies the pathogenesis of addiction, which is mediated by epigenetic mechanisms, such as DNA modifications. A growing body of work has demonstrated distinct DNA epigenetic signatures in brain reward regions that may be associated with addiction susceptibility. Furthermore, factors that influence addiction susceptibility are also known to have a DNA epigenetic basis. In the present review, we discuss the notion that addiction susceptibility has an underlying DNA epigenetic basis. We focus on major phenotypes of addiction susceptibility and review evidence of cell type-specific, time dependent, and sex biased effects of drug use. We highlight the role of DNA epigenetics in these diverse processes and propose its contribution to addiction susceptibility differences. Given the prevalence and lack of effective treatments for addiction, elucidating the DNA epigenetic mechanism of addiction vulnerability may represent an expeditious approach to relieving the addiction disease burden.

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Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.