Nicotinic acetylcholine receptors (nAChRs) can modify synaptic transmission in many brain regions. Our recent studies show that nAChRs contribute to midbrain dopamine (DA) neuron excitability through modulation of both inhibitory GABAergic and excitatory glutamatergic inputs. The nAChR enhancement of glutamate inputs can contribute to LTP induction at this synapse. Interestingly, the nicotinic modulation of GABA transmission exhibits a transient enhancement, followed by a depression of activity. Apparently, desensitization of the nAChRs on GABA neurons inhibits endogenous cholinergic input to these cells, thus leading to a 'disinhibition' of the DA neurons. These studies were carried out in neonatal rats, primarily for technical reasons. Experiments in this proposal will extend these tests to tissue slices from adult rats that have undergone behavioral and pharmacological testing. The activity that an animal displays in a novel environment can predict nicotine self-administration in rats. The advantage of this screen is that animals predisposed to nicotine self-administration can be identified without nicotine exposure, which is known to alter sensitivity. Our preliminary results indicate differences in nAChR expression between high and low responders to novelty. We will extend these observations to test the differences in cellular and synaptic effects of nAChR activation associated with the predisposition to nicotine self-administration. The activity response to novelty has also been correlated with differences in stress hormone levels between individuals, leading to the suggestion that stress hormones contribute to the predisposition to drug-taking. Preliminary data indicate that stress hormones inhibit nAChRs through a direct interaction. We will test the hypothesis that this interaction upregulates the expression of nAChRs within the reward area, strengthens the cellular response to nicotine and thus, enhances the motivating effects of the drug. Nicotine exposure also enhances the acquisition of self-administration behavior, presumably through upregulation of nAChR expression. We will test nAChR effects on DA neuron excitability from animals that have been pre-exposed to nicotine by passive injection and self-administration testing. These studies of nAChR function within the brain reward center will provide important insights into the cellular basis of addiction. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015918-04
Application #
7000425
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Volman, Susan
Project Start
2003-02-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$372,291
Indirect Cost
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Baker, Lorinda K; Mao, Danyan; Chi, Henry et al. (2013) Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug. Eur J Neurosci 37:1004-11
Chang, Ben; Daniele, Claire A; Gallagher, Keith et al. (2011) Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens. J Neurophysiol 106:801-8
Ding, Yunmin; Won, Lisa; Britt, Jonathan P et al. (2011) Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc Natl Acad Sci U S A 108:840-5
Mao, Danyan; Gallagher, Keith; McGehee, Daniel S (2011) Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. J Neurosci 31:6710-20
Kheirbek, Mazen A; Britt, Jon P; Beeler, Jeff A et al. (2009) Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci 29:12115-24
Young, Yuchi; Fan, Ming-Yu; Hebel, J Richard et al. (2009) Concurrent validity of administering the functional independence measure (FIM) instrument by interview. Am J Phys Med Rehabil 88:766-70
Campioni, Matthew R; Xu, Ming; McGehee, Daniel S (2009) Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J Neurophysiol 101:3192-8
Britt, Jonathan P; McGehee, Daniel S (2008) Presynaptic opioid and nicotinic receptor modulation of dopamine overflow in the nucleus accumbens. J Neurosci 28:1672-81

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