Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice.

Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder.

Alcohol-drinking during later life by C57BL/6J mice induces sex- and age-dependent changes in hippocampal and prefrontal cortex expression of glutamate receptors and neuropathology markers.

Heavy drinking can induce early-onset dementia and increase the likelihood of the progression and severity of Alzheimer's Disease and related dementias (ADRD). Recently, we showed that alcohol-drinking by mature adult C57BL/6J mice induces more signs of cognitive impairment in females versus males without worsening age-related cognitive decline in aged mice. Here, we immunoblotted for glutamate receptors and protein markers of ADRD-related neuropathology within the hippocampus and prefrontal cortex (PFC) of these mice after three weeks of alcohol withdrawal to determine protein correlates of alcohol-induced cognitive decline. Irrespective of alcohol history, age-related changes in protein expression included a male-specific decline in hippocampal glutamate receptors and an increase in the expression of a beta-site amyloid precursor protein cleaving enzyme (BACE) isoform in the PFC as well as a sex-independent increase in hippocampal amyloid precursor protein. Alcohol-drinking was associated with altered expression of glutamate receptors in the hippocampus in a sex-dependent manner, while all glutamate receptor proteins exhibited significant alcohol-related increases in the PFC of both sexes. Expression of BACE isoforms and phosphorylated tau varied in the PFC and hippocampus based on age, sex, and drinking history. The results of this study indicate that withdrawal from a history of alcohol-drinking during later life induces sex- and age-selective effects on glutamate receptor expression and protein markers of ADRD-related neuropathology within the hippocampus and PFC of potential relevance to the etiology, treatment and prevention of alcohol-induced dementia and Alzheimer's Disease.