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, 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.

Fig. 1

Changes in brain and body temperatures induced by meth-amphetamine (9 mg/kg, sc) used under quiet resting conditions at 23°C (A), during social interaction with female at 23°C (B), and in a warm (29°C) environment (C). Recordings were made from the nucleus accumbens (NAcc), a representative brain structure, and the temporal muscle, non-motor head muscle that received arterial blood supply from the same source as the brain.

Fig. 2

Changes in several brain parameters (A, albumin-positive cells; B, GFAP-positive cells; C, tissue water; D, morphologically abnormal cells) during acute METH intoxication (9 mg/kg, sc) at normal (23°C) and warm (29°C) ambient temperatures.

Fig. 3

The relationships between brain temperatures and the numbers of albumin- and GFAP-positive cells (A) and tissue water (B) during acute METH intoxication. There was a tight correlation (r is coefficient of correlation) between changes in these parameters. Data are shown for cortex.

Fig. 4

The relationships between morphological abnormalities of cortical cells and brain and muscle temperatures (A), albumin- and GFAP-immunoreactivity (B), and tissue water (C) during acute METH intoxication (9 mg/kg, sc). Each graph shows coefficients of correlation and regression equations.

Fig. 5

The relationships between brain temperatures and several histochemical and morphological parameters (albumin, GFAP, cellular abnormalities) in pentobarbital-anesthetized rats passively warmed to different brain temperatures. Top graphs (A) show mean changes in the brain as a whole (sum of the cortex, thalamus, hippocampus, and hypothalamus) and bottom graphs (B) show changes in individual brain structures. Each point represents the value (ordinate) determined in rats at different brain temperature (abscissa).

Fig. 6

Dependence of tissue water content in the thalamus and cortex upon brain temperature. Data were obtained from pentobarbital-anesthetized rats passively warmed to different brain temperatures. Hatched lines show mean values of tissue water in the thalamus and cortex in awake rats maintained at quiet resting conditions.

Fig. 7

The relationships between different brain parameters (A, Albumin – tissue water; B, Albumin – GFAP; C, Albumin (GFAP) – abnormal cells; and D, Tissue water – abnormal cells) obtained in pentobarbital-anesthetized, passively warmed rats within ~10°C fluctuations in brain temperature (32–42°C).