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other·ophthalmology, neurology, toxicology, public health, pharmacology·PMC10272271

MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201

Psychopharmacology · 13 authors, 6 centres

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FIDELITY 76%

POPULATIONMale ICR (CD-1) mice, 3-4 months old, weighing 25-30 g

INTERVENTIONAcute intraperitoneal administration of MAM-2201 (0.01-6 mg/kg) or AM-2201 (0.01-1 mg/kg)

COMPARISONVehicle (ethanol/Tween 80/saline) and, for antagonism studies, pretreatment with AM-251 (6 mg/kg i.p.)

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TL;DR

MAM-2201, a synthetic cannabinoid found in 'spice' products, potently impairs sensorimotor reflexes, motor activity, sensory gating, and short- and long-term memory in mice, with effects mediated by CB1 receptors. These deficits occur at doses that do not always affect locomotion, indicating specific cognitive and sensory disruption. The findings highlight significant public health risks, particularly for driving and occupational safety.

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**Background:** Synthetic cannabinoids (SCs) like MAM-2201 and its analogue AM-2201 are potent CB1/CB2 receptor agonists found in 'spice' products and 'synthacaine'. Despite reports of intoxication, impaired driving, and psychotic symptoms, the in vivo pharmacodynamic profile of MAM-2201 was poorly characterized. This study aimed to compare the in vitro and in vivo effects of MAM-2201 and AM-2201 in mice, focusing on sensorimotor, motor, sensory gating, and memory functions.

**Methods:** In vitro, competition binding and cAMP assays were performed on human and murine CB1/CB2 receptors. In vivo, male CD-1 mice received acute i.p. injections of MAM-2201 (0.01–6 mg/kg) or AM-2201 (0.01–1 mg/kg). Sensorimotor tests (visual object, visual placing, acoustic, tactile reflexes) were assessed over 5 h. Spontaneous locomotion was measured via ANY-maze for 240 min. Prepulse inhibition (PPI) of acoustic startle was tested at 15 and 120 min post-injection. Novel object recognition (NOR) memory was evaluated at 2 h (short-term) and 24 h (long-term) after drug administration. Antagonism studies used AM-251 (6 mg/kg) 20 min before MAM-2201.

**Key Results:** In vitro, both compounds showed nanomolar affinity for CB1 and CB2 receptors, with MAM-2201 slightly higher (e.g., human CB1 Ki = 1.11 ± 0.12 nM vs. 1.66 ± 0.13 nM for AM-2201). In vivo, MAM-2201 dose-dependently impaired all sensorimotor responses (e.g., visual object: F5,336=376.2, p<0.0001; acoustic: F5,336=297.2, p<0.0001; tactile: F5,336=404.4, p<0.0001). ED50 values for MAM-2201 were lower than AM-2201 for visual object (1.140 vs. 1.976 mg/kg), visual placing (0.291 vs. 0.500 mg/kg), and overall tactile (1.861 vs. 2.120 mg/kg). AM-251 fully prevented these impairments (p<0.001). MAM-2201 (1 and 6 mg/kg) reduced distance traveled and increased immobility time (F4,720=12.95, p<0.0001). PPI was significantly reduced at 0.1 and 1 mg/kg at 15 and 120 min (e.g., 68 dB prepulse: F3,36=11.38, p<0.0001). NOR memory was impaired at 2 h and 24 h for both compounds (MAM-2201: F3,36=45.99, p<0.0001 at 2 h; AM-2201: F3,36=56.13, p<0.0001 at 2 h), with RI reversal at 1 mg/kg. Total object exploration was reduced only at 1 mg/kg.

**Clinical Implications:** MAM-2201 produces profound, CB1-mediated deficits in sensorimotor processing, motor coordination, sensory gating, and working memory in mice, often at doses that spare general locomotion. These effects mirror human intoxication cases (e.g., impaired driving, confusion, motor skill disturbance). The long-lasting memory impairment (up to 24 h) and PPI disruption suggest risks for psychosis and cognitive dysfunction. The findings underscore the public health burden of SCs, particularly for driving under the influence and occupational safety, where even low doses may impair critical functions without obvious motor sedation.

PICO

PPOPULATION

Male ICR (CD-1) mice, 3-4 months old, weighing 25-30 g

IINTERVENTION

Acute intraperitoneal administration of MAM-2201 (0.01-6 mg/kg) or AM-2201 (0.01-1 mg/kg)

OOUTCOME

Sensorimotor responses (visual, acoustic, tactile), spontaneous locomotor activity (distance traveled, immobility time), prepulse inhibition (PPI) of acoustic startle, and novel object recognition (NOR) memory (recognition index at 2 h and 24 h)

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

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76% · B

ORIGINAL PAPER

PMC10272271

MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201

Psychopharmacology

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ABSTRACT

Rationale 1-[(5-fluoropentyl)-1 H -indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in “spice” products and as “synthacaine” for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1 H -indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption. Objectives This study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201. Results In vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB 1 and CB 2 receptors, with preference for the CB 1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB 1 receptor antagonist/partial agonist AM-251, indicating a CB 1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory. Conclusion These findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance.

CITATION EXPORT

Giorgia Corli, Micaela Tirri, Sabrine Bilel et al.. MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201. Psychopharmacology. (2023). https://doi.org/10.1007/s00213-023-06378-8

AUTHORS

13 · 6 CENTRES

Giorgia Corli, Micaela Tirri, Sabrine Bilel, Raffaella Arfè, Teresa Coccini, Elisa Roda, Beatrice Marchetti, Fabrizio Vincenzi, Giorgio Zauli, Pier Andrea Borea, Carlo Alessandro Locatelli, Katia Varani, Matteo Marti

1grid.8484.00000 0004 1757 2064Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, Via Fossato Di Mortara 17-19, 44121 Ferrara, Italy
2grid.511455.1Laboratory of Clinical and Experimental Toxicology, and Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 10, 27100 Pavia, Italy
3grid.8484.00000 0004 1757 2064Department of Translational Medicine, University of Ferrara, Ferrara, Italy
4Research Department, King Khaled Eye Specialistic Hospital, Riyadh, Saudi Arabia
5grid.8484.00000 0004 1757 2064University of Ferrara, Ferrara, Italy
6Department of Anti-Drug Policies, Collaborative Center for the Italian National Early Warning System, Presidency of the Council of Ministers, Ferrara, Italy