Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity.

The adverse effects of amphetamine- (AMPH) and methamphetamine- (METH) induced hyperthermia on vasculature, peripheral organs and peripheral immune system are discussed. Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. Forebrain neurotoxicity can also be indirectly influenced through the effects of AMPH- and METH- induced hyperthermia on vasculature. The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. This BBB breakdown can occur in the amygdala, thalamus, striatum, sensory and motor cortex and hippocampus. Under these conditions, repetitive seizures greatly enhance neurodegeneration in hippocampus, thalamus and amygdala. Even when the BBB is less disrupted, AMPH- or METH- induced hyperthermia effects on brain vasculature may play a role in neurotoxicity. In this case, striatal and cortical vascular function are adversely affected, and even greater ROS, immune and damage responses are seen in the meninges and cortical surface vasculature. Finally, muscle and liver damage and elevated cytokines in blood can result when amphetamines produce hyperthermia. Proteins, from damaged muscle may activate the peripheral immune system and exacerbate liver damage. Liver damage can further increase cytokine levels, immune system activation and increase ammonia levels. These effects could potentially enhance vascular damage and neurotoxicity.