Development and persistence of long-lasting behavioral sensitization to cocaine in female mice: Role of the nNOS gene

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. Methods and Results: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E’ velocity/A’ velocity (E’/A’) ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. Conclusions: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.

Download Full-text

Mechanistic role of antioxidants in rescuing delayed gastric emptying in high fat diet induced diabetic female mice

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111370 ◽

2021 ◽

Vol 137 ◽

pp. 111370

Author(s):

Chethan Sampath ◽

Derek Wilus ◽

Mohammad Tabatabai ◽

Michael L. Freeman ◽

Pandu R. Gangula

Keyword(s):

Gastric Emptying ◽

High Fat Diet ◽

Delayed Gastric Emptying ◽

High Fat ◽

Female Mice

Download Full-text

Role of Mu and Delta Opioid Receptors and their Ligands, Î'-Endorphin and Pre-Pro-Enkephalin, in Stress-Induced Visceral Analgesia in Male and Female Mice

Gastroenterology ◽

10.1016/s0016-5085(17)31010-7 ◽

2017 ◽

Vol 152 (5) ◽

pp. S212

Author(s):

Muriel H. Larauche ◽

Nabila Moussaoui ◽

Mandy Biraud ◽

Won Ki Bae ◽

Wendy Walwyn ◽

...

Keyword(s):

Opioid Receptors ◽

Male And Female ◽

Female Mice ◽

Delta Opioid Receptors

Download Full-text

Differential metabolism of acrylonitrile to cyanide is responsible for the greater sensitivity of male vs female mice: role of CYP2E1 and epoxide hydrolases

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2003.08.006 ◽

2003 ◽

Vol 193 (2) ◽

pp. 293-302 ◽

Cited By ~ 32

Author(s):

Brian Chanas ◽

Hongbing Wang ◽

Burhan I Ghanayem

Keyword(s):

Epoxide Hydrolases ◽

Female Mice

Download Full-text

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1518894112 ◽

2015 ◽

Vol 112 (47) ◽

pp. E6562-E6570 ◽

Cited By ~ 64

Author(s):

Shang-Yi A. Tsai ◽

Jian-Ying Chuang ◽

Meng-Shan Tsai ◽

Xiao-fei Wang ◽

Zheng-Xiong Xi ◽

...

Keyword(s):

Transcriptional Regulation ◽

Nuclear Envelope ◽

Chromatin Remodeling ◽

Behavioral Sensitization ◽

Specific Protein ◽

Cellular Regulation ◽

Sigma 1 Receptor ◽

Withdrawal Treatment ◽

Sigma 1

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER–mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

Download Full-text

Protective role of medroxyprogesterone acetate on N-methyl-N-nitrosourea-induced lymphomas in BALB/c female mice

Leukemia Research ◽

10.1016/s0145-2126(00)00116-8 ◽

2001 ◽

Vol 25 (2) ◽

pp. 165-167 ◽

Cited By ~ 1

Author(s):

Patricia Pazos ◽

Claudia Lanari ◽

Alfredo A. Molinolo

Keyword(s):

Medroxyprogesterone Acetate ◽

Protective Role ◽

Female Mice

Download Full-text

The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

Psychopharmacology ◽

10.1007/s00213-021-05808-9 ◽

2021 ◽

Author(s):

Marlaina R. Stocco ◽

Ahmed A. El-Sherbeni ◽

Bin Zhao ◽

Maria Novalen ◽

Rachel F. Tyndale

Keyword(s):

Neurotransmitter Release ◽

Behavioral Sensitization ◽

Serotonin Release ◽

Striatal Dopamine ◽

Irreversible Inhibitor ◽

Drug Concentrations ◽

Metabolite Concentrations ◽

The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

Download Full-text