PhD, University of North Carolina at Chapel Hill
Daniel McGehee, PhD
- Cellular & Molecular
- Systems / Behavior / Cognitive
The potent nervous system effects of nicotine are clearly evidenced by the widespread use of tobacco products. In addition to reinforcing smoking behavior, nicotine is also reported to have analgesic, anxiolytic and memory-enhancing properties. Many CNS neurons express membrane receptors that bind nicotine with high affinity, and these receptors are ultimately responsible for the behavioral effects of nicotine. The normal activator of these receptors is the neurotransmitter acetylcholine, and there are several nicotinic acetylcholine receptors (nAChR) subtypes expressed in the CNS. Determination of the nAChR subtypes that underlie the various physiological effects of nicotine may lead to the identification of new methods for treating neurological disorders, in addition to the obvious benefit of potentially helping people quit smoking.
The focus of research in my laboratory is the functional role of neuronal nAChRs, under normal conditions and when exposed to applied nicotine. An interesting, but confounding problem in the field is that although nAChRs are expressed throughout the brain and spinal cord, there is very little direct evidence that they mediate synaptic transmission. That is, there are relatively few synapses where acetylcholine release from the presynaptic cell has been shown to activate nicotinic receptors on the postsynaptic cell. Our research, along with that from several other groups, has shown that nicotinic receptors can act by a presynaptic mechanism to influence the release of other neurotransmitters. The combined evidence indicates that a predominant role of nAChRs is to modify rather than mediate synaptic transmission.
We are investigating the cellular mechanisms underlying two important physiological effects of nicotine. The first is the reinforcing or addictive properties of nicotine. All drugs of abuse are known to enhance dopamine (DA) release from midbrain reward centers and this is a crucial step in the reinforcement of drug-taking behavior. We have found that, similar to the role of these receptors in other CNS regions, presynaptic nAChRs can enhance excitatory inputs to midbrain dopamine neurons. A long standing question in the field is how a single nicotine exposure can induce increases in DA release that last for hours, while the nicotinic receptors undergo desensitization in seconds. Our recent results indicate that presynaptic nAChR activation can contribute to the induction of long-term potentiation (LTP) of excitatory transmission at this synapse. LTP is believed to be an important step in memory formation in other brain regions. The idea that nicotine can induce a 'memory trace' within the reward center may explain why this substance is such a strong motivator.
The second main research focus is nAChR-mediated modulation of pain signaling in spinal cord and higher centers. A notable effect of nicotine, reported even by the earliest users of tobacco, is relief of pain. To investigate the underlying mechanisms, we are examining the functional properties and molecular components of nAChRs expressed by neurons within sensory transduction pathways. These experiments involve recording the physiological responses from neurons in spinal cord and brain stem slices that contain descending pain control pathways. In both preparations, there is clear evidence that neurons in these areas express nAChRs. In addition, nAChRs modify synaptic activity in these areas, in a manner that contributes to synaptic plasticity. These studies will continue to provide insights into the role of nAChRs in pain signaling, and may help identify new means of treating chronic pain conditions.
1. H.D. Mansvelder & D.S. McGehee. (2000) Long term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27: 349-357.
2. J.R. Genzen, W. Van Cleve and D.S. McGehee. (2001) Dorsal root ganglion neurons express multiple nicotinic receptor subtypes. Journal of Neurophysiology 86(4): 1773-82.
3. H.D. Mansvelder, J.R. Keath & D.S. McGehee. (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33 (6): 905-919.
4. D.S. McGehee. (2002) Nicotinic receptors and hippocampal synaptic plasticity…it’s all in the timing. Trends in Neurosciences 25(4): 171-172.
5. H.D. Mansvelder & D.S. McGehee. (2002) Cellular and synaptic mechanisms of nicotine addiction. Journal of Neurobiology 53: 606-617.
6. J.R. Genzen and D.S. McGehee. (2003) Short and Long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors. Proceedings of the National Academy of Sciences 100(11):6807-6812.
7. Z.M. Fagen, H.D. Mansvelder, J.R. Keath & D.S. McGehee. (2003) Short and long-term modulation of synaptic inputs to brain reward areas by nicotine. Annals of the New York Academy of Sciences 1003: 185-195.
8. J.R. Genzen & D.S. McGehee. (2005) Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn. Brain Research 1031(2):229-37.
9. D.S. McGehee, M. Iacoviello, R. Mitchum (2006) Cellular and Synaptic Effects of Nicotine. In Medication Treatments for Nicotine Dependence. Eds T.P. George & A.H. Weinberger.
10. Cagniard B, Beeler JA, Britt JP, McGehee DS, Marinelli M, Zhuang X. (2006) Dopamine scales performance in the absence of new learning. Neuron 51(5):541-7.
11. McGehee DS. (2007) Nicotine and synaptic plasticity in prefrontal cortex. Science STKE. 2007(399):pe44.
12. Z.M. Fagen, R. Mitchum, P. Vezina, D.S. McGehee. (2007) Enhanced nicotinic receptor function and drug abuse vulnerability. J. Neurosci. 27(33):8771-8. PMID: 17699659
13. H.D. Mansvelder, Z.M. Fagen, B. Chang, R. Mitchum, D.S. McGehee. (2007) Bupropion inhibits the cellular effects of nicotine in the ventral tegmental area. Biochem Pharmacol. 74(8):1283-91. PMID: 17868653
14. P. Vezina, D.S. McGehee, W.N. Green. (2007) Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuropsychopharmacol Biol Psychiatry. 31(8):1625-38. PMID: 17936462
15. J.R. Keath, M.P. Iacoviello, L.E. Barrett, H.D. Mansvelder, D.S. McGehee. (2007) Differential modulation by nicotine of Substantia Nigra versus Ventral Tegmental Area dopamine neurons. J. Neurophysiol. 98(6):3388-96. PMID: 17942622
16. J.P. Britt, D.S. McGehee (2008) Presynaptic opioid and nicotinic receptor modulation of dopamine overflow in the nucleus accumbens. J. Neuroscience 28(7):1672-81. PMID: 18272687
17. M.R. Campioni, M. Xu, D.S. McGehee. (2009) Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J Neurophysiol. 101(6):3192-8. PMID: 19357347
18. M.A. Kheirbek, J.P. Britt, J.A Beeler, Y. Ishikawa, D.S. McGehee, X. Zhuang (2009) Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci. 29(39):12115-24. PMID: 19793969
19. D.S. McGehee (2009) Nicotine's Allure. Neuron 63(5):564-5. PMID: 19755099
20. D. Mao, D.S. McGehee (2010) Nicotine and Behavioral Sensitization. J Mol Neurosci. 40(12):154-63.