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.

Methamphetamine induces long-term alterations in reactivity to environmental stimuli: correlation with dopaminergic and serotonergic toxicity.

Methamphetamine (METH) abuse is known to induce persistent cognitive and behavioral abnormalities, in association with alterations in serotonin (5-HT) and dopamine (DA) systems, yet the neurobiological mechanisms underpinning this link are elusive. Thus, in the present study we analyzed the long-term impact of an acute toxic regimen of METH (4 mg/kg, subcutaneous x 4 injections, 2 h apart) on the reactivity of adult male rats to environmental stimuli, and correlated it to toxicity on 5-HT and DA innervations. Two separate groups of METH-injected rats were compared to their saline-treated controls on object exploration and startle paradigms, at either 1 or 3 weeks after METH administration, respectively. Twenty-four hours after behavioral testing, animals were sacrificed, and the neurotoxic effects of the METH schedule on DA and 5-HT terminals were measured through immunochemical quantification of their transporters (DAT and 5-HTT). At both 1 and 3 weeks after treatment, METH-injected rats exhibited a significant decline in the number of exploratory approaches to unfamiliar objects, which was significantly correlated with a parallel reduction in DAT immunoreactivity (IR) in the nucleus accumbens (NAc) core. Furthermore, METH-treated rats displayed a significant enhancement in startle magnitude after 3 (but not 1) weeks, which was inversely correlated with a decrement in 5-HTT IR in the Cg3 infralimbic area of prefrontal cortex. Our results suggest that METH induces long-term changes in object exploration and startle responsiveness, which may be respectively underpinned by reductions in DAergic and 5-HTergic brain terminals.

6-Hydroxydopamine lesion in the ventral tegmental area fails to reduce extracellular dopamine in the cerebral cortex.

Dopamine and noradrenaline are both involved in modulation of superior cognitive functions that are mainly dependent on frontal cortex activity. Experimental evidence points to parallel variations in extracellular concentrations of catecholamines in the cerebral cortex, which leads us to hypothesize their corelease from noradrenergic neurons. This study aimed to verify this hypothesis, by means of cerebral microdialysis following destruction of dopaminergic innervation in rats. The unilateral injury of dopaminergic neurons, by 6-hydroxydopamine injection in the ventral tegmental area, dramatically reduced the immunoreactivity for dopamine transporter in the cerebral hemisphere ipsilateral to the lesion. Tissue dopamine content in the ipsilateral nucleus accumbens and medial prefrontal and parietal cortex was also profoundly decreased, whereas noradrenaline was only slightly affected. Despite the lower tissue content in the denervated side, the extracellular dopamine level was not changed in the cortex, although it was markedly decreased in the nucleus accumbens ipsilateral to the lesion. The effect of drugs selective for D(2)-dopaminergic (haloperidol) or alpha(2)-noradrenergic (RS 79948) receptors was verified. Haloperidol failed to modify extracellular dopamine in either cortex but increased it in the nucleus accumbens, such an increase being greatly reduced in the denervated side. On the other hand, RS 79948 increased extracellular dopamine and DOPAC in all areas tested, the increases being of the same degree in both intact and lesioned sides. The results strongly support the hypothesis that the majority of extracellular dopamine in the cortex, unlike that in the nucleus accumbens, originates from noradrenergic terminals.