Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat

Sorenson, Eva M.; Shiroyama, Takashi; Kitai, S.T.

doi:10.1016/s0306-4522(98)00064-5

Cited by 96 publications

(72 citation statements)

References 64 publications

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“…Labeling of the postsynaptic density itself maybe under-detected because the structure can be refractory to pre-embedding labeling methods (Nusser et al, 1995). However, this localization is in line with previous studies that also reported localization of alpha4 immunolabeling at asymmetric synaptic contacts in the cortex (Whiting and Lindstrom, 1988;Schroder, 1989;Okuda 1993, (Nakayama et al, 1997 in the substantia nigra (Sorenson et al, 1998) and the ventral tegmental area (Arroyo-Jim nez et al, 1999). Cholinergic axons form asymmetric-type contacts on 5-HT neurons (Wang et al, 2000), and therefore these receptors may mediate synaptic transmission at these sites.…”

Section: Methodological Considerationssupporting

confidence: 78%

Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on 5-HT neurons in the rat dorsal raphe nucleus

Commons

2008

Neuroscience

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Nicotinic acetylcholine receptors containing the alpha4 and beta2 subunits constitute the most abundant high-affinity binding site of nicotine in the brain and are critical for the addictive qualities of nicotine. Serotonin neurotransmission is thought to be an important contributor to nicotine addiction. Therefore in this study it was examined how alpha4-containing receptors are positioned to modulate the function of serotonin neurons using ultrastructural analysis of immunolabeling for the alpha4 receptor subunit in the dorsal raphe nucleus (DR), a primary source of forebrain serotonin in the rat. Of 150 profiles labeled for the alpha4 subunit, 140 or 93% consisted of either soma or dendrites, these were often small-caliber (distal) dendrites <1.5 um in diameter (63/150 or 42%). The majority (107/150 or 71%) of profiles containing labeling for alpha4 were dually labeled for the synthetic enzyme for serotonin, tryptophan hydroxylase (TPH). Within dendrites immunogold labeling for alpha4 was present on the plasma membrane or near postsynaptic densities. However, labeling for alpha4 was commonly localized to the cytoplasmic compartment often associated with smooth endoplasmic reticulum, plausibly representing receptors in transit to or from the plasma membrane. Previous studies have suggested that nicotine presynaptically regulates activity onto serotonin neurons, however alpha4 immunolabeling was detected in only 10 axons in the DR or 7% of profiles sampled. This finding suggest that alpha4 containing receptors are minor contributors to presynaptic regulation of synaptic activity onto serotonin neurons, but rather alpha4 containing receptors are positioned to influence serotonin neurons directly at postsynaptic sites. Keywordsacetylcholine; nicotine; anxiety; 5-HT-1A; addictionThe dorsal raphe nucleus (DR) is one of the primary sources of serotonin (5-HT) in the forebrain. Cholinergic modulation of the DR likely influences several physiological functions including sleep cycle (Portas et al., 2000), anxiety and pain sensitivity. In addition, the actions of nicotine in the DR may contribute to nicotine addiction. Acute nicotine administration modifies 5-HT release in the forebrain (Toth et al., 1992, Ribeiro et al., 1993, Summers et al., 1996. Chronic nicotine administration produces alterations in 5-HT receptors, transporters and brain metabolism of 5-HT in both humans and animal models (Benwell and Balfour, Correspondence to: Kathryn G. Commons, Ph.D., Children's Hospital, 300 Longwood Ave., Enders 1206e, Boston, MA 02115, Telephone: 617-919-2220, Fax: 617-730-0235, Email: Kathryn.Commons@Childrens.Harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discove...

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Section: Methodological Considerationssupporting

confidence: 78%

Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on 5-HT neurons in the rat dorsal raphe nucleus

Commons

2008

Neuroscience

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“…In the dorsolateral septum (Wong and Gallagher, 1991) and the visual cortex (Roerig et al, 1997), synapses have been uncovered that are insensitive to ␣-bungarotoxin, a specific blocker of ␣7 in the brain. The dopaminergic neurons of the substantia nigra exhibit nicotinic synapses with ␣4 containing receptors (Sorenson et al, 1998). Other synapses have been located, for instance, on the Renshaw cell of the spinal chord (Dourado and Sargent, 2002), which may contain ␣4␤2, and in the ambiguus nucleus of the brainstem (Zhang et al, 1993).…”

Section: Physiologic Modes Of Action Of Acetylcholinementioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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“…The principal source of the cholinergic input is likely the pedunculopontine and laterodorsal tegmental nuclei (Gould et al 1989;Damlama and Tepper 1993). A number of nicotinic receptor subunits are expressed by mesencephalic dopaminergic neurons including a3, a4, a5, a7, b2, and b3 (Sorenson et al 1998), and bath application of nicotine produces an inward current and depolarization that exhibits ᭣ desensitization with a time course of tens of seconds Sorenson et al 1998). The response is sensitive to k-bungarotoxin but not abungarotoxin and is thus more similar to the nicotinic response seen at peripheral autonomic ganglia than at the neuromuscular junction .…”

Section: Cholinergic Afferentsmentioning

confidence: 99%

Electrophysiological Pharmacology of Mesencephalic Dopaminergic Neurons

Diana¹,

Tepper²

2002

Dopamine in the CNS II

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Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat

Cited by 96 publications

References 64 publications

Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on 5-HT neurons in the rat dorsal raphe nucleus

Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on 5-HT neurons in the rat dorsal raphe nucleus

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

Electrophysiological Pharmacology of Mesencephalic Dopaminergic Neurons

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