c-Fos immunoreactivity of neural cells in intoxication due to high-dose methamphetamine

Abstract

Methamphetamine (METH) is a powerful and toxic psychostimulant that is abused worldwide. Although many studies of its toxic functions have been done on animals and humans, the mechanism is still poorly understood. In addition, the doses of METH examined have often been low. Here, we investigated the effects of intoxication due to administration of 20 mg/kg METH on neuronal activity. The mice showed hyperthermia and stereotyped behavior during 60 min after injection. We examined plasma stress hormone levels, which indicated that exposure to METH stimulated the hypothalamic-pituitary-adrenal (HPA) axis and caused release of stress hormones soon after injection. The maximum levels of adrenocorticotropic hormone and corticosterone occurred 10 and 60 min, respectively, after injection. We examined c-Fos protein in 16 different brain regions at 60 min post injection to identify potential brain regions subject to the stimulant effect. Nine regions, including the anterior hypothalamic area, medial preoptic area, lateral hypothalamic area, paraventricular thalamic nucleus, lateral anterior hypothalamic nucleus, lateral septum, striatum, nucleus accumbens, and amygdala, showed a significant increase in c-Fos expression, while the other seven regions did not. These results indicate that responsive neurons in the regions containing c-Fos immunoreactivity (Fos-IR) may undergo cellular reaction to high-dose METH administration. The present study provides support for a relationship among hyperthermia, the HPA axis and neuronal activities in limited brain regions on exposure to 20 mg/kg METH.

Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

“…Previous work argues against a direct relation between reduced circulating plasma CORT levels at time of testing and sensitivity to the interoceptive effects of alcohol (Besheer et al, 2012b); however, it is possible that the blunted accumbal (core) c-Fos response to alcohol in the CORT group may be directly related to decreased plasma CORT level. Indeed, there is support for a positive association between plasma CORT levels and c-Fos expression in the nucleus accumbens in response to drug administration (Badiani et al, 1998;Tomita et al, 2013). Interestingly, under control conditions (ie, after water administration) c-Fos IR in the core does not differ between the CORT and Water groups; however, we cannot discount the possibility that following alcohol administration a relation between plasma CORT levels and c-Fos expression may emerge.…”

Chronic Methamphetamine Self‐Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat

“…Interestingly, IVSA METH and yoked saline rats did not significantly differ in plasma CORT levels, nor in optical density of CRF‐IR fibres. Previous studies have shown increased plasma CORT levels , higher CRF levels in plasma and the amygdala , and increased CRF mRNA expression in the NAc after repeat exposure to psychostimulant drugs. By contrast, and in agreement with the findings of the present study, a lack of an effect on plasma CORT levels after repeated exposure to METH has also been reported .…”

“…This may be related to the time that CORT was measured because we and others collected plasma at least 24 h after the last self‐administration, extinction or reinstatement session, or last METH injection. In studies that found increased CORT levels, measurements were taken 1 and 2 h after METH injection . Indeed, Tomita et al .…”

“…This may be related to the time that CORT was measured because we and others (12,50) collected plasma at least 24 h after the last self-administration, extinction or reinstatement session, or last METH injection. In studies that found increased CORT levels, measurements were taken 1 and 2 h after METH injection (29). Indeed, Tomita et al (29) reported that plasma CORT levels peaked at 60 min after chronic METH administration, after which CORT levels gradually returned to basal levels.…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…In general, however, stress is likely to exacerbate the damaging effects of toxic substances via activation of the HPA axis (Jonhson et al, 2005). Indeed, recent studies have verified the stimulating effects of METH on the HPA axis and have provided evidence of neuronal c-Fos activation in specific brain regions by METH (Tomita et al, 2013). Interestingly, in the same study in mice it was demonstrated that HPA activation by METH is correlated with METH-induced hyperthermia (Tomita et al, 2013).…”