McGehee Laboratory

Daniel McGehee, Ph.D.
Associate Professor, Department of Anesthesia and Critical Care
Committee on Cell Physiology and Committee on Neurobiology

Neuronal nicotinic receptors and synaptic transmission

The potent effects of nicotine on the nervous system are clearly evident by the widespread use of tobacco products. In addition to reinforcing smoking behavior, nicotine also is reported to have analgesic, anxiolytic and memory-enhancing properties (1-3). Many Central Nervous System (CNS) neurons express membrane receptors that bind nicotine with high affinity, and these receptors are ultimately responsible for the physiological 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.

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 on which acetylcholine release from the presynaptic cell activates nicotinic receptors on the postsynaptic cell. Our research, and 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 the predominant role of nAChRs is to modify rather than mediate synaptic transmission (5,6).

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 increase in DA release that lasts for hours, while nicotinic receptors are desensitized 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.

The second main research focus is nAChR-mediated modulation of sensory inputs to the spinal cord. 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 slices, and neuronal cultures. In both preparations, there is clear evidence that primary and secondary sensory neurons express nAChRs. In the tissue slices, we have found that low concentrations of nicotine enhance glutamate release in both the dorsal and ventral horn of the spinal cord. These studies 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.

References

  1. Benowitz, NL, Porchet, H. and Jacob, P. (1990) 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.
  2. Badio, B and Daly, J (1994) Epibatidine, a potent analgesic and nicotinic agonist. Mol. Pharmacol, 45: 563-568.
  3. D.S. McGehee & L.W. Role (1996) Memories of Nicotine. Nature , 383:670-671.
  4. D.S. McGehee (1999) Molecular diversity of neuronal nicotinic acetylcholine receptors. Ann NY Acad Sci 868:565-577.
  5. D.S. McGehee, M.J.S. Heath, S. Gelber, P. Devay & L.W. Role (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science , 269:1692-1696.
  6. D.S. McGehee & L.W. Role (1996) Presynaptic ionotropic receptors. Curr Opin Neurobiol, 6:342-349.
  7. H.D. Mansvelder & D.S. McGehee (2000) Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27:349-357.