Meth math: modeling temperature responses to methamphetamine

Abstract

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

Amphetamine enhances endurance by increasing heat dissipation

“…), which is similar to what we suggested as a possible mechanisms of inhibitory component in the thermoregulatory effects of methamphetamine (Molkov et al. ).…”

“…Recently we published experimental and modeling data on extremely complex dose dependence of temperature effects of methamphetamine (Molkov et al. ). Our interpretation was that in doses exceeding 1 mg/kg methamphetamine activated an inhibitory component, which reversed effects of excitatory influence of lower doses on heat production.…”

Investigation of Two Seized Crystal Meth Labs in Austria – Parameters and Chirality Aspects of Methamphetamine Low Scale Synthesis

“…Negative side effects of methamphetamine can be hyperthermia [9], tremor, irregular heartbeat, high blood pressure, sweating, rapid breathing, anorexia, depression, psychosis, insomnia and fast aging of the body. The risk to develop other diseases or even to die e.g.…”

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats

“…In a second study to evaluate the rescue effect of agmatine, agmatine was administered 15 min after methamphetamine administration. The dose of methamphetamine was 10 mg/kg because this dose produced reliable hyperthermia in rats (Molkov et al , 2014). …”