Therapeutic-like activity of cannabidiolic acid methyl ester in the MK-801 mouse model of schizophrenia: Role for cannabinoid CB1 and serotonin-1A receptors.

Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N-methyl-D-aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU-580), an analogue of CBDA known to act as an agonist of the serotonin-1A receptor (5-HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK-801, .3 mg/kg) once daily for 17 days. After 7 days, they were concurrently given HU-580 (.01 or .05 µg/kg) for 10 days. Behavioural deficits were assessed at two time points. We conducted enzyme-linked immunosorbent assays to measure the concentration of PFC 5-HT1AR and CB1R. We found that MK-801 effectively induced schizophrenia-related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low-dose HU-580 (.01 µg/kg), but not the high dose (.05 µg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK-801 downregulated both CB1R and 5-HT1AR, an effect that was blocked by both low- and high-dose HU-580. This study sheds light on the potential antipsychotic properties of HU-580, particularly in the context of NMDAR-induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU-580 and related compounds in alleviating symptoms.

Cross-sex cecal microbiota transfer alters depressive-like behaviours in mice.

Major depressive disorder (MDD) is a leading cause of non-fatal global disease burden, with females being two-fold more likely than males to be diagnosed with the disorder. Despite this sex-linked disparity of diagnosis, it is unclear what underlies the sex bias in MDD. Recent findings suggest a role for the gut in mediating affective disorders through the gut-brain-axis (GBA). However, few studies have included sex as a biological variable. For this study, cross-sex transfer of cecal microbiota was performed between male and female C57Bl/6 mice to elucidate the effects of sex and the gut microbiome on a standard battery of tests measuring depressive-like behaviours. Specifically, regardless of sex, recipients of male cecal content had a greater sucrose preference than controls and recipients of female cecum, although recipients of male cecal transfer also showed a trend towards increased passive coping on the force swim test. Conversely, in the splash test, recipients of female cecum displayed a decrease in grooming behaviour compared to both controls and recipients of male cecum, suggestive of an increase in depressive-like behaviour. These results support a role for female-specific gut microbes in contributing to female vulnerability to depression, particularly on self-care measures, while male-specific gut microbes may protect in part against an anhedonia-like phenotype, but increase passive coping.

A short pre-conception bout of predation risk affects both children and grandchildren.

Traumatic events that affect physiology and behavior in the current generation may also impact future generations. We demonstrate that an ecologically realistic degree of predation risk prior to conception causes lasting changes in the first filial (F1) and second filial (F2) generations. We exposed male and female mice to a live rat (predator stress) or control (non-predator) condition for 5 min. Ten days later, stressed males and females were bred together as were control males and females. Adult F1 offspring from preconception-stressed parents responded to a mild stressor with more anxiety-like behavior and hyperarousal than offspring from control parents. Exposing these F1 offspring to the mild stressor increased neuronal activity (cFOS) in the hippocampus and altered glucocorticoid system function peripherally (plasma corticosterone levels). Even without the mild stressor, F1 offspring from preconception-stressed parents still exhibited more anxiety-like behaviors than controls. Cross-fostering studies confirmed that preconception stress, not maternal social environment, determined offspring behavioral phenotype. The effects of preconception parental stress were also unexpectedly persistent and produced similar behavioral phenotypes in the F2 offspring. Our data illustrate that a surprisingly small amount of preconception predator stress alters the brain, physiology, and behavior of future generations. A better understanding of the 'long shadow' cast by fearful events is critical for understanding the adaptive costs and benefits of transgenerational plasticity. It also suggests the intriguing possibility that similar risk-induced changes are the rule rather than the exception in free-living organisms, and that such multigenerational impacts are as ubiquitous as they are cryptic.

Antibiotic-induced socio-sexual behavioral deficits are reversed via cecal microbiota transplantation but not androgen treatment.

Recent evidence has demonstrated a sex-specific role of the gut microbiome on social behavior such as anxiety, possibly driven by a reciprocal relationship between the gut microbiome and gonadal hormones. For instance, gonadal hormones drive sex differences in gut microbiota composition, and certain gut bacteria can produce androgens from glucocorticoids. We thus asked whether the gut microbiome can influence androgen-dependent socio-sexual behaviors. We first treated C57BL/6 mice with broad-spectrum antibiotics (ABX) in drinking water to deplete the gut microbiota either transiently during early development (embryonic day 16-postnatal day [PND] 21) or in adulthood (PND 60-85). We hypothesized that if ABX interferes with androgens, then early ABX would interfere with critical periods for sexual differentiation of brain and thus lead to long-term decreases in males' socio-sexual behavior, while adult ABX would interfere with androgens' activational effects on behavior. We found that in males but not females, early and adult ABX treatment decreased territorial aggression, and adult ABX also decreased sexual odor preference. We then assessed whether testosterone and/or cecal microbiota transplantation (CMT) via oral gavage could prevent ABX-induced socio-sexual behavioral deficits in adult ABX-treated males. Mice were treated with same- or other-sex control cecum contents or with testosterone for two weeks. While testosterone was not effective in rescuing any behavior, we found that male CMT restored both olfactory preference and aggression in adult ABX male mice, while female CMT restored olfactory preference but not aggression. These results suggest sex-specific effects of the gut microbiome on socio-sexual behaviors, independent of androgens.

Putative pathological mechanisms of late-life depression and Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive impairment in cognition and memory. AD is accompanied by several neuropsychiatric symptoms, with depression being the most prominent. Although depression has long been known to be associated with AD, controversial findings from preclinical and clinical studies have obscured the precise nature of this association. However recent evidence suggests that depression could be a prodrome or harbinger of AD. Evidence indicates that the major central serotonergic nucleus-the dorsal raphe nucleus (DRN)-shows very early AD pathology: neurofibrillary tangles made of hyperphosphorylated tau protein and degenerated neurites. AD and depression share common pathophysiologies, including functional deficits of the serotonin (5-HT) system. 5-HT receptors have modulatory effects on the progression of AD pathology i.e., reduction in Aß load, increased hyper-phosphorylation of tau, decreased oxidative stress etc. Moreover, preclinical models show a role for specific channelopathies that result in abnormal regional activational and neuroplasticity patterns. One of these concerns the pathological upregulation of the small conductance calcium-activated potassium (SK) channel in corticolimbic structure. This has also been observed in the DRN in both diseases. The SKC is a key regulator of cell excitability and long-term potentiation (LTP). SKC over-expression is positively correlated with aging and cognitive decline, and is evident in AD. Pharmacological blockade of SKCs has been reported to reverse symptoms of depression and AD. Thus, aberrant SKC functioning could be related to depression pathophysiology and diverts its late-life progression towards the development of AD. We summarize findings from preclinical and clinical studies suggesting a molecular linkage between depression and AD pathology. We also provide a rationale for considering SKCs as a novel pharmacological target for the treatment of AD-associated symptoms.

Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments.

Given that available antidepressant pharmacotherapies are not optimally effective, there is a need for alternative treatment options that are rooted in a comprehensive understanding of the illness's pathophysiology. Major depressive disorder (MDD) has been historically attributed to monoamine, i.e., serotonin (5-hydroxytryptamine, 5-HT) imbalance and some brain morphological pathologies that have directed treatment towards particular medications that are only minimally effective. MDD pathophysiologies have now been regarded as linked to chronic inflammation and MDD can be treated with compounds that have anti-inflammatory properties. Individuals vulnerable to MDD have increased baseline neuroinflammatory response that is exacerbated by psychogenic stress. When pro-inflammatory mechanisms are chronically hyperactive, dysfunction of brain-related processes occur. We propose that inflammation is one of the primary mechanisms that trigger biological changes leading to MDD. Inflammatory resolution occurs when homeostasis is achieved after an inflammatory response. However, cascading biological events are likely to prevent resolution from occurring and worsen both inflammation and MDD. Novel and alternative pharmacotherapies-e.g., ketamine, cannabinoids, and psychedelics-provide a richer mechanistic perspective on the role of neuroinflammation and neuroprogression by means of rapid, short-term, and long-term symptom relief potentially based on their anti-inflammatory properties. These drugs ultimately decrease proinflammatory cytokine levels that correspond with improved symptoms. However, it is unclear what differentiates these compounds from others in their mechanistic efficacy. Thus, a closer investigation into their anti-inflammatory effects is imperative in order to better elucidate the link between MDD and inflammation, as well as uncover the mechanisms involved in long-term symptom reduction of MDD.

Antidepressant activity of pharmacological and genetic deactivation of the small-conductance calcium-activated potassium channel subtype-3.

RATIONALE: The voltage-insensitive, small-conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization and is implicated in the pathophysiology of depressive disorders. OBJECTIVE: We ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model and whether it can serve as a molecular target of antidepressant action. METHODS: We assessed the depressive-like behavioral phenotype of CUS-exposed rats and performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knockout mice and selective SK3 channel negative allosteric modulators (NAMs). RESULTS: We found that [125I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity. CONCLUSIONS: Taken together, these findings link depression-related neural and behavioral pathophysiology with abnormal SK channel functioning and suggest that this can be reversed by the selective inhibition of SK3 channels.

Antidepressant action of transcranial direct current stimulation in olfactory bulbectomised adolescent rats.

BACKGROUND: Antidepressant drugs in adolescent depression are sometimes mired by efficacy issues and paradoxical effects. Transcranial direct current stimulation (tDCS) could represent an alternative. AIMS/METHODS: We tested the antidepressant action of prefrontal tDCS and paroxetine (20 mg/kg, intraperitoneal) in olfactory bulbectomised (OBX) adolescent rats. Using enzyme-linked immunosorbent assays and in situ hybridisation, we examined treatment-induced changes in plasma brain-derived neurotrophic factor (BDNF) and brain serotonin transporter (SERT) and 5-HT-1A mRNA. RESULTS: OBX-induced anhedonia-like reductions in sucrose preference (SP) correlated with open field (OF) hyperactivity. These were accompanied by decreased zif268 mRNA in the piriform/amygdalopiriform transition area, and increased zif268 mRNA in the hypothalamus. Acute paroxetine (2 days) led to a profound SP reduction, an effect blocked by combined tDCS-paroxetine administration. Chronic (14 days) tDCS attenuated hyperlocomotion and its combination with paroxetine blocked OBX-induced SP reduction. Correlations among BDNF, SP and hyperlocomotion scores were altered by OBX but were normalised by tDCS-paroxetine co-treatment. In the brain, paroxetine increased zif268 mRNA in the hippocampal CA1 subregion and decreased it in the claustrum. This effect was blocked by tDCS co-administration, which also increased zif268 in CA2. tDCS-paroxetine co-treatment had variable effects on 5-HT1A receptors and SERT mRNA. 5-HT1A receptor changes were found exclusively within depression-related parahippocampal/hippocampal subregions, and SERT changes within fear/defensive response-modulating brainstem circuits. CONCLUSION: These findings point towards potential synergistic efficacies of tDCS and paroxetine in the OBX model of adolescent depression via mechanisms associated with altered expression of BDNF, 5-HT1A, SERT and zif268 in discrete corticolimbic areas.

Effects of chronic exposure to low doses of Δ9- tetrahydrocannabinol in adolescence and adulthood on serotonin/norepinephrine neurotransmission and emotional behaviors.

BACKGROUND: Chronic exposure to the Δ9-tetrahydrocannabinol (THC), the main cannabis pharmacological component, during adolescence has been shown to be associated with an increased risk of depression and suicidality in humans. AIMS: Little is known about the impact of the long-term effects of chronic exposure to low doses of THC in adolescent compared to adult rodents. METHODS: THC (1mg/kg i.p., once a day) or vehicle was administered for 20 days in both adolescent (post-natal day, PND 30-50) and young adult rats (PND 50-70). After a long washout period (20 days), several behavioral paradigms and electrophysiological recordings of serotonin (5-HT) and norepinephrine (NE) neurons were carried out. RESULTS: Adolescent THC exposure resulted in depressive lbehaviors: a significant decrease in latency to first immobility in the forced swim test, increased anhedonia in the sucrose preference test. Decrease entries in the open arm were observed in the elevated plus maze after adolescent and adult exposure, indicating anxiousphenotype. A significant reduction in dorsal raphe serotonergic neural activity without changing locus coeruleus noradrenergic neural activity was found in THC adolescent and adult exposure. CONCLUSIONS: Altogether, these findings suggest that low doses of chronic THC exposure during the developmental period and adulthood could result in increased vulnerability of the 5-HT system and anxiety symptoms; however, depressive phenotypes occur only after adolescent, but not adult exposure, underscoring the higher vulnerability of young ages to the mental effects of cannabis.

A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response.

The muscarinic acetylcholine receptor antagonist scopolamine elicits rapid antidepressant activity, but its underlying mechanism is not fully understood. In a chronic stress model, a single low-dose administration of scopolamine reversed depressive-like reactivity. This antidepressant-like effect was mediated via a muscarinic M1 receptor-SKC pathway because it was mimicked by intra-medial prefrontal cortex (intra-mPFC) infusions of scopolamine, of the M1 antagonist pirenzepine or of the SKC antagonist apamin, but not by the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. Extracellular and whole-cell recordings revealed that scopolamine and ketamine attenuate the SKC-mediated action potential hyperpolarization current and rapidly enhance mPFC neuronal excitability within the therapeutically relevant time window. The SKC agonist 1-EBIO abrogated scopolamine-induced antidepressant activity at a dose that completely suppressed burst firing activity. Scopolamine also induced a slow-onset activation of raphe serotonergic neurons, which in turn was dependent on mPFC-induced neuroplasticity or excitatory input, since mPFC transection abolished this effect. These early behavioral and mPFC activational effects of scopolamine did not appear to depend on prefrontocortical brain-derived neurotrophic factor and serotonin-1A activity, classically linked to SSRIs, and suggest a novel mechanism associated with antidepressant response onset through SKC-mediated regulation of activity-dependent plasticity.

In Vivo Brain Sampling Using a Microextraction Probe Reveals Metabolic Changes in Rodents after Deep Brain Stimulation.

Brain metabolomics is an emerging field that complements the more traditional approaches of neuroscience. However, typical brain metabolomics workflows require that animals be sacrificed and tend to involve tedious sample preparation steps. Microdialysis, the standard technique to study brain metabolites in vivo, is encumbered by significant limitations in the analysis of hydrophobic metabolites, which are prone to adsorption losses on microdialysis equipment. An alternative sampling method suitable for in vivo brain studies is solid-phase microextraction (SPME). In SPME, a small probe coated with a biocompatible polymer is employed to extract/enrich analytes from biological matrices. In this work, we report the use of SPME and liquid chromatography-mass spectrometry for untargeted in vivo analysis of rodent's brains after deep brain stimulation (DBS). First, metabolite changes occurring in brain hippocampi after application of 3 h of DBS to the animals' prefrontal cortex were monitored with the proposed approach. As SPME allows for nonlethal sampling, the same group of animals was sampled again after 8 days of daily DBS therapy. After acute DBS, we detected changes in a broad range of metabolites, including the amino acid citrulline, which may reflect changes in nitric oxide production, as well as various phospho- and glycosphingolipids. Measurements conducted after chronic DBS showed a decrease in hippocampal corticosterone, indicating that DBS may have a regulatory effect in the hypothalamic-pituitary-adrenal axis. Our findings demonstrate the potential of in vivo SPME as a tool of scientific and clinical interest capable of revealing changes in a wide range of metabolites in brain tissue.

Rostrocaudal subregions of the ventral tegmental area are differentially impacted by chronic stress.

RATIONALE: The ventral tegmental area (VTA) is implicated in the pathophysiology of depression and addictive disorders and is subject to the detrimental effects of stress. Chronic stress may differentially alter the activity pattern of its different subregions along the rostrocaudal and dorsoventral axes, which may relate to the variable behavioral sensitivity to stress mediated by these subregions. OBJECTIVES: Here, chronic stress-exposed rats were tested for depressive-like reactivity. In situ hybridization for zif268 as a marker of neuronal activation was combined with in vivo single-unit recording of dopaminergic neurons to assess modifications in the activity of the rostral VTA (rVTA) and caudal VTA (cVTA). Changes in the expression of stress-responsive glucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) were also assessed. RESULTS: Stress-induced anhedonia-like, hyper-anxious, and passive-like responding were associated with reductions in dopaminergic burst activity in the cVTA and an increase in local GABAergic activity, particularly in GABAA receptor sensitivity. On the other hand, stress increased single-spiking activity, burst activity, and zif268 mRNA levels in the rVTA, which were associated with increased glutamatergic tonus and enhanced GR and AMPA receptor (AMPAR) expression. rVTA and cVTA activity differentially correlated with sucrose preference and passivity measures. CONCLUSIONS: These data demonstrate that the rVTA and cVTA respond differently to stress and suggest that while cVTA activity may be related to passivity-like states, the activity of both subregions appears to be related to anhedonia and the processing of incentive value. These region-dependent abnormalities indicate the multi-modular composition of the VTA, which could provide multiple substrates for different symptom features.

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder.

Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE <30% of freezing during extinction). Following 2 weeks of DBS, animals were exposed to novel recall sessions and tested in the open field, novelty-suppressed feeding, and elevated plus maze. zif268 expression was measured in structures involved in mechanisms of fear and stress. In vivo electrophysiology was used to record activity from the basolateral amygdala (BLA). We found that DBS improved extinction deficits and anxiety-like behavior in WE animals, having no significant effects in SE rats. No major differences in absolute zif268 levels were recorded across groups. However, correlation between zif268 expression in the IL and BLA was disrupted in WE animals, a deficit that was countered by DBS treatment. Electrophysiology experiments have shown that DBS reduced BLA firing of both putative principal cells and interneurons in WE rats, with no significant differences being detected between SE and SE DBS animals. In summary, IL DBS mitigated fear, partially improved anxiety-like behavior, reversed neurocircuitry abnormalities, and reduced BLA cell firing in a preclinical model of PTSD.

Evaluation of a novel radiotracer for positron emission tomography imaging of reactive oxygen species in the central nervous system.

INTRODUCTION: Few, if any, radiotracers are available for the in vivo imaging of reactive oxygen species (ROS) in the central nervous system. ROS play a critical role in normal cell processes such as signaling and homeostasis but overproduction of ROS is implicated in several disorders. We describe here the radiosynthesis and initial ex vivo and in vivo evaluation of [11C]hydromethidine ([11C]HM) as a radiotracer to image ROS using positron emission tomography (PET). METHODS: [11C]HM and its deuterated isotopologue [11C](4) were produced using [11C]methyl triflate in a one-pot, two-step reaction and purified by high performance liquid chromatography. Ex vivo biodistribution studies were performed after tail vein injections of both radiotracers. To demonstrate sensitivity of uptake to ROS, [11C]HM was administered to rats treated systemically with lipopolysaccharide (LPS). In addition, ex vivo autoradiography and in vivo PET imaging were performed using [11C]HM on rats which had been microinjected with sodium nitroprusside (SNP) to induce ROS. RESULTS: [11C]HM and [11C](4) radiosyntheses were reliable and produced the radiotracers at high specific activities and radiochemical purities. Both radiotracers demonstrated good brain uptake and fast washout of radioactivity, but [11C](4) washout was faster. Pretreatment with LPS resulted in a significant increase in brain retention of radioactivity. Ex vivo autoradiography and PET imaging of rats unilaterally treated with microinjections of SNP demonstrated increased retention of radioactivity in the treated side of the brain. CONCLUSIONS: [11C]HM has the attributes of a radiotracer for PET imaging of ROS in the brain including good brain penetration and increased retention of radioactivity in animal models of oxidative stress.

The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus.

The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor-mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal 5-HT1A and 5-HT2A/C receptor sensitivity. Acute-single or serial URB597 treatment, compared to vehicle, reduced immobility in the forced swim test (FST), increased open arm visits in the elevated plus maze and shortened feeding latency in the novelty-suppressed feeding test (NSFT). Repeated URB597 treatment yielded more profound behavioural effects, which were associated with an increase in hippocampal brain-derived neurotrophic factor (BDNF). The 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA), but not the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) prevented URB597-mediated antidepressant/anxiolytic-like response in the FST and NSFT, while DSP4 did not further affect URB597-mediated increase in raphe 5-HT neuron firing. Repeated URB597 administration decreased hippocampal pyramidal firing in response to 5-HT2A/C and 5-HT1A stimulation with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) and 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), respectively, suggesting plastic adaptation of these receptors. The effects of acute-single and repeated URB597 administration on hippocampal cell firing in response to DOI or 8-OH-DPAT were similar in magnitude and intensity to the positive control citalopram. These data indicate that URB597 acts, either directly or indirectly, on the 5-HT system, increases hippocampal BDNF expression, and modifies 5-HT1A and 5-HT2A/C function.

Rapid anti-depressant and anxiolytic actions following dopamine D1-D2 receptor heteromer inactivation.

A role for the mesolimbic dopaminergic system in the pathophysiology of depression has become increasingly evident. Specifically, brain-derived neurotrophic factor (BDNF) has been shown to be elevated in the nucleus accumbens of depressed patients and to positively contribute to depression-like behaviour in rodents. The dopamine D1-D2 receptor heteromer exhibits significant expression in NAc and has also been shown to enhance BDNF expression and signalling in this region. We therefore examined the effects of D1-D2 heteromer stimulation in rats by SKF 83959, or its inactivation by a selective heteromer-disrupting TAT-D1 peptide on depression- and anxiety-like behaviours in non-stressed animals and in animals exposed to chronic unpredictable stress. SKF 83959 treatment significantly enhanced the latency to immobility in the forced swim test, increased the latency to drink condensed milk and reduced total milk consumption in the novelty-induced hypophagia test, and additionally reduced the total time spent in the open arms in the elevated plus maze test. These pro-depressant and anxiogenic effects of SKF 83959 were consistently abolished or attenuated by TAT-D1 peptide pre-treatment, signifying the behaviours were mediated by the D1-D2 heteromer. More importantly, in animals exposed to chronic unpredictable stress (CUS), TAT-D1 peptide treatment alone induced significant and rapid anxiolytic and antidepressant-like effects in two tests for CUS-induced anhedonia-like reactivity and in the novelty-suppressed feeding test. Together these findings indicate a positive role for the D1-D2 heteromer in mediating depression- and anxiety-like behaviours and suggest its possible value as a novel therapeutic target.

Melancholic-Like behaviors and circadian neurobiological abnormalities in melatonin MT1 receptor knockout mice.

BACKGROUND: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. METHODS: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. RESULTS: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. CONCLUSIONS: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition.

Father absence in the monogamous california mouse impairs social behavior and modifies dopamine and glutamate synapses in the medial prefrontal cortex.

The role of the father in psycho-affective development is indispensable. Yet, the neurobehavioral effects of paternal deprivation (PD) are poorly understood. Here, we examined the behavioral consequences of PD in the California mouse, a species displaying monogamous bonding and biparental care, and assessed its impact on dopamine (DA), serotonin (5-HT), and glutamate (GLU) transmission in the medial prefrontal cortex (mPFC). In adult males, deficits in social interaction were observed, when a father-deprived (PD) mouse was matched with a PD partner. In adult females, deficits were observed when matching a PD animal with a non-PD control, and when matching 2 PD animals. PD also increased aggression in females. Behavioral abnormalities in PD females were associated with a sensitized response to the locomotor-activating effect of amphetamine. Following immunocytochemical demonstration of DA, 5-HT, and GLU innervations in the mPFC, we employed in vivo electrophysiology and microiontophoresis, and found that PD attenuated the basal activity of low-spiking pyramidal neurons in females. PD decreased pyramidal responses to DA in females, while enhancing responses to NMDA in both sexes. We thus demonstrate that, during critical neurodevelopmental periods, PD leads to sex-dependent abnormalities in social and reward-related behaviors that are associated with disturbances in cortical DA and GLU neurotransmission.

Chronic nandrolone decanoate exposure during adolescence affects emotional behavior and monoaminergic neurotransmission in adulthood.

Nandrolone decanoate, an anabolic androgen steroid (AAS) illicitly used by adult and adolescent athletes to enhance physical performance and body image, induces psychiatric side effects, such as aggression, depression as well as a spectrum of adverse physiological impairments. Since adolescence represents a neurodevelopmental window that is extremely sensitive to the detrimental effects of drug abuse, we investigated the long-term behavioral and neurophysiological consequences of nandrolone abuse during adolescence. Adolescent rats received daily injections of nandrolone decanoate (15 mg/kg, i.m.) for 14 days (PND 40-53). At early adulthood (PND 68), forced swim, sucrose preference, open field and elevated plus maze tests were performed to assess behavioral changes. In vivo electrophysiological recordings were carried out to monitor changes in electrical activity of serotonergic neurons of the dorsal raphe nucleus (DRN) and noradrenergic neurons of the locus coeruleus (LC). Our results show that after early exposure to nandrolone, rats display depression-related behavior, characterized by increased immobility in the forced swim test and reduced sucrose intake in the sucrose preference test. In addition, adult rats presented anxiety-like behavior characterized by decreased time and number of entries in the central zone of the open field and decreased time spent in the open arms of the elevated plus maze. Nandrolone decreased the firing rate of spontaneously active serotonergic neurons in the DRN while increasing the firing rate of noradrenergic neurons in the LC. These results provide evidence that nandrolone decanoate exposure during adolescence alters the emotional profile of animals in adulthood and significantly modifies both serotonergic and noradrenergic neurotransmission.