Tobacco use is a leading cause of preventable deaths worldwide. However, current smoking cessation therapies have very limited long-term success rates. Considerable research effort is therefore focused on identification of central nervous system changes with nicotine exposure because this may lead to more successful treatment options. Although recent work suggests that α6β2* nicotinic acetylcholine receptors (nAChRs) play a dominant role in dopaminergic function in rodent nucleus accumbens, the effects of long-term nicotine exposure remain to be determined. Here, we used cyclic voltammetry to investigate α6β2* nAChR-mediated release with long-term nicotine treatment in nonhuman primate nucleus accumbens shell. Control studies showed that nAChR-mediated dopamine release occurs predominantly through the α6β2* receptor subtype. Unexpectedly, there was a complete loss of α6β2* nAChR-mediated activity after several months of nicotine treatment. This decline in function was observed with both single- and multiple-pulse-stimulated dopamine release. Paired-pulse studies showed that the facilitation of dopamine release with multiple pulsing observed in controls in the presence of nAChR antagonist was lost with long-term nicotine treatment. Nicotine-evoked [(3)H]dopamine release from nucleus accumbens synaptosomes was similar in nicotine- and vehicle-treated monkeys, indicating that long-term nicotine administration does not directly modify α6β2* nAChR-mediated dopamine release. Dopamine uptake rates, as well as dopamine transporter and α6β2* nAChRs levels, were also not changed with nicotine administration. These data indicate that nicotine exposure, as occurs with smoking, has major effects on cellular mechanisms linked to α6β2* nAChR-mediated dopamine release and that this receptor subtype may represent a novel therapeutic target for smoking cessation.
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Individuals with attention deficit hyperactivity disorder (ADHD) have a more difficult time quitting smoking compared to their non-ADHD peers. Little is known about the underlying behavioral mechanisms associated with this increased risk. OBJECTIVES: This study aims to assess the effects of 24-h smoking abstinence in adult smokers with and without ADHD on the following outcomes: smoking-reinforced responding, withdrawal, and cognitive function. METHODS: Thirty-three (n = 16 with ADHD, 17 without ADHD) adult smokers (more than or equal to ten cigarettes/day) were enrolled. Each participant completed two experimental sessions: one following smoking as usual and one following biochemically verified 24-h smoking abstinence. Smoking-reinforced responding measured via a progressive ratio task, smoking withdrawal measured via questionnaire, and cognition measured via a continuous performance test (CPT) were assessed at each session. RESULTS: Smoking abstinence robustly increased responding for cigarette puffs in both groups, and ADHD smokers responded more for puffs regardless of condition. Males in both groups worked more for cigarette puffs and made more commission errors on the CPT than females, regardless of condition. Smoking abstinence also increased ratings of withdrawal symptoms in both groups and smokers with ADHD, regardless of condition, reported greater symptoms of arousal, habit withdrawal, and somatic complaints. Across groups, smoking abstinence decreased inhibitory control and increased reaction time variability on the CPT. Abstinence-induced changes in inhibitory control and negative affect significantly predicted smoking-reinforced responding across groups. CONCLUSIONS: Smokers with ADHD reported higher levels of withdrawal symptoms and worked more for cigarette puffs, regardless of condition, which could help explain higher levels of nicotine dependence and poorer cessation outcomes in this population. Abstinence-induced changes in smoking-reinforced responding are associated with changes in inhibitory control and negative affect regardless of ADHD status, a finding that may lead to novel prevention and treatment programs.
[Show abstract][Hide abstract] ABSTRACT: Nicotine and methamphetamine (METH) cause addiction by triggering neuroplastic changes in brain reward pathways though they each engage distinct molecular targets (nicotine receptors and dopamine transporters respectively). Addiction to both drugs is very prevalent, with the vast majority of METH users also being smokers of cigarettes. This co-morbid occurrence thus raised questions about potential synergistic rewarding effects of the drugs. However, few studies have investigated the chronic neurobiological changes associated with co-morbid nicotine and METH addiction. Here we investigated the effects of these two drugs alone and in combination on the expression of several immediate early genes (IEGs) that are sensitive to drug exposures. Chronic exposure to either nicotine or METH caused significant decreases in the expression of fosb, fra1, and fra2 in the nucleus accumbens (NAc) but not in the dorsal striatum whereas the drug combination increased fra2 expression in both structures. Except for junB mRNA levels that were decreased by the three drug treatments in the NAc, there were no significant changes in the Jun family members. Of the Egr family members, NAc egr2 expression was decreased after nicotine and the drug combination whereas NAc egr3 was decreased after METH and the drug combination. The drug combination also increased striatal egr3 expression. The Nr4a family member, nr4a2/nurr1, showed increased striatal expression after all three drug treatments, while striatal nr4a3/nor-1 expression was increased by the drug combination whereas NAc nr4a1/nurr77 was decreased by nicotine and the drug combination. These observations suggest that, when given in combination, the two drugs exert distinct effects on the expression of IEGs in dopaminergic projection areas from those elicited by each drug alone. The significance of these changes in IEG expression and in other molecular markers in fostering co-morbid METH and nicotine abuse needs to be further evaluated.
[Show abstract][Hide abstract] ABSTRACT: Fast scan cyclic voltammetry in brain slices (slice voltammetry) has been used over the last several decades to increase substantially our understanding of the complex local regulation of dopamine release and uptake in the striatum. This technique is routinely used for the study of changes that occur in the dopamine system associated with various disease states and pharmacological treatments, and to study mechanisms of local circuitry regulation of dopamine terminal function. In the context of this review, we compare the relative advantages of voltammetry using striatal slice preparations vs. in vivo preparations, and highlight recent advances in our understanding of dopamine release and uptake in the striatum specifically from studies that use slice voltammetry in drug-naïve animals and animals with a history of psychostimulant self-administration.
ACS Chemical Neuroscience 04/2013; 4(5). DOI:10.1021/cn400026v · 4.36 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.