Effects of selective allosteric activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats Público

Abstract

Rationale Acetylcholine (ACh) signaling through muscarinic receptors (mAChRs) has been shown to benefit memory performance in some conditions, but pan-mAChR activation also frequently leads to peripheral side effects. Drug therapies that selectively target M1 or M4 muscarinic receptors may alleviate disease-related memory impairments while minimizing side effects mediated by the other muscarinic receptor subtypes. In healthy individuals, the beneficial range of M1 or M4 activation may be narrow and variable, which highlights the importance of considering individual differences in baseline performance when evaluating the efficacy of cholinergic drugs for improving memory performance.

Objectives We tested the ability of three recently developed drugs that selectively activate M1 or M4 receptors at allosteric sites to improve performance of rats on an object recognition memory task above baseline.

MethodsLong-Evans rats were given subcutaneous (s.c.) injections of three different doses of each the M1 allosteric agonist VU0364572, the M1 positive allosteric modulator (PAM) BQCA, or the M4 PAM VU0152100 before performing an object recognition memory task. Each rat also completed three different sessions with 0.9% saline s.c. injections to establish baseline performance.

ResultsThe lowest dose (3.0 mg/kg) of VU0152100 markedly improved memory performance of rats who performed poorly at baseline. Rats' general tendency to explore novel objects was not altered in any drug condition.

Conclusions Drug therapies that selectively target M4 receptors may improve memory performance in individuals with impaired memory.

Table of Contents

Introduction.............................................................. 1

Method..................................................................... 4

Subjects......................................................... 4

Drugs............................................................. 4

Procedure 5

Results..................................................................... 8

Discussion.............................................................. 10

References............................................................. 16

Figures.................................................................... 32

Figure 1: Task schematic............................. 33

Figure 2: Mean discrimination index............. 34

Figure 3: Mean study exploration................. 35

About this Master's Thesis

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School	Laney Graduate School
Department	Psychology
Degree	MA
Submission	Master's Thesis
Language	English
Research Field	Psychology, Psychobiology
Palavra-chave	acetylcholine receptor muscarinic memory schizophrenia baseline performance Alzheimer's disease
Committee Chair / Thesis Advisor	Manns, Joseph, Emory University
Committee Members	Wolff, Phillip, Emory University Hampton, Robert, Emory University

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