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Δ9-​tetrahydrocannabinol Prevents Methamphetamine-​induced Neurotoxicity


garyfisher

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PLoS One. 2014; 9(5): e98079.

 

Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties.  Heavy use increases the activation of neuronal nitric oxide synthase (nNOS)​, prodn. of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects.  Most METH recreational users also consume cannabis.  Preclin. 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 examg. 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 h apart) were pre- or post-​treated with Δ9-​THC (1 or 3 mg​/kg) and sacrificed 3 days after the last METH administration.  Semi-​quant. immunohistochem. 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 redn. 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, resp.

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