[Show abstract][Hide abstract] ABSTRACT: The ability to examine genetically engineered mice in a chronic intravenous (IV) nicotine self-administration paradigm will be a powerful tool for investigating the contribution of specific genes to nicotine reinforcement and more importantly, to relapse behavior. Here we describe a reliable model of nicotine-taking and -seeking behavior in male C57BL/6J mice without prior operant training or food restriction. Mice were allowed to self-administer either nicotine (0.03mg/kg/infusion) or saline in 2-h daily sessions under fixed ratio 1 (FR1) followed by FR2 schedules of reinforcement. In the nicotine group, a dose-response curve was measured after the nose-poke behavior stabilized. Subsequently, nose-poke behavior was extinguished and ability of cue presentations, priming injections of nicotine, or intermittent footshock to reinstate responding was assessed in both groups. C57BL/6J mice given access to nicotine exhibited high levels of nose-poke behavior and self-administered a high number of infusions as compared to mice given access to saline. After this acquisition phase, changing the unit-dose of nicotine resulted in a flat dose-response curve for nicotine-taking and subsequently reinstatement of nicotine-seeking behavior was achieved by both nicotine-associated light cue presentation and intermittent footshock. Nicotine priming injections only triggered significant reinstatement on the second consecutive day of priming. In contrast, mice previously trained to self-administer saline did not increase their responding under those conditions. These results demonstrate the ability to produce nicotine-taking and nicotine-seeking behavior in naive C57BL/6J mice without both prior operant training and food restriction. Future work will utilize these models to evaluate nicotine-taking and relapsing behavior in genetically-altered mice.
Behavioural brain research 02/2012; 230(1):34-9. DOI:10.1016/j.bbr.2012.01.042 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extracellular signal-regulated kinase (ERK) is activated in vivo in a number of brain areas by nicotine and other drugs of abuse. Here we show that nicotine stimulation of cultured mouse cortical neurons leads to a robust induction of ERK phosphorylation that is dependent on nicotine concentration and duration of exposure. Calcium/calmodulin-dependent protein kinase II activity is necessary for nicotine-induced ERK phosphorylation and neither cAMP-dependent protein kinase or protein kinase C appear to be involved. Activity of glutamate receptors, L-type voltage-gated calcium channels, and voltage-gated sodium channels are also required for nicotine-induced ERK phosphorylation. Nicotine-induced ERK phosphorylation was inhibited by high concentrations of mecamylamine, however it was not blocked by other broad nicotinic acetylcholine receptor (nAChR) inhibitors (including hexamethonium and chlorisondamine) or nAChR subtype selective inhibitors (such as methyllycaconitine, alpha-bungarotoxin, dihydro-beta-erythroidine, and alpha-conotoxin Au1B). In accord with these pharmacological results, nicotine-induced ERK phosphorylation was normal in primary cultures made from beta2 or alpha7 nAChR subunit knockout mice. The alpha3/beta4 nAChR agonist cytisine did not induce ERK phosphorylation suggesting that alpha3/beta4 nAChRs were not involved in this process. Taken together, these data define a necessary role for glutamatergic signaling and calcium/calmodulin-dependent protein kinase II in nicotine-induced ERK phosphorylation in cortical neurons and do not provide evidence for the involvement of classical nAChRs.
Journal of Neurochemistry 11/2007; 103(2):666-78. DOI:10.1111/j.1471-4159.2007.04799.x · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide found throughout the brain, particularly in the nucleus accumbens (NAcc) and hypothalamus. CART was initially discovered and named based on the upregulation of its mRNA in the striatum after acute cocaine or amphetamine injection in rats. CART is also known to participate in a wider range of physiological functions including feeding, anxiety, bone resorption, and insulin regulation. In this report, we demonstrate that knockout mice lacking a functional CART gene show similar cocaine-induced locomotor sensitization and cocaine self-administration to their wild type siblings. Intravenous cocaine self-administration did not differ between CART wild type and knockout mice during acquisition, during schedules of reinforcement that require higher response ratios, or across a range of doses. In conclusion, these data indicate that CART is not integral to the effects of psychostimulants in mice lacking CART throughout development, although it may play a regulatory role in the intact animal.
Behavioural Brain Research 08/2006; 171(1):56-62. DOI:10.1016/j.bbr.2006.03.022 · 3.03 Impact Factor