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

Abstract

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.

Keywords: amphetamine; blood-brain barrier; cerebral vasculature; hyperthermia; immune system; meninges; methamphetamine; neurotoxicity.

Figure 1.

The effect of amphetamine (AMPH) on body temperature compared to environmentally-induced hyperthermia (EIH) and normothermic controls. The results of one of the more recent studies in the authors’ laboratory compares the hyperthermia observed during neurotoxic exposures to AMPH with that produced by EIH, which is very similar to heat stroke. The temperature profiles of animals given either 4 doses of either AMPH (n = 10) or normal saline (normothermic controls n = 9) s.c. at an environmental temperature of 22.5°C are shown. Their temperature profiles are compared to 2 groups of animals given 4 doses of saline in an infant incubator held at either 38°C to 39°C (ave. ≈38.5, n = 6) or 39°C to 40°C (ave. ≈39.5, n = 4) which induced hyperthermia (EIH). Animals at the higher incubator temperature became hyperthermic much more rapidly and as a group had slightly higher peak temperatures. They all had ataxia and hind limb dysfunction for 2 to 8 h after cooling. The second group of EIH animals at the lower 38.5°C temperature had a temperature profile almost identical to the AMPH group. The variability of the body temperatures of the AMPH group and the 38.5°C EIH group after the 3 h time point was due to cooling on ice to prevent death. The 39.5°C EIH group was not subjected to any further hyperthermia after 4 h since it would have been lethal (previous studies in the authors’ laboratory).