Methamphetamine neurotoxicity increases brain expression and alters behavioral functions of CB₁ cannabinoid receptors.
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.
Bortolato
Marco
M
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles (CA), USA. bortolat@usc.edu
Frau
Roberto
R
Bini
Valentina
V
Luesu
William
W
Loriga
Roberta
R
Collu
Maria
M
Gessa
Gian Luigi
GL
Ennas
M Grazia
MG
Castelli
M Paola
MP
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
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