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

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