Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation

Abstract

Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels.

Effects of muscarinic M1receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

“…Rather, the delayed effect is similar to the effect of removing the cocaine syringe in this assay [34], consistent with VU0364572 gradually reducing (removing) cocaine's reinforcing effects. Increased reinforcing effect of the food is unlikely to account for the effects, since we never observed increased food-reinforced operant behavior after M 1 receptor stimulation [22,26,33], and others reported increased food-reinforced behavior after blocking M 1 receptors [35].…”

“…VU0364572 treatment significantly blunted the cocaine-stimulated increase in extracellular NAc dopamine in both cocaine-naïve [F(1,10]=62.9, p<0.0001] and cocaine-experienced [F(1,10]=6.13, p=0.03] rats, but with different efficacy. In the cocaine-naïve animals, prior VU0364572 treatment completely blocked the dopamine increase, while the cocaine-experienced animals still showed a significant dopamine increase [F (7,35)=6.98, p<0.0001]. Fig.…”

“…Acute cocaine administration increased NAc glutamate levels in vehicle-and VU0364572treated cocaine-naïve rats ([F (7,35)=5.91, p=0.0001] and [F (7,35)=4.07, p=0.002], respectively) and in vehicle-treated cocaine-experienced rats [F(7,35)=2.59, p=0.03], but the increase was completely abolished in the VU0364572-treated cocaine-experienced rats (Fig. 4J).…”

Pharmacologic Approaches for the Management of Apathy in Neurodegenerative Disorders

“…Additionally, recent animal studies showed interests in using different pharmacologic targets such as antagonist of muscarinic acetylcholine receptors (Hailwood et al, 2019) or selective 5-HT2C receptor ligand (Bailey et al, 2018) to enhance amotivation and goal-oriented behaviors.…”

Deciphering the scopolamine challenge rat model by preclinical functional MRI

“…The muscarinic cholinergic antagonist SCO is frequently used to model various aspects of cognitive dysfunction during early drug development [6]. Recently though, the facilitation of motivated behavior was demonstrated by SCO that was able to rescue antipsychotic-induced motivational impairments [26]. An important aspect of the “SCO challenge” model is, that it could also result in an increased release of acetylcholine in the brain by blocking presynaptic muscarinic receptors.…”