Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid

Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats. These data revealed that VPA-exposed male, but not female, rats exhibit reduced social responding in the three-chamber and olfactory habituation/dishabituation (OHD) test during adolescence. In comparison, VPA-exposed female, but not male, adolescent rats exhibited anxiety-like behaviour in the elevated plus maze (EPM) and open field test (OFT). In VPA-exposed female rats, increasing 2-AG levels augmented anxiety-like behaviour in the EPM and OFT, while increasing AEA levels reduced stress coping behaviour in the swim stress test. These data highlight sexual dimorphic behaviours in the VPA model and indicate that enhancing endocannabinoid levels may exacerbate negative affective behaviour in VPA-exposed females. Thus, considerations should be paid to the possible sex-specific effects of cannabinoids for the treatment of symptoms associated with autism.

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Dextromethorphan affects ventilation differently in male and female rats

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.5.1911 ◽

1996 ◽

Vol 81 (5) ◽

pp. 1911-1916 ◽

Cited By ~ 9

Author(s):

Evelyn H. Schlenker

Keyword(s):

Oxygen Consumption ◽

Aspartic Acid ◽

Subcutaneous Administration ◽

Female Rats ◽

Male Rats ◽

Male And Female ◽

Time Points ◽

Specific Effects ◽

Male And Female Rats ◽

Gender Specific

Schlenker, Evelyn H. Dextromethorphan affects ventilation differently in male and female rats. J. Appl. Physiol. 81(5): 1911–1916, 1996.—Subcutaneous administration of aspartic acid results in a long-lasting but reversible depression of ventilation in male but not in female rats. Aspartic acid acts on N-methyl-d-aspartate receptors. The present study tested the hypothesis that a noncompetitive N-methyl-d-aspartate-receptor antagonist, dextromethorphan (Dex), would depress ventilation in female rats and stimulate it in male rats. Moreover, Dex administered prior to aspartic acid should prevent the aspartic acid-induced depression of ventilation in male rats. In female rats, Dex caused a 30% depression of ventilation relative to saline at 5 and 10 mg/kg ( P < 0.01) but not at the highest dose (20 mg/kg). In male rats, Dex had no effect on ventilation. At a dose of 20 mg/kg, Dex depressed oxygen consumption to 50% of the saline value at all time points in female rats ( P < 0.001) and in male rats 45 and 60 min after administration. The time points when Dex depressed ventilation and oxygen consumption were different in female rats, suggesting that the depression of ventilation was not the result of a depression in oxygen consumption. During a hypercapnic challenge (7% CO2), female rats treated with 5 and 10 mg/kg of Dex exhibited a smaller increase in ventilatory response relative to saline treatment. At a dose of 20 mg/kg, the hypercapnic responsiveness of male rats was markedly stimulated (85.8 ± 8.95 ml/min) relative to saline (50.6 ± 9.14 ml/min; P < 0.001). Finally, Dex administered before aspartic acid prevented the aspartic acid-induced depression of ventilation in male rats. Thus, in rats, Dex has gender-specific effects on ventilation and these effects are not associated with changes in oxygen consumption.

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Regionally Specific Effects of Oxytocin on Reinstatement of Cocaine Seeking in Male and Female Rats

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyy025 ◽

2018 ◽

Vol 21 (7) ◽

pp. 677-686 ◽

Cited By ~ 15

Author(s):

Rachel A Weber ◽

Carly N Logan ◽

Kah-Chung Leong ◽

Joanna Peris ◽

Lori Knackstedt ◽

...

Keyword(s):

Female Rats ◽

Male And Female ◽

Specific Effects ◽

Male And Female Rats ◽

Cocaine Seeking

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Oxytocin has sex-specific effects on social behaviour and hypothalamic oxytocin immunoreactive cells but not hippocampal neurogenesis in adult rats

10.1101/859165 ◽

2019 ◽

Author(s):

Paula Duarte-Guterman ◽

Stephanie E. Lieblich ◽

Wansu Qiu ◽

Jared E.J. Splinter ◽

Kimberly A. Go ◽

...

Keyword(s):

Blood Brain Barrier ◽

Body Mass ◽

Hippocampal Neurogenesis ◽

Female Rats ◽

Brain Barrier ◽

Social Investigation ◽

Male And Female ◽

Specific Effects ◽

Male And Female Rats ◽

17Β Estradiol

AbstractOxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZANTM (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either: oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZANTM (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17β-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZANTM reduced sedation observed post-injection and increased some central effects (oxytocin levels in the hypothalamus and ventral hippocampus neurogenesis) relative to oxytocin in PBS indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, sedation, and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17β-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females.

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Behavioural responses to single and repeated restraint in male and female rats

Behavioural Processes ◽

10.1016/0376-6357(92)90052-f ◽

1992 ◽

Vol 28 (1-2) ◽

pp. 97-109 ◽

Cited By ~ 41

Author(s):

M.E. Albonetti ◽

F. Farabollini

Keyword(s):

Female Rats ◽

Male And Female ◽

Behavioural Responses ◽

Male And Female Rats

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Chronic treatment with CP 55,940 during the peri-adolescent period differentially affects the behavioural responses of male and female rats in adulthood

Psychopharmacology ◽

10.1007/s00213-003-1550-7 ◽

2003 ◽

Vol 170 (3) ◽

pp. 301-308 ◽

Cited By ~ 94

Author(s):

Miguel Biscaia ◽

Susana Marín ◽

Beatriz Fernández ◽

Eva M. Marco ◽

Marina Rubio ◽

...

Keyword(s):

Chronic Treatment ◽

Female Rats ◽

Male And Female ◽

Behavioural Responses ◽

Male And Female Rats ◽

Cp 55,940 ◽

Adolescent Period

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Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

10.1101/2021.01.14.426662 ◽

2021 ◽

Author(s):

E. Andrew Townsend ◽

R. Kijoon Kim ◽

Hannah L. Robinson ◽

Samuel A. Marsh ◽

Matthew L. Banks ◽

...

Keyword(s):

Food Choice ◽

Opioid Withdrawal ◽

Female Rats ◽

Self Administration ◽

Choice Procedure ◽

Specific Effects ◽

Male And Female Rats ◽

Administration Regimen ◽

Extended Access ◽

Withdrawal Signs

AbstractBackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

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