Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence.
Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.
Laboratory of Biochemistry and Neurosciences, Faculty of Sciences and Technics, Hassan 1er University, B.P. 577, Route of Casablanca, Settat, Morocco. oualid.ab@gmail.com.
Oualid
O
Abboussi
Department of Pharmacology, Faculty of Medicine, Hassan II University, 19 Rue Tarik Bnou Ziad, Casablanca, Morocco.
Nadia
N
Said
Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University, Medical Center, PO Box 9600, Mailbox S5-P, 2300 RC, Leiden, The Netherlands.
Karim
K
Fifel
Department of Pharmacology, Faculty of Medicine, Hassan II University, 19 Rue Tarik Bnou Ziad, Casablanca, Morocco.
Sara
S
Lakehayli
Department of Pharmacology, Faculty of Medicine, Hassan II University, 19 Rue Tarik Bnou Ziad, Casablanca, Morocco.
Abdelouahhab
A
Tazi
Laboratory of Biochemistry and Neurosciences, Faculty of Sciences and Technics, Hassan 1er University, B.P. 577, Route of Casablanca, Settat, Morocco.
Soumaya
S
El Ganouni
D000375:Aging; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009025:Morpholines / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology*; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000494:pharmacology*
D000814:Aniline Compounds; D002186:Cannabinoids; C493595:Drd3 protein, rat; D007189:Indans; D009025:Morpholines; D010880:Piperidines; D050637:Receptors, Dopamine D3; D058832:Serotonin 5-HT4 Receptor Antagonists; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333
5-HT4 receptors; Adolescence; Anxiety; Cannabinoids; D3 receptors; Memory