Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum

Grady, Sharon R.; Meinerz, Natalie M.; Cao, Jing; Reynolds, Anne; Picciotto, Marina R.; Changeux, Jean Pierre; McIntosh, J. Michael; Marks, Michael J.; Collins, Allan C.

doi:10.1046/j.1471-4159.2001.00019.x

Cited by 148 publications

(93 citation statements)

References 38 publications

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“…All release experiments were conducted at room temperature using methods described previously (Grady et al, 1997(Grady et al, , 2001. In brief, after 3 H-neurotransmitter uptake was complete, aliquots of synaptosomes (80 l) were distributed onto filters and perfused with perfusion buffer [uptake buffer containing 0.1% bovine serum albumin, 1 M atropine, and either 10 M nomifensine for…”

Section: Methodsmentioning

confidence: 99%

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Nashmi

Xia²,

Deshpande³

et al. 2007

J. Neurosci.

248

320

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Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to nicotine itself, and to endogenous acetylcholine, are altered by continued exposure to the drug. To address this problem, we developed mice whose ␣4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased ␣4 fluorescence in several regions; among these, midbrain and hippocampus were assessed functionally. Although the midbrain dopaminergic system dominates reward pathways, chronic nicotine does not change ␣4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional ␣4* receptors localize to the GABAergic neurons of the VTA and substantia nigra pars reticulata. In consequence, GABAergic neurons from chronically nicotine-treated mice have a higher basal firing rate and respond more strongly to nicotine; because of the resulting increased inhibition, dopaminergic neurons have lower basal firing and decreased response to nicotine. In hippocampus, chronic exposure to nicotine also increases ␣4* fluorescence on glutamatergic axons of the medial perforant path. In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli enhances induction of long-term potentiation in the medial perforant path, showing that the upregulated ␣4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional ␣4* receptors therefore provides a possible explanation for two effects of chronic nicotine: sensitization of synaptic transmission in forebrain and tolerance of dopaminergic neuron firing in midbrain.

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Section: Methodsmentioning

confidence: 99%

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Nashmi

Xia²,

Deshpande³

et al. 2007

J. Neurosci.

248

320

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“…Those receptors that are expressed on or near nerve terminals modulate calcium-dependent release of neurotransmitters [35,36,37,38] including dopamine [39,40,41,42], norepinephrine [43,44], glutamate [45,46], GABA [47], and acetylcholine [48,49]. Nicotinic agonist-stimulated release of dopamine has been studied extensively in the nucleus accumbens because these nAChRs may play a major role in regulating the reinforcing effects of nicotine [50,51,52].…”

mentioning

confidence: 99%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

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232

223

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. 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 discovered w...

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“…Nicotine influences DA transmission by activation of nicotinic acetylcholine receptors on DA neurons in the striatum [89][90][91][92][93] as well as on a variety of other neurotransmitter systems that are known to mediate nigrostriatal DA release, including glutamtergic, GABAergic, noradrenalinergic and cholinergic systems [52,53,[94][95][96][97][98]. In advanced PD patients, improvements in motor and cognitive symptoms were observed with administration of nicotine [55,56,99] however some studies showed no effect [100][101][102].…”

Section: Discussionmentioning

confidence: 99%

Unilateral 6-OHDA <i>th-fgfr1</i>(<i>tk-</i>) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments

Kucinski¹,

Wersinger²,

Stachowiak³

et al. 2012

Health

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In the developing and adult brain, neurotrophic growth factors support the growth and protection of dopaminergic neuronal systems. Recently, links between impaired neurotrophin support of dopamine (DA) neurons has been described in Parkinson's Disease (PD). Fibroblast growth factor (FGF) has a unique association with DA neurons in that FGF signaling is vitally important for the development and protection of adult DA neurons. We assessed the role of substantia nigra (SN)-expressed FGFs in the nigrostriatal dopaminergic system using a transgenic mouse, th-fgfr1(tk-). In these mice, generated by expression of dominant negative FGFR1(TK-) from the tyrosine hydroxylase (TH) gene promoter, reduced FGF signaling results in smaller and less dense adult nigrostriatal DA neurons, similar to what is observed in PD. With unilateral 6-hydroxydopamine (6-OHDA) lesions, th-fgfr1(tk-) mice exhibited extensive unilateral nigrostriatal damage with robust spontaneous (non-drug induced) asymmetrical turning and a decreased latency to remain on the accelerating rotarod. L-DOPA remains the gold standard for PD therapy despite debilitating hyperkinetic and dyskinetic side effects. The nicotinic acetylcholine system has recently been targeted as an alternative system to combat PD motor symptoms. Nicotine effectively stimulates dopaminergic transmission in the nigrostriatal pathway and mediates movement. Using unilaterally lesioned th-fgfr1(tk-) mice, long term (11 day) oral administration of nicotine increased spontaneous bidirectional turning and increased the latency before falling from the accelerating rotarod. In a separate analysis, L-DOPA treatment reversed directionality of rotation and further deepened motor discoordination, suggesting activation of hypersensitive postsynaptic DA receptors in the denervated striata. These results in a transgenic model of PD provide insights into the cellular mechanisms underlying L-DOPA and nicotinic therapies and offer further evidence of nicotine's capacity to facilitate movement and enhance motor coordination in PD.

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Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum

Cited by 148 publications

References 38 publications

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Unilateral 6-OHDA <i>th-fgfr1</i>(<i>tk-</i>) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments

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Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum

Cited by 148 publications

References 38 publications

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Unilateral 6-OHDA &lt;i&gt;th-fgfr1&lt;/i&gt;(&lt;i&gt;tk-&lt;/i&gt;) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments

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Resources

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Unilateral 6-OHDA <i>th-fgfr1</i>(<i>tk-</i>) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments