Facilitation of acetylcholine release and cognitive performance by an M(2)-muscarinic receptor antagonist in aged memory-impaired

Abstract

Aged memory-impaired (AI) and unimpaired (AU) 24–25-month-old Long- Evans rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possibly relate to cognitive disabilities. AI and AU rats were classified on the basis of their performance in the Morris swim maze task. Choline acetyltransferase activity (ChAT) was not differentially altered in various cortical and hippocampal areas between these two groups. Similarly, quantitative receptor autoradiography did not reveal significant differences in 3H-pirenzepine/muscarinic M1 and 3H- hemicholinium-3/high-affinity choline uptake binding sites in AI versus AU rats. In contrast, 3H-AF-DX 384/putative muscarinic M2 binding was significantly increased in certain cortical and hippocampal areas of the age-impaired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingly, the muscarinic M2 antagonist BIBN-99 reversed, in a dose-dependent manner, the impaired ACh release as well as the cognitive deficits observed in the AI group. Similarly, BIBN-99 reversed scopolamine-induced amnesia in young animals. The efficacy of BIBN-99 likely relates to its antagonistic properties on negative muscarinic M2 autoreceptors that are apparently increased in the AI animals, leading to altered ACh release. Taken together, these findings strengthen the role of ACh in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic functions, such as Alzheimer's disease.

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

“…benzodiazepin-6-one), a selective muscarinic M 2 receptor antagonist (Doods et al, 1993a,b) reported to enhance spatial learning in AI rats (Quirion et al, 1995), was synthesized in our laboratories and stored in a desiccator in powdered form. In behavioral experiments, AI rats treated with BI BN-99 were given an additional 3 d of training (three trials per day).…”

“…In behavioral experiments, AI rats treated with BI BN-99 were given an additional 3 d of training (three trials per day). On each of these days, a 0.5 mg / kg dose of BI BN-99 (in 0.9% NaC l, s.c.) or vehicle was administered 45 min before training began (Quirion et al, 1995). Performance during drug treatment was averaged for the entire 3 d testing period.…”

“…Spatial learning is particularly impaired in aged rats, but some aged subjects show severe deficits in spatial learning, whereas others are indistinguishable from young controls (Gage et al, 1984;Barnes and McNaughton, 1985;Deupree et al, 1991;Quirion et al, 1995;Backman et al, 1996). The basis for this variability is unknown, but it is well documented that spatial learning in rodents is strongly hippocampus dependent (Morris et al, 1982(Morris et al, , 1990Hollup et al, 2001).…”

Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors

“…For example Barnabi and Cechetto (2001) reported that VNS-induced excitation of insular cortex was attenuated by atropine (0.1 M) injected into the ventroposterior parvocellular nucleus of the thalamus, while higher doses (1.0 M) had no effect. Several other studies have demonstrated that muscarinic receptor blockade can increase the release of acetylcholine by preventing presynaptic m2 receptor activation (Quirion et al, 1995;Douglas et al, 2001). This may lead to muscarinic antagonist induced increases in nicotinic receptor activation further complicating any interpretation (Hasselmo and Sarter, 2011).…”

[Nphe1]‐Nociceptin (1‐13)‐NH2, a nociceptin receptor antagonist, reverses nociceptin‐induced spatial memory impairments in the Morris water maze task in rats

“…A circular pool, 160 cm in diameter, was used for Morris water maze experiments (Quirion et al, 1995). The pool was ®lled up with tap water, made opaque with powdered milk, and maintained at 22+18C.…”