Effects of M2 antagonists on in vivo hippocampal acetylcholine levels

Stillman, Michael J.; Shukitt‐Hale, Barbara; Galli, Rachel L.; Levy, Aharon; Lieberman, Harris R.

doi:10.1016/s0361-9230(96)00180-3

Cited by 30 publications

(14 citation statements)

References 25 publications

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“…A direct consequence of brain M2 autoreceptor inhibition is an elevation of acetylcholine release in the synaptic cleft. Methoctramine and other M2 receptor antagonists have been shown to enhance the release of acetylcholine in different brain structures (13,21,22). We demonstrate here that centrally administered M2 antagonist methoctramine significantly and dose-dependently decreases systemic TNF levels.…”

Section: Discussionmentioning

confidence: 51%

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov

Ochani

Gallowitsch-Puerta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

297

215

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TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this ''cholinergic antiinflammatory pathway'' inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. muscarinic receptors ͉ systemic inflammation ͉ TNF ͉ vagus nerve T he overproduction of cytokines, including TNF, mediates tissue damage during the response to injury or pathogenic invasion (1). Physiological and molecular mechanisms that control TNF production maintain cytokine homeostasis and minimize or prevent damage during the host response to infection, injury, arthritis, and other disorders (1-3). Recently, we found (4-6) that electrical or pharmacological activation of the efferent vagus nerve inhibits the release of TNF and attenuates the development of endotoxin-induced shock in rodents. Stimulation of the efferent vagus nerve activates the release of acetylcholine. Although the vagus nerve is a ''classical'' cholinergic regulator of visceral functions in which peripheral muscarinic acetylcholine receptors have a major mediating role, the vagusnerve cytokine-inhibiting activity (which is termed ''the cholinergic antiinflammatory pathway'') requires signaling through nicotinic ␣ 7 subunit-containing receptors (4, 5).Studies have implicated muscarinic receptor-dependent mechanisms in the central modulation and integration of vagal regulation of visceral functions. For example, vagus nerve control of glycogen synthesis in the liver, the Bezold-Jarish cardiovascular reflex and the regulation of exocrine pancreatic secretion are modulated centrally by brain muscarinic receptor mechanisms (7-10). Thus, we reasoned that brain muscarinic receptors could be involved in the central regulation of the vagus-nerve immunomodulatory function. Our results indicate that central cholinergic activation by selective muscarinic receptor ligands significantly inhibits systemic TNF in endotoxemic rats and activates th...

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Section: Discussionmentioning

confidence: 51%

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov

Ochani

Gallowitsch-Puerta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

297

215

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“…These effects are mainly attributed to M 2 receptor antagonism, whereas the involvement of M 1 or other muscarinic receptor activity is less obvious (Billard et al 1995;Stillman et al 1996). In this regard, it appears that M 1 receptor agonists invariably augment ACh release in the brain (Ogane et al 1990;Murakami et al 1996;Suzuki et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Effects of Typical and Atypical Antipsychotics and Receptor Selective Compounds on Acetylcholine Efflux in the Hippocampus of the Rat

Shirazi-Southall

2002

Neuropsychopharmacology

190

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Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as (MDL 100,907), the 5-HT 2C (SB 242,084), the 5-HT 6 KEY WORDS : Antipsychotic; Schizophrenia; Olanzapine; Clozapine; Microdialysis; Acetylcholine Impairments in cognitive processes, such as deficits in executive function, verbal memory and attention, are prevalent in most patients with schizophrenia (Breier 1999). Some atypical antipsychotic drugs appear to improve not only the positive symptoms, but also the negative symptoms and the cognitive deficits when compared with classical neuroleptics (Kinon and Lieberman 1996;Meltzer and McGurk 1999;Remington and Kapur 2000). For example, some atypical antipsychotic drugs have been shown to improve attention, motor and executive function in schizophrenic patients (Meltzer and McGurk 1999 NO . 5 cal and clinical studies have indicated that atypical antipsychotics, such as clozapine, olanzapine and risperidone, potently inhibit serotonin 5-HT 2 receptor function and affect a variety of other receptors in the brain (Meltzer et al. 1989;Leysen et al. 1992;Bymaster et al. 1996). In particular, clozapine and olanzapine show a complex pharmacological profile, being described as "multi-acting-receptor-targeted antipsychotic agents" (MARTAs) .Acetylcholine has been shown to be an important neurotransmitter in motor function, attention and various aspects of cognition. Cholinergic synapses are prevalent in many areas of the brain, including the striatum, the prefrontal cortex and the hippocampus. Neuronal processes within the hippocampus, in particular, mediate declarative memory, and participate in cognitive mapping in both experimental animals and humans (Eichenbaum et al. 1999). It appears likely therefore that a dysfunction in cholinergic neurotransmission within the hippocampus may be responsible for the cognitive impairments often encountered in schizophrenia. In turn, the beneficial effects of some atypical antipsychotic drugs in the treatment of cognitive deficits in schizophrenia may be related to their selective action on cholinergic function in the hippocampus, as a consequence of their multireceptor pharmacological profile.Earlier in vivo microdialysis experiments have revealed a selective action of clozapine on ACh outflow in limbocortical, dopaminergic regions of the brain, such as the prefrontal cortex, as compared with classical neuroleptics (Parada et al. 1997;Moore et al. 1999). In general, antipsychotic drugs appear to either increase or have no effect on ACh efflux within the striatum, a dopaminergic region of the brain related to...

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“…Scopolamine markedly elevates extrasynaptic ACh at the time of PA training mainly because of the blockade of presynaptic M 2 muscarinic receptors (Ö gren et al, 1996;Stillman et al, 1996). At the same time scopolamine blocks and scopolamine (0.2 mg/kg s.c.) 90 and 40 min before the training session, respectively.…”

Section: Discussionmentioning

confidence: 99%

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

Misane

Ögren

2003

Neuropsychopharmacol

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Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT 1A receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1) a functional 5-HT 1A receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2) the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT 1A receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease.

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Effects of M2 antagonists on in vivo hippocampal acetylcholine levels

Cited by 30 publications

References 25 publications

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Effects of Typical and Atypical Antipsychotics and Receptor Selective Compounds on Acetylcholine Efflux in the Hippocampus of the Rat

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

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