Environmental Conditions Modulate Neurotoxic Effects of Psychomotor Stimulant Drugs of Abuse

Abstract

Psychomotor stimulants such as methamphetamine (METH), amphetamine, and 3,4-Metylenedioxymethamphetamine (MDMA or ecstasy) are potent addictive drugs. While it is known that their abuse could result in adverse health complications, including neurotoxicity, both the environmental conditions and activity states associated with their intake could strongly enhance drug toxicity, often resulting in life-threatening health complications. In this review we analyze results of animal experiments that suggest that even moderate increases in environmental temperatures and physiological activation, the conditions typical of human raves parties, dramatically potentiate brain hyperthermic effects of METH and MDMA. We demonstrate that METH also induces breakdown of the blood-brain barrier (BBB), acute glial activation, brain edema, and structural abnormalities of various subtypes of brain cells; these effects are also strongly enhanced when the drug is used at moderately warm environmental conditions. We consider the mechanisms underlying environmental modulation of acute drug neurotoxicity and focus on the role of brain temperature, a critical homeostatic parameter that could be affected by metabolism-enhancing drugs and environmental conditions and affect neural activity and functions.

5-HT2C serotonin receptor blockade prevents tau protein hyperphosphorylation and corrects the defect in hippocampal synaptic plasticity caused by a combination of environmental stressors in mice

“…Perhaps, tau phosphorylation in the CA3 region is already saturated in response to stress, whereas exposure to stress unmasks a detrimental effect of low doses of MDMA in the CA1 region. This synergism is in line with a large body of evidence showing that environmental conditions have a strong impact on MDMA intoxication [16,17,22,23]. Of note, 12.5 mg/kg in mice roughly correspond to 50 mg of MDMA in humans [29], which is below the dose of ecstasy typically taken by drug abusers.…”

“…For example, acute injection of MDMA in mice, at doses that are roughly equivalent to those recreationally used by humans, causes a transient hippocampal dysfunction and memory deficit, which depends on the inhibition of the Wnt pathway, with ensuing activation of glycogen synthase kinase-3␤ (GSK-3␤), and increased phosphorylation of tau protein [13]. The harmful effects of environmental stressors are only considered within the context of their association with drugs of abuse because loud noise, bright lights, densely packed crowds of dancers, and high ambient temperature are known to amplify the neurotoxic effects of MDMA and other club drugs [14][15][16][17][18][19][20][21][22][23]. An important question is whether combined sensory and physical stressors may cause learning impairment and cognitive dysfunction on their own, and whether the underlying mechanisms are drug targetable.…”

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes

“…Neurotoxic outcomes of METH abuse and HIV-1 CNS infection include, but are not limited to: brain hyperthermia, release of inflammatory mediators and reactive oxygen species (ROS), excitotoxicity, and astrogliosis (Cisneros and Ghorpade, 2012; Kiyatkin and Sharma, 2012; Rippeth et al, 2004); however, the molecular basis for these effects remains elusive. Additionally, as the most abundant cells of the CNS, astrocytes are a significant cell type affected by peripheral stimuli, such as METH and HIV-1.…”

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress

“…In support of this hypothesis, methamphetamine exposure and withdrawal has been reported to increase the permeability of the blood brain barrier to otherwise impermeable binding proteins (Kiyatkin and Sharma, 2012; Sharma and Ali, 2006). Furthermore, failure to show differences in bound steroid in the plasma, as in the current study, does not preclude increased binding protein in the cerebrospinal fluid (Schwarz and Pohl, 1994).…”