Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis

Hernández‐López, Salvador; Góngora-Alfaro, José L.; Martínez‐Fong, Daniel; Rosales, Manuel G.; Aceves, Jorge

doi:10.1016/0306-4522(94)90378-6

Cited by 13 publications

(2 citation statements)

References 39 publications

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“…In vitro, stimulation of the PPN induced excitatory post-synaptic potentials in dopamine neurons in the SNc, which were suppressed by muscarinic antagonists (42). In vivo, direct cholinergic activation of postsynaptic nicotinic and muscarinic receptors in the SNc leads to dopamine efflux in striatum and behavioral sequelae associated with dopamine, including stereotypies, increased feeding and circling behavior (5,53,82,127). By contrast, atropine injected into the VTA increased the threshold for self-stimulation reward through electrodes placed in the hypothalamus, and these effects were reversed by carbachol (63).…”

Section: Mesopontine Cholinergic Projectionsmentioning

confidence: 99%

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

2003

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Binding studies initially suggested that the muscarinic agonist, xanomeline, was a subtype selective muscarinic M 1 receptor agonist, and a potential new treatment for Alzheimer's disease. However, later in vitro and in vivo functional studies suggest that this compound is probably better described as a subtype selective M 1 /M 4 muscarinic receptor agonist. This subtype selectivity profile has been claimed to explain the limited classical cholinomimetic side effects, particularly gastrointestinal, seen with xanomeline in animals. However, in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for xanomeline and in the patient population this led to a >50% discontinuation rate. Clearly, the preclinical studies have not been able to predict this adverse profile of xanomeline, and this suggests that either xanomeline is not as subtype selective as predicted from preclinical research or that there are differences between humans and animals with regard to muscarinic receptors. Nevertheless, in Alzheimer's patients xanomeline dose-dependently improves aspects of behavioral disturbance and social behavior including a reduction in hallucinations, agitation, delusions, vocal outbursts and suspiciousness. The effects on cognition are not as robust and mainly seen at the highest doses tested. These effects in Alzheimer's patients have given impetus to the suggestion that muscarinic agonists have potential antipsychotic effects. The current review assesses the antipsychotic profile of xanomeline within the framework of the limited clinical studies with cholinergic agents in man, and the preclinical research on xanomeline using various models commonly used for the assessment of new antipsychotic drugs. In general, xanomeline has an antipsychotic-like profile in various dopamine models of psychosis and this agrees with the known interactions between the cholinergic and dopaminergic systems in the brain. Moreover, current data suggests that the actions of xanomeline at the M 4 muscarinic receptor subtype might mediate its antidopaminergic effects. Particularly intriguing are studies showing that xanomeline, even after acute administration, selectively inhibits the firing of mesolimbic dopamine cells relative to dopamine cell bodies projecting to the striatum. This data suggest that xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects. The preclinical data on the whole are promising for an antipsychotic-like profile. If in a new formulation (i.e., transdermal) xanomeline has less adverse effects, this drug may be valuable in the treatment of patients with psychosis.

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Section: Mesopontine Cholinergic Projectionsmentioning

confidence: 99%

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

2003

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“…These mesopontine cholinergic (MPCh) neurons have extensive projections to the thalamus (Pare et al ., 1988; Steriade et al ., 1988) and a region of the medial pontine reticular formation (Semba & Fibiger, 1992) where injection of cholinergic agonists induces a rapid eye movement (REM)‐like state (Baghdoyan et al ., 1989). These neurons also provide important cholinergic afferents to the ventral tegmental area (Cornwall et al ., 1990; Woolf et al ., 1990) and substantia nigra (Beninato & Spencer, 1988; Oakman et al ., 1995), through which they modulate dopamine release in the limbic and motor regions of the basal ganglia (Blaha & Winn, 1993; Hernandez‐Lopez et al ., 1994). Mechanisms controlling the activity of MPCh neurons are not well understood, but the regulation of intracellular calcium ([Ca 2+ ] i ) is likely to be of considerable importance, as observed for many neurons (for review, see Ghosh & Greenberg, 1995).…”

Section: Introductionmentioning

confidence: 99%

Transmitter modulation of spike‐evoked calcium transients in arousal related neurons: muscarinic inhibition of SNX‐482‐sensitive calcium influx

Kohlmeier

Leonard

2006

Eur J of Neuroscience

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Nitric oxide synthase (NOS)-containing cholinergic neurons in the laterodorsal tegmentum (LDT) influence behavioral and motivational states through their projections to the thalamus, ventral tegmental area and a brainstem 'rapid eye movement (REM)-induction' site. Action potential-evoked intracellular calcium transients dampen excitability and stimulate NO production in these neurons. In this study, we investigated the action of several arousal-related neurotransmitters and the role of specific calcium channels in these LDT Ca(2+)-transients by simultaneous whole-cell recording and calcium imaging in mouse (P14-P30) brain slices. Carbachol, noradrenaline and adenosine inhibited spike-evoked Ca(2+)-transients, while histamine, t-ACPD, a metabotropic glutamate receptor agonist, and orexin-A did not. Carbachol inhibition was blocked by atropine, was insensitive to blockade of G-protein-coupled inward rectifier (GIRK) channels and was not inhibited by nifedipine, omega-conotoxin GVIA or omega-agatoxin IVA, which block L-, N- and P/Q-type calcium channels, respectively. In contrast, SNX-482 (100 nm), a selective antagonist of R-type calcium channels containing the alpha1E (Cav2.3) subunit, attenuated carbachol inhibition of the somatic spike-evoked calcium transient. To our knowledge, this is the first demonstration of muscarinic inhibition of native SNX-482-sensitive R-channels. Our findings indicate that muscarinic modulation of these channels plays an important role in the feedback control of cholinergic LDT neurons and that inhibition of spike-evoked Ca(2+)-transients is a common action of neurotransmitters that also activate GIRK channels in these neurons. Because spike-evoked calcium influx dampens excitability, our findings suggest that these 'inhibitory' transmitters could boost firing rate and enhance responsiveness to excitatory inputs during states of high firing, such as waking and REM sleep.

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Comparison of the behavioural effects of infusion of carbachol and acetylcholinesterase into the rat substantia nigra

Hawkins

Greenfield²

1996

Pharmacology Biochemistry and Behavior

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Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis

Cited by 13 publications

References 39 publications

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

Transmitter modulation of spike‐evoked calcium transients in arousal related neurons: muscarinic inhibition of SNX‐482‐sensitive calcium influx

Comparison of the behavioural effects of infusion of carbachol and acetylcholinesterase into the rat substantia nigra

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