Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.
Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively.
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, Cagliari, Italy.
M Paola
MP
Castelli
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Camilla
C
Madeddu
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Alberto
A
Casti
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Angelo
A
Casu
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Paola
P
Casti
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Maria
M
Scherma
CNR Institute of Neuroscience-Cagliari, National Research Council-Italy, Cittadella Universitaria di Monserrato, Cagliari, Italy.
Liana
L
Fattore
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, Cagliari, Italy; National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy.
Paola
P
Fadda
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
M Grazia
MG
Ennas
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D013759:Dronabinol / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats
D000697:Central Nervous System Stimulants; D018696:Neuroprotective Agents; D008694:Methamphetamine; D013759:Dronabinol; D052248:Nitric Oxide Synthase Type I