title: Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice(1,2,3).
abstract: Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca(2+) influx and desensitizes α4β2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge.
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital , Seattle, Washington 98105.
authors: Granville P
authors: GP
authors: Storey
authors: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California 90095.
authors: Gabriel
authors: 0000-0002-1229-5489
authors: G
authors: Gonzalez-Fernandez
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital , Seattle, Washington 98105.
authors: Ian J
authors: IJ
authors: Bamford
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital , Seattle, Washington 98105.
authors: Matthew
authors: 0000-0003-0917-0295
authors: M
authors: Hur
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital , Seattle, Washington 98105.
authors: Jonathan W
authors: 0000-0001-8719-2209
authors: JW
authors: McKinley
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital , Seattle, Washington 98105.
authors: Lauren
authors: L
authors: Heimbigner
authors: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California 90095.
authors: Ani
authors: 0000-0002-6370-9848
authors: A
authors: Minasyan
authors: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California 90095.
authors: Wendy M
authors: WM
authors: Walwyn
authors: Department of Neurology, The Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital, Seattle, Washington 98105; Departments of Pediatrics and Psychology, the Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital, Seattle, Washington 98105; Departments of Pediatrics and Neurology, Yale School of Medicine, New Haven, Connecticut 06520.
authors: Nigel S
authors: NS
authors: Bamford
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000008:administration & dosage*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D058999:Drug-Seeking Behavior / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009044:Motor Cortex / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D011978:Receptors, Nicotinic / Q000502:physiology; D012201:Reward; D012646:Self Administration; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D000661:Amphetamine
keywords: acetylcholine; addiction; amphetamine; nicotine; self-administration; sensitization; striatum