Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats

Vannucchi, Maria Giuliana; Scali, Carla; Kopf, Silvia R.; Pepeu, Giancarlo; Casamenti, Fiorella

doi:10.1016/s0306-4522(97)00091-2

Cited by 93 publications

(71 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, it is most likely that the non-selective mAChR agonist oxotremorine decreased ACh release in the mPFC, NAC and STR via activation of inhibitory M 2 autoreceptors, as previously suggested for the STR Westerink et al 1990;Marshall and Wurtman 1993;Pramanik and Ögren 1993). On the other hand, scopolamine (0.5 mg/kg), a non-selective mAChR antagonist, which increased ACh release only in the mPFC, may have done so via blockade of M 2 autoreceptors in the mPFC ( Vannucchi et al 1997), and possibly the NBM as well, because direct administration of scopolamine (10 g) into the NBM was reported to increase cortical ACh release (Bertorelli et al 1991).…”

Section: Discussionmentioning

confidence: 72%

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Ichikawa

2002

Neuropsychopharmacology

228

124

View full text Add to dashboard Cite

The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, (Perry et al. 1999) and working memory (Winkler et al. 1995), and thus, may be important to either the cognitive dysfunction of schizophrenia or the ability of antipsychotic drugs (APDs) to improve some or all aspects of that cognitive deficit (Meltzer and McGurk 1999). The atypical APDs, clozapine, olanzapine, risperidone, and quetiapine, have, in fact, been reported to improve some domains of cognitive dysfunction (see Meltzer and McGurk 1999; Purdon 1999 for reviews), in addition to psychopathology (Leucht et al. 1999) in schizophrenia, more so than typical APDs, e.g., haloperidol and phenothiazines. The basis for these advantages is unclear.The atypical APDs share in common a relatively more potent antagonist action at serotonin (5-HT) 2A NO . 3 al. 1989;Schotte et al. 1996) and ␣ 1 -and ␣ 2 -adrenoceptors (Hertel et al. 1999). These features have been related to their ability to increase DA release in the mPFC (Hertel et al. 1999; Kuroki et al. 1999; Ichikawa et al. 2001). However, a possible role for ACh in mediating these effects is receiving increasing attention. Clozapine and olanzapine, but not risperidone, quetiapine, ziprasidone, or iloperidone (Schotte et al. 1996;Bymaster et al. 1999), have significant direct agonist or antagonist effects upon various subtypes of muscarinic ACh receptors (mAChRs) (Tandon 1999), whereas the typical APDs, thioridazine and mesoridazine, are also potent mAChR antagonists (Niedzwiecki et al. 1989a,b;Bolden et al. 1992). Furthermore, trihexyphenidyl and biperiden (Bolden et al. 1992), mAChR antagonists which reduce typical APD-induced extrapyramidal symptoms (EPS), have been reported to cause complex clinical effects in patients with schizophrenia, e.g., working memory impairment (King 1990) and worsening of psychosis while decreasing negative symptoms (Tandon et al. 1992). It is possible that clozapine and olanzapine influence clinical symptoms in schizophrenia via a direct effect upon main cholinergic transmission (Zorn et al. 1994; Bymaster et al. 1996).As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al. 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al. 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key ...

show abstract

Section: Discussionmentioning

confidence: 72%

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Ichikawa

2002

Neuropsychopharmacology

228

124

View full text Add to dashboard Cite

show abstract

“…Although the passive avoidance paradigm is a nonspecific aversive memory test that involves a number of brain structures, it exhibits well-documented validity in depicting memory impairments as a result of aging, or pharmacological and genetic manipulations. [42][43][44][45][46] Acquisition and/or retention in the passive avoidance test are dependent on the integrity of the hippocampal cholinergic pathway. 35,[42][43][44]47,48 M2-and M2/M4-KO mice, but not M4-KO mice, showed impaired memory retention in the passive avoidance paradigm.…”

Section: Discussionmentioning

confidence: 99%

“…[42][43][44][45][46] Acquisition and/or retention in the passive avoidance test are dependent on the integrity of the hippocampal cholinergic pathway. 35,[42][43][44]47,48 M2-and M2/M4-KO mice, but not M4-KO mice, showed impaired memory retention in the passive avoidance paradigm. These deficits were reminiscent of those produced by the nonselective muscarinic antagonist scopolamine or by ligands that impair cognition by dysregulating cholinergic neurotransmission at the level of the septohippocampal pathway.…”

Section: Discussionmentioning

confidence: 99%

“…These deficits were reminiscent of those produced by the nonselective muscarinic antagonist scopolamine or by ligands that impair cognition by dysregulating cholinergic neurotransmission at the level of the septohippocampal pathway. [42][43][44][45]49,50 Dysregulated acetylcholine release in response to environmental stimuli and deficits in the passive avoidance paradigm are not likely to be because of nonspecific phenotypic alterations such as hyperlocomotion in the KO mice. In fact, M4-KO mice that display increased basal locomotor activity 9 do not show deficits in the passive avoidance, whereas M2-KO mice, that perform poorly in the passive avoidance test, display normal locomotor activity (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

et al. 2003

View full text Add to dashboard Cite

Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post-and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2-and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2-and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

show abstract

“…The efficacy of BIBN-99 in aged but not young tissue implies that ACh, released either tonically or during theta stimulation, is a limiting factor for 5 Hz LTP induction in AI rats. In this regard, basal hippocampal ACh levels in situ are not only reduced in aged F344 rats, but both BIBN-99 and the structurally related M 2 blocker AF DX384 (Ϯ)-5,11 [2,3-b](1,4)-benzodiazepine-6-one) have been shown to elevate hippocampal ACh levels more robustly in aged than young subjects (Quirion et al, 1995;Vannucchi et al, 1997). Blockade of M 2 receptors on ACh terminals could facilitate ACh release and enhance pyramidal cell excitability via diverse postsynaptic mechanisms, including inhibition of the M-current and the sAHP (Brown and Adams, 1980;Pitler and Alger, 1990;Krause and Pedarzani, 2000;Krause et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Theta-Frequency Synaptic Potentiation in CA1In VitroDistinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats

et al. 2002

View full text Add to dashboard Cite

Hippocampal-dependent learning and memory deficits have been well documented in aging rodents. The results of several recent studies have suggested that these deficits arise from weakened synaptic plasticity within the hippocampus. In the present study, we examined the relationship between hippocampal long-term potentiation (LTP) in vitro and spatial learning in aged (24-26 months) Fischer 344 rats. We found that LTP induced in the CA1 region using theta-frequency stimulation (5 Hz) is selectively impaired in slices from a subpopulation of aged rats that had shown poor spatial learning in the Morris water maze. LTP at 5 Hz in aged rats that did not show learning deficits was similar to that seen in young (4-6 months) controls. We also found that 5 Hz LTP amplitude strongly correlated with individual learning performance among aged rats. The difference in 5 Hz LTP magnitude among aged rats was not attributable to an altered response to 5 Hz stimulation or to differences in the NMDA receptormediated field EPSP. In addition, no performance-related differences in LTP were seen when LTP was induced with 30 or 70 Hz stimulation protocols. Finally, both 5 Hz LTP and spatial learning in learning-impaired rats were enhanced with the selective muscarinic M 2 antagonist ]benzodiazepin-6-one). These findings reinforce the idea that distinct types of hippocampal LTP offer mechanistic insight into age-associated cognitive decline.

show abstract

Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats

Cited by 93 publications

References 36 publications

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

Theta-Frequency Synaptic Potentiation in CA1In VitroDistinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats

Contact Info

Product

Resources

About