The long-term goal of this research is to develop new and effective treatments for drug addiction. We recently discovered that several agents blocking cholinergic alpha3beta4 nicotinic receptors reduce morphine, methamphetamine and nicotine self-administration in rats. In the brain alpha3beta4 nicotinic receptors are preferentially localized in the medial habenula and interpeduncular nucleus. Since the 1980's it has been known that the habenulo-interpeduncular pathway functions as a reward system that is separate from the mesolimbic pathway. Although it has long been known that the habenulo-interpeduncular pathway and the mesolimbic pathway interact and probably modulate each other, few studies have explored how this occurs and how manipulations of one can affect the other. The goal of this proposal is to examine the role of cholinergic mechanisms in the habenulo-interpeduncular pathway as a potential substrate for new treatments. The central hypothesis is that blocking cholinergic transmission in the habenulo-interpeduncular pathway will attenuate drug self-administration. Research will be organized into three specific aims: (1) We will establish that habenulo-interpeduncular cholinergic transmission influences drug self-administration. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the intravenous self-administration of prototypicai drugs of abuse (morphine, methamphetamine, and nicotine). (2) We will establish that drugs of abuse enhance cholinergic transmission in the habenulo-interpeduncular pathway. Activation of the cholinergic habenulo-interpeduncular pathway may be an alternate or supplementary mechanism mediating or modulating the rewarding effects of drugs of abuse. Our working hypothesis is that drugs of abuse will raise extracellular levels of acetylcholine in the medial habenula and/or interpeduncular nucleus. (3) We will establish that the cholinergic habenulo-interpeduncular pathway modulates the dopaminergic mesolimbic pathway. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the effects of abused drugs on extracellular levels of dopamine in the nucleus accumbens. The work proposed here may ultimately result in new kinds of treatments for drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016283-03
Application #
7090115
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
2004-07-15
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$270,003
Indirect Cost
Name
Albany Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
McCallum, Sarah E; Cowe, Matthew A; Lewis, Samuel W et al. (2012) ?3?4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo. Neuropharmacology 63:434-40
Polston, J E; Pritchett, C E; Sell, E M et al. (2012) 18-Methoxycoronaridine blocks context-induced reinstatement following cocaine self-administration in rats. Pharmacol Biochem Behav 103:83-94
Polston, J E; Glick, S D (2011) Music-induced context preference following cocaine conditioning in rats. Behav Neurosci 125:674-80
McCallum, Sarah E; Taraschenko, Olga D; Hathaway, Ethan R et al. (2011) Effects of 18-methoxycoronaridine on ghrelin-induced increases in sucrose intake and accumbal dopamine overflow in female rats. Psychopharmacology (Berl) 215:247-56
Polston, J E; Rubbinaccio, H Y; Morra, J T et al. (2011) Music and methamphetamine: conditioned cue-induced increases in locomotor activity and dopamine release in rats. Pharmacol Biochem Behav 98:54-61
Taraschenko, Olga D; Maisonneuve, Isabelle M; Glick, Stanley D (2011) Resistance of male Sprague-Dawley rats to sucrose-induced obesity: effects of 18-methoxycoronaridine. Physiol Behav 102:126-31
Glick, Stanley D; Sell, Elizabeth M; McCallum, Sarah E et al. (2011) Brain regions mediating ?3?4 nicotinic antagonist effects of 18-MC on nicotine self-administration. Eur J Pharmacol 669:71-5
Taraschenko, Olga D; Maisonneuve, Isabelle M; Glick, Stanley D (2010) 18-Methoxycoronaridine, a potential anti-obesity agent, does not produce a conditioned taste aversion in rats. Pharmacol Biochem Behav 96:247-50
Carnicella, Sebastien; He, Dao-Yao; Yowell, Quinn V et al. (2010) Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration. Addict Biol 15:424-33
Arias, Hugo R; Rosenberg, Avraham; Feuerbach, Dominik et al. (2010) Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states. Biochim Biophys Acta 1798:1153-63

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