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.

Fig. 1

The effects of systemic scopolamine upon PR performance. a Scopolamine significantly enhances breakpoint. Scopolamine increases measures of general activity including b the rate of IR beam breaks and c non-target (blank) screen touches. d Scopolamine does not affect response rates. Error bars represent SEM. *p < 0.05; **p < 0.01

Fig. 2

The effects of systemic subtype-selective muscarinic receptor antagonists, biperiden (M1, a–e), telenzepine (M1, f–g) and tropicamide (M4, h, i) on PR performance. a Biperiden significantly increases breakpoint. b The duration of post-reinforcement pausing is reduced by biperiden administration. c Biperiden significantly affects response rates. d The rate of decay in responding is significantly reduced by biperiden. e Biperiden significantly reduces the pausing between response bouts. f Telenzepine has no effect on PR breakpoints. g Telenzepine does not affect the duration of post-reinforcement pausing. Tropicamide significantly increases both h breakpoint and i non-target screen responses. Error bars represent SEM. *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 3

Biperiden facilitates the behavioural effects of amphetamine on PR performance (a, b) and the effectiveness of scopolamine and biperiden in reversing a haloperidol-induced deficit in PR (c) and ERC performance (d, e). a The dose of amphetamine is represented by the graph fill, whereas the dose of biperiden is indicated by the graph pattern. Biperiden facilitates the enhancement in breakpoints caused by amphetamine but does not affect breakpoint when administered in isolation. b One milligram per kilogram biperiden does not enhance the general effect of amphetamine on IR beam breaks. c Scopolamine and biperiden successfully reverse a haloperidol-induced deficit on PR breakpoint. d Biperiden, but not scopolamine reverses a haloperidol-induced deficit on the trials completed in an ERC task. e Both scopolamine and biperiden reduce the chow consumed during ERC testing. a, b Amph: amphetamine; Bip: biperiden; all doses in mg/kg c–e Halo: haloperidol 0.1 mg/kg Scop: Scopolamine 0.3 mg/kg Bip: biperiden 3 mg/kg