aconitine and Tobacco-Use-Disorder

We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice. We evaluated increased serum corticosterone (SCS) as an indicator of NIC withdrawal, as it is a quantitative indicator of naloxone (opioid receptor antagonist, NLX)-precipitated morphine withdrawal in mice. In this study, NLX precipitated an SCS increase in mice receiving repeated NIC, by a dose-dependent mechanism, and correlated with the dose and number of days of repeated NIC administration. When an opioid receptor antagonist (naltrexone) was concomitantly administered with repeated NIC, the NLX-precipitated SCS increase was not elicited. Concomitant administration of the α7 nicotinic acetylcholine receptor (nAChR) antagonist (methyllycaconitine) with repeated NIC, but not the α4β2 nAChR antagonist (dihydro-β-erythroidine), did not elicit an SCS increase by NLX. Thus, a physical dependence on NIC was in part mediated by the activation of the endogenous opioid system, located downstream of α7 nAChR.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Biomarkers; Corticosterone; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Nicotine; Opioid Peptides; Substance Withdrawal Syndrome; Tobacco Use Disorder

Previous research has shown that individual differences in response to novelty predict self-administration and the locomotor response to psychostimulant drugs of abuse. The aim of the present study was to determine if individual differences in response to novelty based on inescapable or free-choice novelty tests predict dopamine transporter (DAT) function and trafficking as well as nicotine-induced modulation of DAT. Results show that the maximal velocity (Vmax) of [3H]dopamine uptake into prefrontal cortex (PFC) synaptosomes correlated negatively with the locomotor response to inescapable novelty. In contrast, Vmax correlated positively with novelty place preference in the free-choice novelty test. The divergent correlations between DAT and the two behavioral phenotypes suggest a differential contribution of DAT in these phenotypes, which are known not to be isomorphic. Furthermore, rats categorized as high responders to inescapable novelty had lower Vmax values, which were accompanied by less DAT expression at the cell surface in PFC compared with low responders, suggesting that inherent individual differences in DAT cellular localization may underlie the differential response to novelty. Compared with the saline control, nicotine increased Vmax and cell surface DAT immunoreactivity in PFC from high responders but not from low responders. Similarly, nicotine increased Vmax and cell surface DAT in PFC in rats classified as low in novelty place preference but not in rats classified as high in novelty place preference. Thus, despite the different behavioral phenotypes, the pharmacological effect of nicotine to increase DAT function and cell surface expression was apparent, such that rats with inherently lower DAT function show a greater sensitivity to the neurochemical effect of nicotine.

Topics: Aconitine; Animals; Behavior, Animal; Binding, Competitive; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Exploratory Behavior; Male; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Phenotype; Prefrontal Cortex; Presynaptic Terminals; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Synaptosomes; Tobacco Use Disorder

Tobacco use is implicated in approximately 440,000 deaths per year, making it the leading cause of preventable death in the United States. Although it is generally recognized that tobacco use is correlated with a variety of health-related complications, many smokers are unsuccessful in their efforts to stop smoking using current cessation therapies.. Given that nicotine is the addictive component of tobacco, successful smoking cessation therapies must address the various processes, including reward, which contribute to nicotine addiction. As such, determining the nicotinic receptor subtypes involved in nicotine reward is of utmost importance to understanding how nicotine addiction progresses.. Conditioned place preference (CPP) in three-chamber conditioning boxes was performed. For antagonist studies, drug was given on all conditioning sessions 10 min before nicotine or saline injection and placement in the boxes.. We have demonstrated that a pretreatment with the alpha4beta2 subunit of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro-beta-erythroidine (2.0 mg/kg, s.c.) blocked nicotine (0.5 mg/kg, s.c.) CPP in wild-type mice (C57BL/6 mice). In contrast, pretreatment with an antagonist of the alpha7 subunit of the nAChR, methyllycaconitine (MLA, 5.0 or 10.0 mg/kg, s.c.), had no effect on this behavior. Finally, we showed that mice lacking the beta2 subunit of the nAChR did not exhibit nicotine CPP while alpha7 knock-out mice did.. Taken together, these data suggest that the beta2 subunit of the nAChR is critically involved in nicotine reward as measured by CPP.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Choice Behavior; Conditioning, Psychological; Dihydro-beta-Erythroidine; Female; Heterozygote; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motivation; Premedication; Receptors, Nicotinic; Reinforcement Schedule; Social Environment; Tobacco Use Disorder

Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicotine self-administration and precipitate elevations in brain reward thresholds and somatic signs of withdrawal in animals chronically exposed to nicotine. Both the positive-reinforcing effects of acute nicotine and the negative effects of nicotine withdrawal have been hypothesized to contribute to the development and maintenance of nicotine dependence. The aim of the present study was to use methyllycaconitine (MLA), an alpha 7 nAChR antagonist, to investigate the role of alpha 7 receptors in the reinforcing effects of nicotine and nicotine withdrawal. MLA was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion). Nevertheless, MLA administration, at all doses tested, had no effect on brain reward thresholds or the number of somatic signs of withdrawal observed in rats chronically exposed to either nicotine or saline. In conclusion, the alpha 7 nAChR subtype appears to play a significant role in the reinforcing effects of acute nicotine administered intravenously, but not in nicotine dependence, as reflected in the lack of precipitation of the nicotine withdrawal syndrome in nicotine-treated animals.

Topics: Aconitine; Animals; Behavior, Animal; Brain; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Male; Nicotine; Nicotinic Antagonists; Rats; Rats, Wistar; Reward; Self Administration; Substance Withdrawal Syndrome; Tobacco Use Disorder