Synaptic remodeling of GluA1 and GluA2 expression in the nucleus accumbens promotes susceptibility to cognitive deficits concomitant with downstream GSK3ß mediated neurotoxicity in female mice during abstinence from voluntary oral methamphetamine.

Stimulant-use disorders can present with long-term cognitive and mental health deficits. Little is known about the underlying molecular mechanisms perpetuating sex differences in cognitive and behavioral deficits in preclinical models of addiction to stimulants such as methamphetamine (MA). The current study investigated the neurochemical shifts underlying sex disparities in MA-induced working memory deficits and an addictive phenotype following abstinence from chronic MA abuse. We used our previously reported mouse model of voluntary oral methamphetamine administration (VOMA) consisting of an acquisition phase (days 1-14) characterized by escalating doses of MA and a binge phase (days 14-28) characterized by static doses. Female VOMA mice exhibited sustained MA consumption during the binge phase, demonstrating sex-specific vulnerabilities to the maintenance of MA addiction. The 8-arm radial maze was used to test spatial working memory performance following abstinence from VOMA. Results indicate working memory deficits correlated to higher MA consumption in females only. Hippocampal and accumbal tissue were collected and analyzed by immunoblotting. Female VOMA mice had decreased GluA1, but not GluA2, in the hippocampus, which may perpetuate synaptic destabilization and working memory deficits. Female-specific increases in GluA1 and p-GSK3ß expression in accumbal tissue suggest vulnerability toward abstinence-induced drug craving and heightened downstream neurotoxicity. Our study reveals female-specific neurochemical shifts in hippocampal and accumbal AMPA receptor signaling following abstinence from chronic MA consumption that may perpetuate female susceptibility to MA-induced cognitive deficits. These data demonstrate a novel molecular pathway that would exacerbate memory deficits and perpetuate an addictive phenotype in female populations following MA abuse.

Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice.

BACKGROUND: Female populations exhibit vulnerabilities to psychostimulant addiction, as well as cognitive dysfunction following bouts of abuse. AIMS: The goal for this study was to advance our understanding of the mechanisms that produce sex disparities in drug addiction. METHODS: We used an animal model for voluntary oral methamphetamine administration (VOMA) and focused on male and female mice that consumed 7.6-8.2 mg/kg of methamphetamine (MA) per day during the last 18 days of the paradigm. RESULTS: The VOMA-exposed female mice displayed increased locomotor activity in the drug-administration context compared to male mice, demonstrating sex-specific changes in contextual sensitization. During 2 weeks of forced abstinence, mice underwent further behavioral testing. We show that abstinence increased open-arm entries on the elevated plus maze in both sexes. There were no differences in immobility on the tail suspension test. In a hippocampal-dependent radial arm maze task, VOMA-treated female mice, but not male mice, showed working memory deficits. Hippocampal tissue was collected and analyzed using Western blotting. VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria. Female VOMA mice also exhibited a decrease in the memory protein marker, protein kinase M zeta (PKMζ), in the hippocampus. CONCLUSIONS: Our study reveals sex-specific effects following abstinence from chronic MA consumption on hippocampal κOR and PKMζ expression, suggesting that these neural changes in female mice may underlie spatial memory deficits and identify an increased susceptibility to dysregulated neural mechanisms. These data validate VOMA as a model sensitive to sex differences in behavior and hippocampal neurochemistry following chronic MA exposure.

Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases.

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19- and MHCI- The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.

Endocannabinoid influence on partner preference in female rats.

The present study investigated the role of the endocannabinoid system on sexual motivation in the female rat. In Experiment 1, gonadally intact female rats were first tested for partner preference after a vehicle injection. Approximately 2 weeks later, all rats were tested again after an injection of the endocannabinoid antagonist, SR141716 (SR; also known as Rimonabant; 1.0mg/kg). During the first 10 min of each partner preference test, subjects could spend time near either a male or female stimulus animal that was placed behind a wire mesh (No-Contact). During the second 10 min of each partner preference test, subjects had unrestricted access to both stimulus animals (Contact). When the female subjects were treated with SR, they made fewer visits to either stimulus animal during the no-contact phase of the partner preference test compared to when they were treated with vehicle. In Experiment 2, ovariectomized (OVX) subjects primed with estrogen were administered SR or vehicle and tested for partner preference (Experiment 2A). Approximately 2 weeks later, the subjects from the control group were tested again after an injection of SR (Experiment 2B). In contrast to Experiment 1, treatment with SR reduced the number of visits specifically to the male stimulus during the contact phase of the test in Experiment 2. Experiment 3 tested the effects of SR on general locomotion and found no effect of SR on line crossings in an open field. Finally, in Experiment 4, OVX estrogen- and progesterone-primed subjects were administered the endocannabinoid agonist anandamide (AEA: 1.0mg/kg) or vehicle and tested for partner preference. AEA-treated subjects made more visits to the male stimulus than vehicle-treated subjects during the contact phase of the test. The results of the present study suggest that the endocannabinoid system may contribute to sexual motivation in female rats by specifically altering approach behavior.

Acute withdrawal but not long-term withdrawal from methamphetamine affects sexual behavior in female rats.

The present study was designed to investigate the long-term effects of repeated methamphetamine (MA) exposure on sexual motivation in female rats tested after a period of drug abstinence. In Experiment 1, female subjects received three injections of MA (1.0mg/kg/day, every other day) or saline and were tested for paced mating behavior (where females could control the receipt of sexual stimulation from one male rat) 21 days after their last injection. In Experiment 2, female subjects received 12 consecutive injections of MA (1.0mg/kg/day) or saline and were tested for mate choice (where females could control the receipt of sexual stimulation from two male rats simultaneously) 6 days after their last injection. Experiment 3 was identical to Experiment 2 except that female subjects received no baseline mating test and were tested for mate choice 24h and 6 days after their last injection. Open field tests were conducted in each experiment to measure locomotor activity after repeated exposure to MA. Although repeated MA exposure increased locomotor activity, mating behavior was not facilitated after either a short (6 days) or long (21 days) period of drug abstinence. Nevertheless, sexual behavior was disrupted during the 24h acute withdrawal period. Therefore, although the present study found no evidence of cross-sensitization between female sexual behavior and MA after either a short or a long period of drug abstinence, sexual behavior in sexually naïve female rats is sensitive to the depressive state associated with acute withdrawal from MA. In conclusion, the results of the present study suggest that MA acts differently from other psychomotor stimulants, and that the effects of MA withdrawal on sexual behavior differ between male and female rats.