Dan L McElroy1, Andrew J Roebuck2, Gavin A Scott3, Quentin Greba1, Sumanta Garai4, Eileen M Denovan-Wright5, Ganesh A Thakur4, Robert B Laprairie5,6, John G Howland7. 1. Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada. 2. Yukon University, Whitehorse, YT, Y1A 5K4, Canada. 3. Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada. 4. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. 5. Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada. 6. College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, S7N 2Z4, Canada. 7. Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada. john.howland@usask.ca.
Abstract
RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS: GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS:GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
Authors: Jan Brosda; Linda Hayn; Charlotte Klein; Michael Koch; Cora Meyer; Rieka Schallhorn; Nico Wegener Journal: Pharmacol Biochem Behav Date: 2011-04-05 Impact factor: 3.533
Authors: Amina M Bagher; Robert B Laprairie; J Thomas Toguri; Melanie E M Kelly; Eileen M Denovan-Wright Journal: Eur J Pharmacol Date: 2017-07-19 Impact factor: 4.432