Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

Changes in hypothalamic mu-opioid receptor expression following acute olanzapine treatment in female rats: Implications for feeding behavior.

Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.

Characterization of pain-, anxiety-, and cognition-related behaviors in the complete Freund's adjuvant model of chronic inflammatory pain in Wistar-Kyoto rats.

Introduction: Chronic pain is often associated with comorbid anxiety and cognitive dysfunction, negatively affecting therapeutic outcomes. The influence of genetic background on such interactions is poorly understood. The stress-hyperresponsive Wistar-Kyoto (WKY) rat strain, which models aspects of anxiety and depression, displays enhanced sensitivity to noxious stimuli and impaired cognitive function, compared with Sprague-Dawley (SD) counterparts. However, pain- and anxiety-related behaviors and cognitive impairment following induction of a persistent inflammatory state have not been investigated simultaneously in the WKY rats. Here we compared the effects of complete Freund's adjuvant (CFA)-induced persistent inflammation on pain-, negative affect- and cognition-related behaviors in WKY vs. SD rats. Methods: Male WKY and SD rats received intra-plantar injection of CFA or needle insertion (control) and, over the subsequent 4 weeks, underwent behavioral tests to assess mechanical and heat hypersensitivity, the aversive component of pain, and anxiety- and cognition-related behaviors. Results: The CFA-injected WKY rats exhibited greater mechanical but similar heat hypersensitivity compared to SD counterparts. Neither strain displayed CFA-induced pain avoidance or anxiety-related behavior. No CFA-induced impairment was observed in social interaction or spatial memory in WKY or SD rats in the three-chamber sociability and T-maze tests, respectively, although strain differences were apparent. Reduced novel object exploration time was observed in CFA-injected SD, but not WKY, rats. However, CFA injection did not affect object recognition memory in either strain. Conclusions: These data indicate exacerbated baseline and CFA-induced mechanical hypersensitivity, and impairments in novel object exploration, and social and spatial memory in WKY vs. SD rats.

Kappa opioid activation changes protein profiles in different regions of the brain relevant to depression.

Depression is a widespread disorder with a significant burden on individuals and society. There are various available treatments for patients with depression. However, not all patients respond adequately to their treatment. Recently, the opioid system has regained interest in depression studies. Research in animals and humans suggest that blocking the kappa opioid receptor (KOR) may potentially alleviate the symptoms of depression. The mechanism behind this effect is not fully understood. Stress and alterations in hypothalamic-pituitary-adrenal axis (HPA-axis) activity are thought to play a crucial role in depression. This study aimed to characterize stress hormones and stress-related protein expression following activation of KOR using a selective agonist. The longitudinal effect was investigated 24 h after KOR activation using the selective agonist U50,488 in Sprague Dawley rats. Stress-related hormones and protein expression patterns were explored using multiplex bead-based assays and western blotting. We found that KOR activation caused an increase in both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in serum. Regarding protein assays in different brain regions, phosphorylated glucocorticoid receptors also increased significantly in thalamus (THL), hypothalamus (HTH), and striatum (STR). C-Fos increased time-dependently in THL following KOR activation, extracellular signal-regulated kinases 1/2 (ERK1/2) increased significantly in STR and amygdala (AMG), while phosphorylated ERK1/2 decreased during the first 2 h and then increased again in AMG and prefrontal cortex (PFC). This study shows that KOR activation alters the HPA axis and ERK signaling which may cause to develop mood disorders.

Spatial quantification of single cell mRNA and ligand binding of the kappa opioid receptor in the rat hypothalamus.

Detailed quantification of brain tissue provides a deeper understanding of changes in expression and function. We have created a pipeline to study the detailed expression patterns of the kappa opioid receptor in the rat hypothalamus using high resolution fluorescence microscopy and receptor autoradiography. The workflow involved structured serial sampling of rat hypothalamic nuclei, in situ detection of mRNA and receptor expression, and advanced image analysis. Our results demonstrate how maintaining spatial information can lead to increased understanding of RNA and protein expression. In addition, we show the detailed expression patterns of the kappa opioid receptor in the rat hypothalamus.

Single dose S-ketamine rescues transcriptional dysregulation of Mtor and Nrp2 in the prefrontal cortex of FSL rats 1 hour but not 14 days post dosing.

There is a pressing need to identify biological indicators of major depression to help guide proper diagnosis and optimize treatment. Animal models mimicking aspects of depression constitute essential tools for early-stage exploration of relevant pathways. In this study, we used the Flinders Sensitive and Resistant Line (FSL/FRL) to explore central and peripheral transcriptional changes in vascular endothelial growth factor (VEGF) pathway genes and their temporal regulation after a single dose of S-ketamine (15 mg/kg). We found that S-ketamine induced both rapid (1 hour) and sustained (2 and 14 days) antidepressant-like effects in the FSL rats. Analysis of mRNA expression revealed significant strain effects of Vegf, Vegf164, Vegfr-1, Nrp1, Nrp2, Rictor, and Raptor in the prefrontal cortex (PFC) and of Vegf164, GbetaL, and Tsc1 in the hippocampus (HIP), which indicates suppression of VEGF signaling in the FSL rats compared to FRL rats. This notion was further substantiated by reduced expression of Vegf and Mtor in plasma from FSL rats. In the brain, S-ketamine induced transcriptional changes in the acute phase, not the sustained phase. There were significant treatment effects of S-ketamine on Vegfr-2 in both PFC and HIP and on Vegf and Vegfr-1 in HIP. Moreover, we found that S-ketamine specifically restored reduced levels of Nrp2 and Mtor in the PFC of the FSL rats. In conclusion, this study substantiates the use of the FRL/FSL rats to explore the depressive-like behavior at the transcriptional level of the VEGF pathway genes and study their regulation in response to various treatment paradigms.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus.

The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.

In vivo electrophysiological study of the targeting of 5-HT3 receptor-expressing cortical interneurons by the multimodal antidepressant, vortioxetine.

The antidepressant vortioxetine has high affinity for the ionotropic 5-HT3 receptor (5-HT3 R) as well as other targets including the 5-HT transporter. The procognitive effects of vortioxetine have been linked to altered excitatory:inhibitory balance in cortex. Thus, vortioxetine purportedly inhibits cortical 5-HT3 R-expressing interneurons (5-HT3 R-INs) to disinhibit excitatory pyramidal neurons. The current study determined for the first time the effect of vortioxetine on the in vivo firing of putative 5-HT3 R-INs whilst simultaneously recording pyramidal neuron activity using cortical slow-wave oscillations as a readout. Extracellular single unit and local field potential recordings were made in superficial layers of the prefrontal cortex of urethane-anaesthetised rats. 5-HT3 R-INs were identified by a short-latency excitation evoked by electrical stimulation of the dorsal raphe nucleus (DRN). Juxtacellular-labelling found such neurons had the morphological and immunohistochemical properties of 5-HT3 R-INs: basket cell or bipolar cell morphology, expression of 5-HT3 R-IN markers and parvalbumin-immunonegative. Vortioxetine inhibited the short-latency DRN-evoked excitation of 5-HT3 R-INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5-HT3 R antagonist ondansetron inhibited the short-latency DRN-evoked excitation of 5-HT3 R-INs. However unlike vortioxetine, ondansetron did not decrease cortical slow-wave oscillations, suggesting a dissociation between this effect and inhibition of 5-HT3 R-INs. The 5-HT reuptake inhibitor escitalopram had no consistent effect on any electrophysiological parameter measured. Overall, the current findings suggest that vortioxetine simultaneously inhibits (DRN-evoked) 5-HT3 R-INs and excites pyramidal neurons, thereby changing the excitatory:inhibitory balance in cortex. However, under the current experimental conditions, these two effects were dissociable with only the former likely involving a 5-HT3 R-mediated mechanism.

Mu-opioid receptor agonism differentially alters social behaviour and immediate early gene expression in male adolescent rats prenatally exposed to valproic acid versus controls.

Mu-opioid receptors (MOPs) mediate and modulate social reward and social interaction. However, few studies have examined the functionality of this system in rodent models of social impairment. Deficits in social motivation and cognition are observed in rodents following pre-natal exposure to the anti-epileptic valproic acid (VPA), however it is not known whether MOP functionality is altered in these animals. The present study examined the effects of acute administration of the prototypical MOP agonist morphine (1 mg/kg) on social behavioural responding in the 3-chamber test and immediate early gene expression in adolescent rats (postnatal day 28-43) prenatally exposed to VPA vs saline-exposed controls. Pharmacokinetic analysis of morphine concentration, MOP binding and expression were also examined. The data revealed that sociability and social novelty preference in the 3-chamber test were reduced in rats prenatally exposed to VPA compared to saline-exposed control counterparts. Morphine reduced both sociability and social novelty preference behaviour in saline-, but not VPA-, exposed rats. Analysis of immediate early gene expression revealed that morphine reduced the expression of cfos in the prefrontal cortex of both saline- and VPA-exposed rats and reduced expression of cfos and junb in the hippocampus of VPA-exposed rats only. Pharmacokinetic analysis revealed similar concentrations of morphine in the plasma and brain of both saline- and VPA-exposed rats and similar thalamic MOP occupancy levels. Gene and protein expression of MOP in prefrontal cortex and hippocampus did not differ between saline and VPA-exposed rats. These data indicate differential effects of morphine on social responding and immediate early gene expression in the hippocampus of VPA-exposed rats compared with saline-exposed controls. This study provides support for altered MOP functionality in rats prenatally exposed to VPA, which may underlie the social deficits observed in the model.

Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state.

ABSTRACT: Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon are poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared with Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared with SD counterparts. Equivalent plasma morphine levels in the 2 rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal gray (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of the vlPAG, namely, the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in the MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.

Df(h15q13)/+ Mouse Model Reveals Loss of Astrocytes and Synaptic-Related Changes of the Excitatory and Inhibitory Circuits in the Medial Prefrontal Cortex.

The 15q13.3 deletion is associated with multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism. The Df(h15q13)/+ mouse model was recently generated that recapitulates several phenotypic features of the human 15q13.3 deletion syndrome (DS). However, the biological substrates underlying these phenotypes in Df(h15q13)/+ mice have not yet been fully characterized. RNA sequencing followed by real-time quantitative PCR, western blotting, liquid chromatography-mass spectrometry, and stereological analysis were employed to dissect the molecular, structural, and neurochemical phenotypes of the medial prefrontal cortex (mPFC) circuits in Df(h15q13)/+ mouse model. Transcriptomic profiling revealed enrichment for astrocyte-specific genes among differentially expressed genes, translated by a decrease in the number of glial fibrillary acidic protein positive cells in mPFC of Df(h15q13)/+ mice compared with wild-type mice. mPFC in Df(h15q13)/+ mice also showed a deficit of the inhibitory presynaptic marker GAD65, in addition to a reduction in dendritic arborization and spine density of pyramidal neurons from layers II/III. mPFC levels of GABA and glutamate neurotransmitters were not different between genotypes. Our results suggest that the 15q13.3 deletion modulates nonneuronal circuits in mPFC and confers molecular and morphometric alterations in the inhibitory and excitatory neurocircuits, respectively. These alterations potentially contribute to the phenotypes accompanied with the 15q13.3DS.

The rat hippocampal gliovascular system following one week vortioxetine and fluoxetine.

We have previously reported that vortioxetine, unlike the selective serotonin reuptake inhibitor fluoxetine, produces a rapid increase of dendritic spine number and Brain Derived Neurotrophic Factor (BDNF)-associated formation of synapses with mitochondrial support in the rat hippocampal CA1 and dentate gyrus. As a continuation of this line of research, and given the putative role of brain glial cells in mediating antidepressant responses the present study investigated early effects of vortioxetine on hippocampal microvasculature and Vascular Endothelial Growth Factor (VEGF) and astrocytes and microglia cells. Rats were treated for 1 week with vortioxetine (1.6 g/kg food chow) or fluoxetine (160 mg/L drinking water) at pharmacologically relevant doses. Stereological principles were used to estimate the number of ALDH1L1 positive astrocytes and Iba1 positive microglia cells, and the length of microvessels in subregions of hippocampus. VEGF protein levels were visualized with immunohistochemistry. Our results showed that vortioxetine significantly increased the number of ramified (resting) microglia and astrocytes accompanied by VEGF level elevation, whereas fluoxetine had no effect after 7 days treatment on these measures. Our findings suggest that astrocytes and microglia may have a role in mediating the pharmacological effects of vortioxetine in rats and that these effects are mediated through mechanisms that go beyond inhibition of the serotonin transporter and may target specific 5-HT receptors. It remains to be investigated whether these findings are relevant for the therapeutic effects of vortioxetine.

Layers II/III of Prefrontal Cortex in Df(h22q11)/+ Mouse Model of the 22q11.2 Deletion Display Loss of Parvalbumin Interneurons and Modulation of Neuronal Morphology and Excitability.

The 22q11.2 deletion has been identified as a risk factor for multiple neurodevelopmental disorders. Behavioral and cognitive impairments are common among carriers of the 22q11.2 deletion. Parvalbumin expressing (PV+) interneurons provide perisomatic inhibition of excitatory neuronal circuits through GABAA receptors, and a deficit of PV+ inhibitory circuits may underlie a multitude of the behavioral and functional deficits in the 22q11.2 deletion syndrome. We investigated putative deficits of PV+ inhibitory circuits and the associated molecular, morphological, and functional alterations in the prefrontal cortex (PFC) of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. We detected a significant decrease in the number of PV+ interneurons in layers II/III of PFC in Df(h22q11)/+ mice together with a reduction in the mRNA and protein levels of GABAA (α3), a PV+ putative postsynaptic receptor subunit. Pyramidal neurons from the same layers further experienced morphological reorganizations of spines and dendrites. Accordingly, a decrease in the levels of the postsynaptic density protein 95 (PSD95) and a higher neuronal activity in response to the GABAA antagonist bicuculline were measured in these layers in PFC of Df(h22q11)/+ mice compared with their wild-type littermates. Our study shows that a hemizygotic deletion of the 22q11.2 locus leads to deficit in the GABAergic control of network activity and involves molecular and morphological changes in both the inhibitory and excitatory synapses of parvalbumin interneurons and pyramidal neurons specifically in layers II/III PFC.

Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats.

Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT3-R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-dl-phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies.

Kappa Opioid Receptor-mediated Modulation of Social Responding in Adolescent Rats and in Rats Prenatally Exposed to Valproic Acid.

The kappa opioid receptor (KOP) system modulates social play responding, however a paucity of studies have examined effects on social motivation and cognition in the absence of play. Prenatal exposure to the anti-epileptic and mood stabiliser valproic acid (VPA) is associated with impaired social responding and altered gene expression of KOP (oprk1) and dynorphin (pdyn) in several brain regions. The present study examined if pharmacological modulation of KOP altered social motivation and cognition, immediate early gene (IEG) and oprk1-pdyn expression in adolescent male rats and rats prenatally exposed to VPA. In control rats, the KOP antagonist DIPPA enhanced sociability, while both DIPPA and the KOP agonist U50488 decreased social novelty preference. In rats exposed prenatally to VPA, neither U50488 nor DIPPA altered sociability or social novelty preference. Analysis of IEG expression revealed that DIPPA reduced expression of egr-1 expression in the prefrontal cortex of control rats and U50488 increased junb expression in the PFC of both control and VPA-exposed rats. VPA-exposed rats exhibited increased expression of oprk1 and pdyn in the prefrontal cortex and amygdala compared with control rats. DIPPA and U50488 increased oprk1 expression in the amygdala of control rats and decreased oprk1 expression in the prefrontal cortex of VPA-exposed rats. Taken together, these data demonstrate that pharmacological modulation of the KOP system alters social motivation and cognition in control rats, an effect not observed in rats prenatally exposed to VPA. These data provide support that prenatal exposure to VPA is associated with alterations in the expression and functionality of KOP system.

Opioid system modulation of cognitive affective bias: implications for the treatment of mood disorders.

A significant number of patients (30%) do not adequately respond to commonly prescribed antidepressants (e.g. SSRIs, SNRIs, and TCAs). Opioid receptors and their endogenous peptides have demonstrated a clear role in the regulation of mood in animal models and may offer an alternative approach to augment existing therapies. Nevertheless, there is an urgent need to find better ways to predict a patient's response to drug treatment, to improve overall drug responding, and to reduce the time to symptom remission using novel diagnostic and efficacy biomarkers. Cognitive processes, such as perception, attention, memory, and learning, are impaired in patients with mood disorders. These processes can be altered by emotions, a phenomenon called cognitive affective bias. Negative affective biases are a key feature of major depressive disorder (MDD) and may present concurrently with other cognitive deficits. Importantly, a significant percentage of patients report residual cognitive impairments even after effective drug treatment. This approach offers a new opportunity to predict patient treatment responses, potentially improving residual cognitive symptoms and patient outcomes. This review will (1) describe the underlying neurocircuitry of affective cognition and propose how negative biases may occur, (2) outline the role of opioid receptors in affective cognition, executive function, and MDD, and (3) present evidence from the published literature supporting a modulatory role for opioid drugs on negative affective bias, with a focus on kappa-opioid receptor antagonists, currently in development for clinical use for treatment-resistant MDD.

Prenatal exposure to valproic acid reduces social responses and alters mRNA levels of opioid receptor and pre-pro-peptide in discrete brain regions of adolescent and adult male rats.

Altered social behaviours are a hallmark of several psychiatric and developmental disorders. Clinical and preclinical data have demonstrated that prenatal exposure to valproic acid (VPA), an anti-epileptic and mood stabiliser, is associated with impaired social responses, and thus provides a useful model for the evaluation of neurobiological mechanisms underlying altered social behaviours. The opioid system is widely recognised to regulate and modulate social behaviours, however few studies have examined if the endogenous opioid system is altered in animal models of social impairment. The present study examined social behavioural responses of adolescent and adult male rats prenatally exposed to VPA, and the expression of mRNA encoding opioid receptors and pre-pro-peptides in discrete brain regions. Adolescent and adult rats prenatally exposed to VPA spent less time engaging in social behaviours in the direct social interaction test and exhibited reduced sociability and social novelty preference in the 3-chamber sociability test, compared to saline-treated counterparts. The VPA-exposed adolescent rats exhibited significantly reduced kappa opioid receptor (oprk1) and pre-pro-dynorphin (pdyn) mRNA expression in the cerebral cortex, and reduced oprk1 and nociceptin/orphanin FQ (oprl1) mRNA expression in the hypothalamus. Adult rats prenatally exposed to VPA exhibited decreased mRNA expression of oprk1 and pdyn in hypothalamus, reduced pro-opiomelanocortin(pomc) in the striatum and an increase in delta opioid receptor (oprd1) mRNA in the amygdaloid cortex, when compared to saline-treated counterparts. Mu opioid receptor (oprm1) mRNA expression did not differ between saline and VPA-exposed rats in any region examined. The data demonstrate that impaired social behaviours in adolescent and adult rats prenatally exposed to VPA is accompanied by altered mRNA expression of opioid receptors and pre-pro-peptides in a region specific manner. In particular, both adolescent and adult VPA-exposed rats exhibit reduced oprk1-pdyn mRNA expression in several brain regions, which are associated with deficits in social behavioural responding in the model.

Opioid receptor modulation of neural circuits in depression: What can be learned from preclinical data?

Major depressive disorder (MDD) is a heterogeneous clinical syndrome involving distinct pathological processes. Core features of MDD include anhedonia, reduced motivation, increased anxiety, negative affective bias, cognitive impairments, and dysregulated neuroplasticity mechanisms. There are multiple biological hypotheses related to MDD, including dysfunction of the opioid system. Although opium was abandoned as an antidepressant after the introduction of monoaminergic drugs, there has been renewed interest in targeting the opioid system for MDD. In this review, we discuss the preclinical support of this idea using a neurocircuitry- and molecular neuroplasticity-based approach. This article highlights how the opioid system potently modulates mesolimbic circuitry underlying motivation and reward processing, limbic circuitry underlying fear and anxiety responses, cortical and hippocampal circuitry underlying a variety of cognitive functions, as well as broad functional and structural plasticity mechanisms. Ultimately, a more thorough understanding of how the opioid system modulates these core functional domains may lead to novel treatment strategies and molecular targets in the treatment of MDD.

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats.

BACKGROUND: The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined. AIMS AND METHODS: The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants. RESULTS: Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing. CONCLUSION: Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.