Coadministration of Galanin Antagonist M40 with a Muscarinic M₁Agonist Improves Delayed Nonmatching to Position Choice Accuracy in Rats with Cholinergic Lesions

Abstract

The neuropeptide galanin is overexpressed in the basal forebrain in Alzheimer's disease (AD). In rats, galanin inhibits evoked hippocampal acetylcholine release and impairs performance on several memory tasks, including delayed nonmatching to position (DNMTP). Galanin(1-13)-Pro2-(Ala-Leu)2-Ala-NH2 (M40), a peptidergic galanin receptor ligand, has been shown to block galanin-induced impairment on DNMTP in rats. M40 injected alone, however, does not improve DNMTP choice accuracy deficits in rats with selective cholinergic immunotoxic lesions of the basal forebrain. The present experiments used a strategy of combining M40 with an M1 cholinergic agonist in rats lesioned with the cholinergic immunotoxin 192IgG-saporin. Coadministration of intraventricular M40 with intraperitoneal 3-(3-S-n-pentyl-1,2,5-thiadiazol-4-yl)-1,2,5, 6-tetrahydro-1-methylpyridine (TZTP), an M1 agonist, improved choice accuracy significantly more than a threshold dose of TZTP alone. These results suggest that a galanin antagonist may enhance the efficacy of cholinergic treatments for the cognitive deficits of AD.

Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease

“…The deficits in learning and memory observed in GAL-tg mice are consistent with previous reports of memory loss induced by the central administration of galanin in rats and mice (17)(18)(19)(20)(21)(22)(23)(24). Selective deficits on the probe trial of the Morris water task are consistent with our earlier findings in Sprague-Dawley rats, in which intraventricularly administered galanin induced probe trial search deficits, following a normal acquisition curve for the visible and hidden platform training trials (24).…”

“…In hippocampal slices, galanin reduces long-term potentiation and cholinergically induced excitatory postsynaptic potentials (15,16). In rodents, the administration of galanin into the lateral ventricles, hippocampus, and medial septum͞diagonal band impairs performance during learning and memory tasks, including delayed nonmatching to position, the Morris water maze, T-maze delayed alternation, starburst radial maze, spontaneous alternation, and passive avoidance tests (17)(18)(19)(20)(21)(22)(23)(24).…”

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

“…M 1 receptor agonists have been reported to improve working memory in animals (Aura et al 1997;McDonald et al 1998) and xanomeline, a M 1 receptor agonist with minimal M 2 receptor blockade Shannon et al 1994Shannon et al , 2000, has also improved cognition, and decreased hallucinatory and delusional symptoms in Alzheimer's disease (Bodick et al 1997;Bymaster et al 1997) and perhaps schizophrenia, whereas M 1 receptor antagonists may worsen working memory in patients with schizophrenia (McEvoy 1987;Spohn and Strauss 1989;King 1990) and in animals (Bymaster et al 1993;Aura et al 1997;Roldan et al 1997). The atypical APD-induced cortical ACh release would be expected to increase M 1 receptor stimulation by diminishing M 1 receptor antagonism where it exists.…”

Galanin overexpressing transgenic mice

“…Galanin administered into the lateral ventricles and ventral hippocampus impairs performance on learning and memory tasks, including Tmaze delayed alternation, delayed nonmatching to position, Morris water maze, starburst maze, passive avoidance, and spontaneous alternation (reviewed in Crawley, 1995;McDonald et al, 1998a;O È gren et al, 1998;Wrenn and Crawley, 2001). Deleterious actions of galanin are particularly evident when cholinergic neurotransmission is reduced by treatment with the muscarinic antagonist scopolamine (Robinson et al, 1993) or lesions with a cholinergic immunotoxin (McDonald et al, 1998b).…”