Anastasia Suraev

Adolescent pre-treatment with oxytocin protects against adult methamphetamine-seeking behavior in female rats

The neuropeptide oxytocin (OT), given acutely, reduces self‐administration of the psychostimulant drug methamphetamine (METH). Additionally, chronic OT administration to adolescent rats reduces levels of alcohol consumption in adulthood, suggesting developmental neuroplasticity in the OT system relevant to addiction‐related behaviors. Here, we examined whether OT exposure during adolescence might subsequently inhibit METH self‐administration in adulthood. Female Sprague‐Dawley rats were administered vehicle or OT (1 mg/kg, i.p.) once daily from postnatal days (PND) 28 to 37 (adolescence). At PND 62 (adulthood), rats were trained to self‐administer METH (intravenous, i.v.) in daily 2‐hour sessions for 10 days under a fixed ratio 1 (FR1) reinforcement schedule, followed by determination of dose‐response functions (0.01–0.3 mg/kg/infusion, i.v.) under both FR1 and progressive ratio (PR) schedules of reinforcement. Responding was then extinguished, and relapse to METH‐seeking behavior assessed following priming doses of non‐contingent METH (0.1–1 mg/kg, i.p.). Finally, plasma was collected to determine pre‐treatment effects on OT and corticosterone levels. Results showed that OT pre‐treatment did not significantly inhibit the acquisition of METH self‐administration or FR1 responding. However, rats pre‐treated with OT responded significantly less for METH under a PR reinforcement schedule, and showed reduced METH‐primed reinstatement with the 1 mg/kg prime. Plasma OT levels were also significantly higher in OT pre‐treated rats. These results confirm earlier observations that adolescent OT exposure can subtly, yet significantly, inhibit addiction‐relevant behaviors in adulthood.

Chronic Methamphetamine Self-Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat.

The neuropeptide oxytocin attenuates reward and abuse for the psychostimulant methamphetamine (METH). Recent findings have implicated the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in oxytocin modulation of acute METH reward and relapse to METH‐seeking behaviour. Surprisingly, the oxytocin receptor (OTR) is only modestly involved in both regions in oxytocin attenuation of METH‐primed reinstatement. Coupled with the limited investigation of the role of the OTR in psychostimulant‐induced behaviours, we primarily investigated whether there are cellular changes to the OTR in the NAc core and STh, as well as changes to oxytocin plasma levels, after chronic METH i.v. self‐administration (IVSA) and after extinction of drug‐taking. An additional aim was to examine whether changes to central corticotrophin‐releasing factor (CRF) and plasma corticosterone levels were also apparent because of the interaction of oxytocin with stress‐regulatory mechanisms. Male Sprague–Dawley rats were trained to lever press for i.v. METH (0.1 mg/kg/infusion) under a fixed‐ratio 1 schedule or received yoked saline infusions during 2‐h sessions for 20 days. An additional cohort of rats underwent behavioural extinction for 15 days after METH IVSA. Subsequent to the last day of IVSA or extinction, blood plasma was collected for enzyme immunoassay, and immunofluorescence was conducted on NAc core and STh coronal sections. Rats that self‐administered METH had higher oxytocin plasma levels, and decreased OTR‐immunoreactive (‐IR) fibres in the NAc core than yoked controls. In animals that self‐administered METH and underwent extinction, oxytocin plasma levels remained elevated, OTR‐IR fibre density increased in the STh, and a trend towards normalisation of OTR‐IR fibre density was evident in the NAc core. CRF‐IR fibre density in both brain regions and corticosterone plasma levels did not change across treatment groups. These findings demonstrate that oxytocin systems, both centrally within the NAc core and STh, as well as peripherally through plasma measures, are dysregulated after METH abuse.

Active coping toward predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system

An active coping style displayed under stress - which involves proactive investigatory responses toward environmental threats - has been associated with reduced vulnerability to psychiatric illness. However, the neurobiological determinants of coping styles are not well understood. When rats are exposed to a naturalistic stressor (cat fur) in a group, some individuals in the group show robust active investigation of the stimulus while others show a passive response involving retreat, immobility and close aggregation with conspecifics. Here we explored endocrine and epigenetic correlates of these contrasting coping styles. Male Wistar rats (n=48) were exposed to cat fur in groups of 4 and the passive and active responders were identified and assessed for endocrine and epigenetic differences. Three days after the final cat fur exposure, active responders had substantially lower plasma levels of corticosterone and progesterone than passive responders. Plasma and testicular testosterone levels did not differ between active and passive responders. Active responders had markedly less methylation of the AVP CGCG promoter region located at base 4970 in the posterodorsal region of the medial amygdala but did not differ in the methylation status of the CCGG sequence located at base 2243. This is in agreement with prior research suggesting that AVP and progesterone act in opposition within the medial amygdala to modulate stress-related behaviors. The present study reports striking endocrine and epigenetic differences between active and passive responders, providing insight into potential systems involved in the manifestation of differing coping styles.

Intranasal oxytocin in the treatment of anorexia nervosa: Randomized controlled trial during re-feeding

BACKGROUND Nutritional rehabilitation in anorexia nervosa (AN) is impeded by fear of food, eating and change leading to treatment resistance. Oxytocin (OT) exerts prosocial effects and modulates trust, fear, anxiety and neuroplasticity. The current placebo-controlled RCT examined the effects of intranasal oxytocin (IN-OT) in AN. The aim was to ascertain whether repeated doses of IN-OT enhance treatment outcomes in AN. METHODS AN patients self-administered 36 IU IN-OT or placebo daily for 4-6 weeks during hospital treatment. The outcome measures were change in the Eating Disorders Examination (EDE) scale, weight gain, cognitive rigidity, social anxiety, obsessive and autistic symptoms. The effects of the first and last doses of IN-OT were assessed relative to placebo before and after a high-energy afternoon snack, to determine potential dampening of cortisol and anxiety levels by OT. RESULTS Weight gain was similar in both groups. The EDE eating concern subscale score was significantly lower after IN-OT treatment as was cognitive rigidity. There were no significant differences in social anxiety or any of the other outcomes at follow-up. After four weeks IN-OT, salivary cortisol levels were significantly lowered in anticipation of an afternoon snack compared to placebo. Morning plasma OT levels did not change after chronic IN-OT or with weight restoration. CONCLUSION IN-OT might enhance nutritional rehabilitation in AN by reducing eating concern and cognitive rigidity. Lower salivary cortisol levels in response to IN-OT suggest diminished neuroendocrine stress responsiveness to food and eating. Such effects require replication with inclusion of more sensitive subjective measures.

Contrasting regional Fos expression in adolescent and young adult rats following acute administration of the antidepressant paroxetine

Adolescents and adults may respond differently to antidepressants, with poorer efficacy and greater probability of adverse effects in adolescents. The mechanisms underlying this differential response are largely unknown, but likely relate to an interaction between the neural effects of antidepressants and brain development. We used Fos immunohistochemistry to examine regional differences in adolescent (postnatal day (PND) 28) and young adult (PND 56) male, Wistar rats given a single injection of the selective serotonin reuptake inhibitor paroxetine (10mg/kg). Paroxetine induced widespread Fos expression in both adolescent and young adult rats. Commonly affected areas include the bed nucleus of the stria terminalis (dorsolateral), medial preoptic area, paraventricular hypothalamic and thalamic nuclei and central nucleus of the amygdala. Fos expression was generally lower in adolescents with significantly greater Fos expression observed in young adults in the prelimbic cortex, supraoptic nucleus, basolateral amygdala, lateral parabrachial and Kölliker-Fuse nuclei. However, a small subset of regions showed greater adolescent Fos expression including the nucleus accumbens shell, lateral habenula and dorsal raphe. Paroxetine increased plasma corticosterone concentrations in young adults, but not adolescents. Plasma paroxetine levels were not significantly different between the age groups. These results indicate a different c-Fos signature of acute paroxetine in adolescent rats, with greater activation in key mesolimbic and serotonergic regions, but a more subdued cortical, brainstem and hypothalamic response. This suggests that the atypical response of adolescents to paroxetine may be related to a blunted neuroendocrine response, combined with insufficient top-down regulation of limbic regions involved in reward and impulsivity.

Knowledge and attitudes of Australian general practitioners towards medicinal cannabis: a cross-sectional survey.

Objectives To examine the knowledge and attitudes of Australian general practitioners (GP) towards medicinal cannabis, including patient demand, GP perceptions of therapeutic effects and potential harms, perceived knowledge and willingness to prescribe. Design, setting and participants A cross-sectional survey completed by 640 GPs (response rate=37%) attending multiple-topic educational seminars in five major Australian cities between August and November 2017. Main outcome measures Number of patients enquiring about medicinal cannabis, perceived knowledge of GPs, conditions where GPs perceived it to be beneficial, willingness to prescribe, preferred models of access, perceived adverse effects and safety relative to other prescription drugs. Results The majority of GPs (61.5%) reported one or more patient enquiries about medicinal cannabis in the last three months. Most felt that their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. Over half (56.5%) supported availability on prescription, with the preferred access model involving trained GPs prescribing independently of specialists. Support for use of medicinal cannabis was condition-specific, with strong support for use in cancer pain, palliative care and epilepsy, and much lower support for use in depression and anxiety. Conclusions The majority of GPs are supportive or neutral with regards to medicinal cannabis use. Our results highlight the need for improved training of GPs around medicinal cannabis, and the discrepancy between GP-preferred models of access and the current specialist-led models.

Nrg1 deficiency modulates the behavioural effects of prenatal stress in mice

Abstract Little is known about the exact genes that confer vulnerability or resilience to environmental stressors during early neurodevelopment. Partial genetic deletion of neuregulin 1 (Nrg1) moderates the neurobehavioural effects of stressors applied in adolescence and adulthood, however, no study has yet examined its impact on prenatal stress. Here we examined whether Nrg1 deficiency in mice modulated the impact of prenatal stress on various behaviours in adulthood. Male heterozygous Nrg1 mice were mated with wild‐type female mice who then underwent daily restraint stress from days 13 to 19 of gestation. Surprisingly, prenatal stress had overall beneficial effects by facilitating sensorimotor gating, increasing sociability, decreasing depressive‐like behaviour, and improving spatial memory in adulthood. Such benefits were not due to any increase in maternal care, as prenatal stress decreased nurturing of the offspring. Nrg1 deficiency negated the beneficial behavioural effects of prenatal stress on all measures except sociability. However, Nrg1 deficiency interacted with prenatal stress to trigger locomotor hyperactivity. Nrg1 deficiency, prenatal stress or their combination failed to alter acute stress‐induced plasma corticosterone concentrations. Collectively these results demonstrate that Nrg1 deficiency moderates the effects of prenatal stress on adult behaviour, but it does so in a complex, domain‐specific fashion. HighlightsPrenatal stress (PS) had a beneficial effect on various behaviours in adult mice.PS improved sensorimotor gating, sociability, spatial memory and stress coping.Nrg1 deficiency reduced all the benefits of PS except for enhanced sociability.Nrg1 deficiency and prenatal stress combined to trigger locomotor hyperactivity.

Author Correction: Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.