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Neurobiological substrates of nicotine addiction

Institution: Scripps Research Institute
Investigator(s): Athina Markou, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12RT-0231 Award: $723,613
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco smoking, which is attributed partly to the addictive properties of nicotine, continues to be a worldwide problem of drug abuse. Considering that the risk for developing diseases associated with tobacco smoking is reduced when smoking is stopped, there is much incentive to invest research resources in elucidating the neurobiological substrates of nicotine dependence and the factors that lead to relapse to assist in the development of treatments for dependence on nicotine. With the present grant, work initiated under Specific Aim 1 began the exploration and identification of the neuronal substrates of nicotine dependence by identifying brain sites where antagonism of nicotinic acetylcholine receptors (nAchRs) is sufficient to induce aspects of the nicotine withdrawal syndrome (i.e., precipitated withdrawal) in rats. Elevations in brain reward thresholds can be precipitated in nicotine-treated rats with a variety of nAchR antagonists injected systemically or into specific brain sites. These threshold elevations are similar to those seen during spontaneous nicotine withdrawal. We investigated the effects of the nAchR antagonist dihydro-β-erythroidine (DHβE) injected into limbic brain sites, such as the nucleus accumbens and the ventral tegmental area, on brain reward thresholds in nicotine- and saline-treated rats. The results indicated that administration of the nAchR antagonist into the ventral tegmental area, but not into the shell of the nucleus accumbens, was sufficient to induce the reward threshold elevations associated with spontaneous nicotine withdrawal. This experimental outcome indicated that there is decreased nAchR number/function with the development of nicotine dependence in the ventral tegmental area that may contribute to withdrawal symptomatology and relapse. Elevations in brain reward thresholds reflect "diminished interest or pleasure" in the rewarding electrical stimuli and are an operational measure of the depressive symptom of anhedonia that characterizes tobacco withdrawal. Studies under Specific Aim 2 develop and use new animal models of nicotine dependence to explore whether the adaptations that occur in the function of the cholinergic system with the development of nicotine dependence in specific brain sites (explored in Specific Aim 1) are long-lasting and persistent. These long-lasting adaptations in the function/number of nAchRs was revealed by administering the nAchR antagonist mecamylamme long after the overt somatic aspects of spontaneous nicotine withdrawal have subsided. Rats were allowed to become dependent through daily intravenous nicotine self-administration. Different groups of rats had different access conditions to nicotine (1-6 hr 5 days/week or daily). The results indicated that, although there was no escalation in nicotine intake, subjects that had access to nicotine for 6 hours/day or even 1 hour/day developed dependence faster and their dependence was longer lasting than that of rats that had limited access to nicotine 1 hr/day, 5 days/week. These results indicate that dependence is long lasting, and can be revealed when the nAchR system is probed. Such long lasting dependence may contribute to relapse to tobacco smoking.
Publications

Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duartion of nicotine withdrawal in rats.
Periodical: Psychopharmacology Index Medicus:
Authors: Skjei KL, Markou A ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 280-292

Cocaine-seeking behavior after extended cocaine-free periods in rats: role of conditioned stimuli.
Periodical: Psychopharmacology Index Medicus:
Authors: Semenova S, Markou A ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 192-200

Clozapine treatment attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats that exhibited hyposensitivity to the initial effects of clozapine.
Periodical: Biological Psychiatry Index Medicus:
Authors: Semenova S, Markou A ART
Yr: 2003 Vol: 54 Nbr: 11 Abs: Pg: 1249-1264

Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat.
Periodical: Psychopharmacology Index Medicus:
Authors: Cryan JF, Bruijnzeel AW, Skjei KL, Markou A ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 347-358

Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats.
Periodical: Synapse Index Medicus:
Authors: Bruijnzeel AW, Markou A ART
Yr: 2003 Vol: 50 Nbr: Abs: Pg: 20-28

Decreased prepulse inhibition durin gnicotine withdrawal in DBA/2J is reversed by nicotine self-administration.
Periodical: European Journal of Pharmacology Index Medicus:
Authors: Semenova S, Bespalov A, Markou A ART
Yr: 2003 Vol: 472 Nbr: Abs: Pg: 99-110

Neuroadaptations to chronic exposure to drugs of abuse: relevance to depressive sympomatology seen across psychiatric diagnostic categories.
Periodical: Neurotoxicity Research Index Medicus:
Authors: Markou A, Kenny PJ ART
Yr: 2002 Vol: 4 Nbr: 4 Abs: Pg: 297-313

Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion.
Periodical: Drug Discovery Today Index Medicus:
Authors: Cryan JF, Gasparini F, van Heeke G, Markou A ART
Yr: 2003 Vol: 8 Nbr: 22 Abs: Pg: 1025-1034

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice.
Periodical: Psychopharmacology Index Medicus:
Authors: Paterson NE, Semenova S, Gasparini F, Markou A ART
Yr: 2003 Vol: 167 Nbr: Abs: Pg: 257-264

The GABA-B receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.
Periodical: Psychopharmacology Index Medicus:
Authors: Paterson NE< Froestl W, Markou A ART
Yr: 2004 Vol: 172 Nbr: Abs: Pg: 179-186

Adaptations in cholinergic transmission in the ventral tegmental area associated with the affective signs of nicotine withdrawal in rats.
Periodical: Neuropharmacology Index Medicus:
Authors: Bruijnzeel AW, Markou A ART
Yr: 2004 Vol: 47 Nbr: Abs: Pg: 572 - 579

Characterization of the effects of bupropion on the reinforcing and incentive-motivational properties of nicotine and food in rats.
Periodical: College on Problems of Drug Dependence Index Medicus:
Authors: Bruijnzeel AW, Markou A ABS
Yr: 2003 Vol: Nbr: Abs: Pg:

Increased sensitivity to the nicotinic receptor antagonist dihydro-beta-erythroidine injected into the ventral tegmental area of rats chronically exposed to nicotine.
Periodical: European Behavioural Pharmacology Society Index Medicus:
Authors: Bruijnzeel AW, Markou A ABS
Yr: 2003 Vol: Nbr: Abs: Pg:

Idazoxan treatment partially attenuated the affective aspects of nicotine withdrawal in rats.
Periodical: European Behavioural Pharmacology Society Index Medicus:
Authors: Semenova S, Markou A ABS
Yr: 2003 Vol: Nbr: Abs: Pg:

Behavioral and neurobiological mechnaisms underlying nicotine addiction.
Periodical: American College of Neuropsychopharmacology: Scientific Abstracts Index Medicus:
Authors: Markou A, Bruijnzeel A, Kenny PJ ABS
Yr: 2003 Vol: Nbr: Abs: Pg: 5

Nicotine withdrawal and craving.
Periodical: American College of Neuropsychopharmacology: Scientific Abstracts Index Medicus:
Authors: Markou A, Kenny PJ, Patterson N ABS
Yr: 2003 Vol: Nbr: Abs: Pg: 43

Dissociable effects of NMDA receptor blockade on nicotine self-administration and nicotine-induced facilitation of brain reward function in rats.
Periodical: American College of Neuropsychopharmacology: Scientific Abstracts Index Medicus:
Authors: Kenny PJ, Markou A ABS
Yr: 2003 Vol: Nbr: Abs: Pg: 72

Repeated administration of the GABA B receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-reinstatement of nicotine seeking-rats in rats.
Periodical: Neuropsychopharmacology Index Medicus:
Authors: Paterson N, Froestl W, Markou A ART
Yr: 2005 Vol: 30 Nbr: Abs: Pg: 119 - 128

Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Kenny PJ, Markou A ART
Yr: 0 Vol: Nbr: Abs: Pg:

Glutamatergic mechanisms underlying nicotine addiction.
Periodical: European Neuropsychopharmacology Index Medicus:
Authors: Markou A, Kenny PJ, Paterson NE, Semenova S ABS
Yr: 2004 Vol: 14 Nbr: 3 Abs: Pg: S152 - S153

Decreased sensitivity to the effects of dopamine D1-like, but not D2-like, receptor antagonism in the posterior hypothalamic region/anterior ventral tegmental area on brain reward function during chronic exposure to nicotine in rats.
Periodical: Brain Research Index Medicus:
Authors: Bruijnzeel AW, Markou A ABS
Yr: 0 Vol: 1058 Nbr: Abs: Pg: 91-100

Active immunisation against nicotine blocks the reward facilitating effects of nicotine and partially prevents nicotine withdrawal in the rat as measured by dopamine output in the nucleus accumbens, brain reward thresholds and somatic signs.
Periodical: Naunyn-Schmiedeberg's Archives of Pharmacology Index Medicus:
Authors: Lindblom N, de Villiers S, Semenova S, Kalayanov G, Gordon S, Schilstrom B, Johansson A ART
Yr: 2005 Vol: 372 Nbr: 2 Abs: Pg: 182-194

Mild anxiogenic effects of nicotine withdrawal in mice.
Periodical: European Behavioural Pharmacology Society Index Medicus:
Authors: Jonkman S, Henry B, Semenova S, Markou A ABS
Yr: 2005 Vol: 516 Nbr: Abs: Pg: 40-45