People | Faculty | Daniel McGehee
Associate Professor, Department of Anesthesia and Critical Care
Committee on Cellular and Molecular Physiology
Postdoc, Columbia University, Neurobiology
Ph.D., University of North Carolina at Chapel Hill, Physiology
B.S., Guilford College, Biology
Office: AMB O-324 (MC 4028)
Neuronal nicotinic receptors and their role in synaptic transmission
The potent nervous system effects of the 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 (1-3). 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 (4). 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.
Research in my laboratory is focused on the functional role of the nicotinic acetylcholine receptors (nAChR) in the nervous system. Although these 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. Along with research from several laboratories, my research has shown that nicotinic receptors can act by a presynaptic mechanism to influence the release of other neurotransmitters (5,6).
We are investigating the cellular mechanisms underlying two important physiological effects of nicotine. A major focus 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 (7). 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.
Another research focus is nAChR-mediated modulation of sensory inputs to the spinal cord. A notable effects of nicotine, reported even by the earliest users of tobacco, is that it can relieve 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 slices (see Figure), as well as neuronal cultures. In both preparations, there is clear evidence that primary and secondary sensory neurons express nAChRs, and in the slices low concentrations of nicotine can enhance glutamate release in both the dorsal and ventral horn of the spinal cord. These studies will continue to provide insights into the role of nAChRs in spinal circuits, and may help identify new means of treating the debilitating symptoms associated with the loss of sensory and motor neuron function.
Benowitz, N.L., Porchet, H. and Jacob, P. Pharmacokinetics, metabolism, and pharmacodynamics of nicotine. In: "Nicotine Psychopharmacology: Molecular, Cellular, and Behavioural Aspects", Edited by S. Wonnacott, M.A.H. Russell, and I.P. Stolerman. Oxford UK: Oxford University Press pp 112-157, 1990.
Badio, B. and Daly, J. Epibatidine, a potent analgesic and nicotinic agonist. Mol. Pharmacol., 45:563-568, 1994.
D.S. McGehee, M.J.S. Heath, S. Gelber, P. Devay and L.W. Role. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science, 269, 1692-1696, 1995.
D.S. McGehee and L.W. Role. Memories of nicotine. Nature, 383:670-671, 1996.
D.S. McGehee and L.W. Role. Presynaptic ionotropic receptors. Current Opinion in Neurobiology, 6:342-349, 1996.
D.S. McGehee. Molecular diversity of neuronal nicotinic acetylcholine receptors. Ann NY Acad. Sci., 868: 565-577, 1999.
H.D. Mansvelder and D.S. McGehee. Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron, 27, 349-357, 2000.
Figure 1. Spinal cord dorsal horn neurons visualized using infrared DIC microscopy. These neurons are approximately 150 mm from the surface of the tissue slice.