Effects of the cannabinoid receptor 1 positive allosteric modulator GAT211 and acute MK-801 on visual attention and impulsivity in rats assessed using the five-choice serial reaction time task

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 109; p. 110235
• Main Authors: Onofrychuk, Timothy J., Cai, Shuang, McElroy, Dan L., Roebuck, Andrew J., Greba, Quentin, Garai, Sumanta, Thakur, Ganesh A., Laprairie, Robert B., Howland, John G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 13.07.2021
• Subjects: 5CSRT task; Allosteric modulator; Animals; Attention - drug effects; Behavior, Animal - drug effects; Cannabinoid Receptor Agonists - pharmacology; Choice Behavior - drug effects; Dizocilpine Maleate - pharmacology; Endocannabinoid system; Excitatory Amino Acid Antagonists - pharmacology; Impulsive Behavior - drug effects; Indoles - pharmacology; Male; Rats; Rats, Long-Evans; Reaction Time - drug effects; Touchscreen; Visual Perception - drug effects; 5CSRT task; Touchscreen; Endocannabinoid system; Allosteric modulator
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2020.110235

Altered interactions between endocannabinoid and glutamate signaling may be involved in the pathophysiology of schizophrenia and acute psychosis. As cognitive disturbances are involved in schizophrenia, increased understanding of the roles of these neurotransmitter systems in cognition may lead to the development of novel therapeutics for disorder. In the present study, we examined the effects of a recently synthesized cannabinoid receptor 1 (CB1R) positive allosteric modulator GAT211 in a rodent model of acute psychosis induced by systemic treatment with MK-801. To assess cognitive function, we used the Five-Choice Serial Reaction Time (5CSRT) task, conducted in touchscreen-equipped operant conditioning chambers. Our measures of primary interest were accuracy – indicative of visual attentional capacity – and the number of premature responses – indicative of impulsivity. We also measured latencies, omissions, and perseverative responding during all test sessions. Thirteen adult male Long Evans rats were trained on the 5CSRT and were then tested using a repeated measures design with acute MK-801 (0 or 0.15 mg/kg, i.p.) and GAT211 (0, 3, or 10 mg/kg, i.p.) administration. Acute MK-801 severely impaired accuracy, increased omissions, and increased the number of premature responses. MK-801 also significantly increased correct response latencies, without significant effects on incorrect or reward correction latencies. GAT211 had no significant effects when administered alone, or in combination with acute MK-801. These data confirm the dramatic effects of acute MK-801 treatment on behavioral measures of attention and impulsivity. Continued investigation of CB1R positive allosteric modulators as potential treatments for the cognitive symptoms of schizophrenia and related disorders should be pursued in other rodent models. •Acute MK-801 decreased accuracy and increased premature responding in the five choice serial reaction time task.•The cannabinoid 1 receptor positive allosteric modulator GAT211 did not affect task performance.•GAT211 did not affect the disruption in task performance cause by MK-801.•These findings are discussed in the context of the cognitive deficits observed in schizophrenia.