title: Methamphetamine neurotoxicity increases brain expression and alters behavioral functions of CB₁ cannabinoid receptors.
abstract: Cannabis is the most common secondary illicit substance in methamphetamine (METH) users, yet the outcomes of the concurrent consumption of both substances remain elusive. Capitalizing on recent findings on the implication of CB₁ cannabinoid receptors in the behavioral effects of METH, we hypothesized that METH-induced neurotoxicity may alter the brain expression of CB₁, thereby affecting its role in behavioral functions. To test this possibility, we subjected rats to a well-characterized model of METH neurotoxicity (4 mg/kg, subcutaneous × 4 injections, 2 h apart), and analyzed their CB₁ receptor brain expression three weeks later. METH exposure resulted in significant enhancements of CB₁ receptor expression across several brain regions, including prefrontal cortex, caudate-putamen, basolateral amygdala, CA1 hippocampal region and perirhinal cortex. In parallel, a different group of METH-exposed rats was used to explore the responsiveness to the potent cannabinoid agonist WIN 55,212-2 (WIN) (0.5-1 mg/kg, intraperitoneal), within several paradigms for the assessment of emotional and cognitive functions, such as open field, object exploration and recognition, and startle reflex. WIN induced anxiolytic-like effects in METH-exposed rats and anxiogenic-like effects in saline-treated controls. Furthermore, METH-exposed animals exhibited a significantly lower impact of WIN on the attenuation of exploratory behaviors and short-term (90 min) recognition memory. Conversely, METH neurotoxicity did not significantly affect WIN-induced reductions in locomotor activity, exploration time and acoustic startle. These results suggest that METH neurotoxicity may alter the vulnerability to select behavioral effects of cannabis, by inducing distinct regional variations in the expression of CB₁ receptors.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles (CA), USA. bortolat@usc.edu
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.forename: Valentina
authors.initials: V
authors.lastname: Bini
authors.forename: William
authors.initials: W
authors.lastname: Luesu
authors.forename: Roberta
authors.initials: R
authors.lastname: Loriga
authors.forename: Maria
authors.initials: M
authors.lastname: Collu
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: M Grazia
authors.initials: MG
authors.lastname: Ennas
authors.forename: M Paola
authors.initials: MP
authors.lastname: Castelli
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D002421:Caudate Nucleus / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008694:Methamphetamine; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000523:psychology*; D017397:Prefrontal Cortex / Q000378:metabolism; D011699:Putamen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D000697:Central Nervous System Stimulants; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D008694:Methamphetamine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone