(+)‐Methamphetamine‐induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia

Abstract

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a one-day binge regimen of MA (10 mg/kg × 4 at 2 h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h was determined. SHAM-MA animals showed typical patterns of hyperthermia whereas ADX-MA animals were normothermic. SHAM-MA and ADX-MA treated animals both showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA and ADX-MA treated groups showed equivalently impaired CWM impairments two weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72 h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.

Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats

“…This finding is consistent with data that drugs that target DA systems and produce decreases in DA levels affect CWM performance, while drugs that preferentially act on 5-HT do not (Herring et al, 2008;Herring et al, 2010;Vorhees et al, 2010b). However, drugs such as methamphetamine affect DA, 5-HT, and glutamate making it unclear which mechanism contributes most to the effect of the drug on route-based navigation.…”

“…CWM deficits are observed under infrared conditions following exposure to drugs that reduce the levels of neostriatal dopamine (DA) (i.e., (+)-methamphetamine and (+)-amphetamine), but not to drugs that primarily reduce the levels of forebrain serotonin (5-HT) (i.e., (±)-3,4-methylenedioxymethampetamine (MDMA) or (±)-fenfluramine) (Herring et al, 2008;Herring et al, 2010;Vorhees et al, 2010a). These data suggest that route-based navigation may be predominately mediated by dopaminergic neurons in the neostriatum.…”

Acute Effects of 3,4-Methylenedioxymethamphetamine and Methylphenidate on Circulating Steroid Levels in Healthy Subjects

“…Corticosteroids may also facilitate the development of hyperthermia associated with amphetamines, a potentially fatal complication of recreational ecstasy use [54,55]. In rats, adrenalectomy or administration of a glucocorticoid receptor antagonist suppressed methamphetamine- and MDMA-induced increases in body temperature [56,57,58]. Human data are lacking, but MDMA-induced elevations of steroids may contribute to the clinical toxicity of ecstasy [16,29].…”

Long-term effects of exposure to methamphetamine in adolescent rats

“…Preclinical models of mAMPH exposure have been crucial in our understanding of the mechanisms by which mAMPH can lead to such impairments. Administration of either binge or escalating dose mAMPH in adult rats results in a broad array of learning and memory impairments (Belcher et al, 2005; Clark et al, 2007; Herring et al, 2010; Reichel et al, 2012; Kosheleff et al, 2012). …”