Other Chemospecific Neurons with Autoreceptors

Cholinergic terminals have inhibitory receptors of the muscarinic 2 subtype, which exert a negative feedback influence on release. Considerable evidence also exists for nicotinic receptors exerting a positive influence on acetylcholine release. As acetylcholine is a key neurotransmitter in Alzheimer's disease, these two types of receptors represent targets for the development of drugs to enhance acetylcholine release from the remaining fibers, that is, muscarinic type 2 antagonists and nicotinic agonists.

Glutamatergic terminals have autoreceptors of the metabotropic subtype 2 that, when overactivated, attenuate glutamate release. Recently, agonists have been developed in the hope of helping treat conditions such as opiate withdrawal symptoms, given that this condition increases glutamatergic activity that stimulates NE activity. Indeed, this condition cannot be controlled using only the a2-adrenergic agonist clonidine to attenuate physical and psychological agitation.

GABA neurons inhibit the release of their own neuro-transmitter via GABAB autoreceptors. However, the exact role that the GABA agonist baclofen exerts on these auto-receptors to mediate the antispasmodic effect of this drug in patients with spinal cord lesions remains to be clarified.

Finally, histamine neurons bear autoreceptors of the H3 subtype that inhibit histamine release. Although selective H3 antagonists have been developed and demonstrated to increase arousal and decrease food intake in animals, they have not yet reached the therapeutic armamentarium. They are interestingly devoid of peripheral side effects because H3 receptors are virtually absent outside the central nervous system.

In summary, autoreceptors are crucial neuronal elements because they are intimately involved in modulating the overall function of their neurons. As for most types of neurons, their presence probably represents more the rule than the exception. They have been exploited in human therapeutics using either agonists, mainly to decrease neurotransmitter release, or antagonists, to promote neuronal output. Their discovery and characterization have already led to advances of certain disorders and should yield further therapeutic indications in the future.

SUGGESTED READING

Blier, P., & Bergeron, R. (1998). The use of pindolol to potentiate antidepressant medication. Journal of Clinical Psychiatry, 59, 16-23.

Langer, S. Z. (1997). 25 years since the discovery of presynaptic receptors: Present knowledge and future perspectives. Trends in Pharmacological Sciences, 18, 95-99.

Pineyro, G., & Blier, P. (1999). Autoregulation of serotonin neurons: Role in antidepressant drug action. Pharmacological Reviews, 51, 533-591.

Starke, K., Göthert, M., & Kilbinger, H. (1989). Modulation of neurotransmitter release by presynaptic autoreceptors. Physiological Reviews, 69, 864-988.

Pierre Blier University of Florida

See also: Neurotransmitters

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