Antidepressant actions of ketamine engage cell-specific translation via eIF4E.

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.

Selective Enhancement of REM Sleep in Male Rats through Activation of MT1 Receptors Located in the Locus Coeruleus Norepinephrine neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMs without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus coeruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.Significance Statement Rapid eye movement sleep (REMS) is involved in the processes of memory consolidation and emotional regulation, but drugs selectively enhancing REMS are scant. Herein, we show that the first-in-class selective melatonin MT1 receptor agonist UCM871, by inhibiting the activity of norepinephrine neurons in the locus coeruleus, an important nucleus regulating the sleep/wake cycle, selectively increases the duration of REMS. These findings enhance our current understanding of the neurobiology and pharmacology of REMS and provide a possible novel mechanism and target for disorders associated with REMS dysfunctions.

Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms.

BACKGROUND: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. METHODS: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. RESULTS: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. CONCLUSIONS: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.

Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 µg/kg) injection failed to increase SB. However, repeated LSD (30 µg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms.

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. SIGNIFICANCE STATEMENT: Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Sleep Quality After Quetiapine Augmentation in Patients With Treatment-Resistant Depression and Personality Disorders.

PURPOSE/BACKGROUND: Quetiapine is a first-line augmenting agent for treatment-resistant depression (TRD) and is used off-label in insomnia. Quetiapine and its active metabolite norquetiapine act mostly on 5-HT2A, 5-HT2C, H1, and D2 as antagonists and on 5-HT1A as partial agonists. Patients with TRD often have comorbid personality disorder (PD), and evidence suggests an association between sleep disturbance and recovery among patients with PD. Here, we aimed to evaluate the effects of quetiapine on sleep in TRD patients with and without PD (PD+/PD-). METHODS/PROCEDURES: We reviewed health records of 38 patients with TRD (20 TRD/PD+) who had been treated with a pharmacotherapy regimen including quetiapine. Clinical outcomes were determined by comparing changes in sleep items of the Hamilton Depression Rating Scale at the beginning (T0) and after 3 months of an unchanged treatment (T3). FINDINGS/RESULTS: Patients with TRD/PD+ and TRD/PD- taking quetiapine showed significant improvement in sleep items from T0 to T3 (P < 0.001, ηp2 ≥ 0.19). There was a significant personality × time interaction for sleep-maintenance insomnia (P = 0.006, ηp2 = 0.23), with TRD/PD+ showing a greater improvement at T3 compared with TRD/PD- (P = 0.01). While exploring other sleep items, no personality × time interaction was found. In the TRD/PD- group, improvement in sleep items was associated with an overall improvement in depressive symptoms (r = 0.55, P = 0.02). IMPLICATIONS/CONCLUSIONS: Quetiapine induced greater improvements in sleep-maintenance insomnia among TRD/PD+ patients than TRD/PD-. These findings suggest quetiapine could have a therapeutic role for insomnia in PD underscoring a distinct underlying neurobiological mechanism of sleep disturbance in people living with PD.

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

Acanthoscurria gomesiana spider-derived Mygalin in the prelimbic prefrontal cortex modulates neuropathic pain and depression comorbid.

Depression has a high rate of comorbidity with neuropathic pain. This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the Acanthoscurria gomesiana spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive-like behavior) tests. BDA neural tract tracer-labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N-methyl-D-aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive-like effects, and the NMDA agonist reversed these effects.

Parental Death During Adolescence: A Review of the Literature.

While extensive research exists on parental loss in childhood and the related psychological interventions, little has been done in the adolescent population. Adolescence is a particular phase of life characterized by a singular psychological, emotional, neurological, and endocrinological development, paralleled by the process of self-affirmation and an opening toward social relationships. This complex neuropsychological phase should thus be understood independently from children and adults. The objective of this work was to review the literature studying the impacts of parental loss in adolescents. The current review identified a wide range of behavioral and emotional responses to parental death in adolescence, including depression, suicidal ideations, anxiety, insomnia, addiction and impaired function at school and home. The role of peers, school life, and family and social environment are important for the recovery from loss. More studies are required to better understand the different psychological trajectories in adolescence after parental death and tailor mental health interventions accordingly.

Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine.

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

Sex Differences in Responses to Antidepressant Augmentations in Treatment-Resistant Depression.

BACKGROUND: Women are nearly twice as likely as men to suffer from major depressive disorder. Yet, there is a dearth of studies comparing the clinical outcomes of women and men with treatment-resistant depression (TRD) treated with similar augmentation strategies. We aimed to evaluate the effects of the augmentation strategies in women and men at the McGill University Health Center. METHODS: We reviewed health records of 76 patients (42 women, 34 men) with TRD, treated with augmentation strategies including antidepressants (AD) with mood stabilizers (AD+MS), antipsychotics (AD+AP), or in combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery-Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology (QIDS-C16), and Clinical Global Impression rating scale (CGI-S) at the beginning and after 3 months of an unchanged treatment. Changes in individual items of the HAMD-17 were also compared between the groups. RESULTS: Women and men improved from beginning to 3 months on all scales (P < .001, η p2 ≥ 0.68). There was also a significant sex × time interaction for all scales (P < .05, η p2 ≥ 0.06), reflecting a greater improvement in women compared with men. Specifically, women exhibited greater improvement in early (P = .03, η p2 = 0.08) and middle-of-the-night insomnia (P = .01, η p2 = 0.09) as well as psychomotor retardation (P < .001 η p2 = 0.16) and psychic (P = .02, η p2 = 0.07) and somatic anxiety (P = .01, η p2 = 0.10). CONCLUSIONS: The combination of AD+AP/MS generates a significantly greater clinical response in women compared with men with TRD, supporting the existence of distinct pharmacological profiles between sexes in our sample. Moreover, they emphasize the benefit of augmentation strategies in women, underscoring the benefit of addressing symptoms such as insomnia and anxiety with AP and MS.

Distinct Effects of Antidepressants in Association With Mood Stabilizers and/or Antipsychotics in Unipolar and Bipolar Depression.

PURPOSE/BACKGROUND: There is a dearth of studies comparing the clinical outcomes of patients with treatment-resistant unipolar (TRD) depression and depression in bipolar disorder (BD) despite similar treatment strategies. We aimed to evaluate the effects of the pharmacological combinations (antidepressants [AD], mood stabilizers [MS], and/or antipsychotics [AP]) used for TRD and BD at the McGill University Health Center. METHODS/PROCEDURES: We reviewed health records of 206 patients (76 TRD 130 BD) with TRD and BD treated with similar augmentation strategies including AD with MS (AD+MS) or AP (AD+AP) or combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-time Hamilton Depression Rating Scale (HAMD-17), Quick Inventory of Depressive Symptomatology, and Clinical Global Impression-Severity of Illness at the beginning (T0) and after 3 months of an unchanged treatment (T3). FINDINGS/RESULTS: Baseline HAMD-17 scores in TRD were higher than in BD (P < 0.001), but TRD patients had a greater improvement at end point (P = 0.003). Antidepressants with AP generated greater reductions in HAMD-17 in TRD compared with BD (P = 0.02). Importantly, in BD patients, the addition of AD compared with other treatment strategies failed to improve the outcome. The limitations of this study include possibly unrepresentative subjects from tertiary care settings, incomplete matching of BD and TRD subjects, nonrandomized treatment with unmatched agents, doses, and times, unknown treatment adherence, and nonblinded retrospective outcome assessments. Nevertheless, the findings may reflect real-world interactions of clinically selected pharmacotherapies. IMPLICATIONS/CONCLUSIONS: Combination of augmentation strategies such as AD+AP and/or MS showed a better clinical improvement in patients with TRD compared with BD suggesting a limited evidence for AD potentiation in BD.

Supraspinal melatonin MT2 receptor agonism alleviates pain via a neural circuit that recruits mu opioid receptors.

Melatonin, through its G protein-coupled receptor (GPCR) (MTNR1B gene) MT2 , is implicated in analgesia, but the relationship between MT2 receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured [SNI]), the selective melatonin MT2 agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the nonselective opioid antagonist naloxone and the selective MOR antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pronociceptive ON-cells, and the enhancement of the firing of the antinociceptive OFF-cells, induced by the microinjection of the MT2 agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT2 receptors are expressed in both excitatory (CaMKIIα+ ) and inhibitory (GAD65+ ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons coexpressed MOR and MT2 receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT2 receptor agonism requires MORs to exert its antiallodynic effects, mostly through an interneuronal circuit involving MOR and MT2 receptors.

Lifetime Cannabis Use Disorder Is Not Associated With Lifetime Impulsive Behavior and Severe Violence in Patients With Schizophrenia Spectrum Disorders From a High-Security Hospital.

PURPOSE/BACKGROUND: The link between substances of abuse, impulsivity, and violence in psychotic patients remains unclear. This study aims at unraveling whether cannabis use disorder is associated with violent and/or psychotic behavior in patients who are hospitalized in a high-security hospital. METHODS/PROCEDURES: We conducted a cross-sectional retrospective study in 124 patients with schizophrenia spectrum disorders admitted to a high-security hospital. Lifetime violent behavior was assessed using the History of Aggressive Behavior Form-Subject of the MacArthur Violence Risk Assessment Study and impulsivity using the Psychopathy Checklist-Revised (considering items: "proneness to boredom," "lack of self-control," and "impulsive thoughtless gestures"). Substance use disorder was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Positive and Negative Syndrome Scale was also administered. FINDINGS/RESULTS: Violent and nonviolent psychotic patients showed similar prevalence of cannabis use disorder. Alcohol and cocaine use disorders were more prevalent among violent psychotic patients. Cannabis use disorder was not associated with any dimension of impulsivity, whereas alcohol use disorder was positively correlated to impulsive thoughtless gestures (standardized ß = 0.213, P = 0.027) and cocaine use disorder with proneness to boredom (standardized ß = 0.290, P = 0.002). Finally, logistic regression analysis revealed that, unlike cannabis and cocaine use disorders, alcohol use disorder (odds ratio, 3.964; 95% confidence interval, 1.729-9.087; P = 0.001) was a factor associated with violence. IMPLICATIONS/CONCLUSIONS: These findings show that cannabis and alcohol are largely abused and coabused by psychotic patients with a propsensity for violence, but only alcohol is associated with impulsive and violent behavior. Therefore, especially alcohol abuse should be seriously considered by practitioners when evaluating the dangerousness of patients with schizophrenia spectrum disorders.

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.

Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery.

Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the α2δ subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined along with novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia.

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.

Dysfunction of serotonergic activity and emotional responses across the light-dark cycle in mice lacking melatonin MT2 receptors.

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT2 receptor knockout (MT2 -/- ) mice show a decreased nonrapid eye movement sleep over 24 hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons and anxiety- and depression-like behavior. We found that the 5-HT burst-firing activity was tonically reduced across the whole 24 hours in MT2 -/- mice compared with MT2 +/+ mice.  Importantly, the physiological changes in the spontaneous firing activity of DRN 5-HT neurons during the light/dark cycle were nullified in MT2 -/- mice, with a higher DRN 5-HT neural firing activity during the light phase in MT2 -/- than in MT2 +/+  mice. The role of MT2 receptors over DRN 5-HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose dependently inhibited DRN 5-HT activity, mostly during the dark phase. Compared with MT2 +/+ , MT2 -/- mice displayed an anxiety-like phenotype in the novelty-suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark than during the light phase in MT2 +/+ mice, the opposite was seen in MT2 -/- mice. No differences between MT2 +/+ and MT2 -/- mice were observed for depression-like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT2 receptor genetic inactivation impacts 5-HT neurotransmission and interferes with anxiety levels by perturbing the physiologic light/dark pattern.

Nociceptive responses in melatonin MT2 receptor knockout mice compared to MT1 and double MT1 /MT2 receptor knockout mice.

Melatonin, a neurohormone that binds to two G protein-coupled receptors MT1 and MT2, is involved in pain regulation, but the distinct role of each receptor has yet to be defined. We characterized the nociceptive responses of mice with genetic inactivation of melatonin MT1 (MT1 -/- ), or MT2 (MT2 -/- ), or both MT1 /MT2 (MT1 -/- /MT2 -/- ) receptors in the hot plate test (HPT), and the formalin test (FT). In HPT and FT, MT1 -/- display no differences compared to their wild-type littermates (CTL), whereas both MT2 -/- and MT1 -/- /MT2 -/- mice showed a reduced thermal sensitivity and a decreased tonic nocifensive behavior during phase 2 of the FT in the light phase. The MT2 partial agonist UCM924 induced an antinociceptive effect in MT1 -/- but not in MT2 -/- and MT1 -/- /MT2 -/- mice. Also, the competitive opioid antagonist naloxone had no effects in CTL, whereas it induced a decrease of nociceptive thresholds in MT2 -/- mice. Our results show that the genetic inactivation of melatonin MT2 , but not MT1 receptors, produces a distinct effect on nociceptive threshold, suggesting that the melatonin MT2 receptor subtype is selectively involved in the regulation of pain responses.

Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives.

Melatonin (MLT), a neuromodulator mainly acting through two G-protein coupled receptors MT1 and MT2, regulates many brain functions, including circadian rhythms, mood, pain and sleep. MLT and non-selective MT1/MT2 receptor agonists are clinically used in neuropsychiatric and/or sleep disorders. However, the selective roles of the MT1 and MT2 receptors need to be clarified. Here, we review the role of the MT1 receptor in neuropsychopharmacology, describe the anatomical localization of MT1 receptors in the brain, discuss the medicinal chemistry, biochemistry and molecular aspects of the receptor, and explore the findings linking MT1 receptors to psychiatric and neurological disorders. MT1 receptors are localized in brain regions which regulate circadian rhythms, sleep, and mood, such as the suprachiasmatic nucleus, cortex, hippocampus, dorsal raphe nucleus and lateral hypothalamus. Their activation modulates intracellular signaling pathways also targeted by psychoactive drugs, including antidepressants and mood stabilizers. MT1 receptor knockout mice display increased anxiety, a depressive-like phenotype, increased propensity to reward and addiction, and reduced Rapid-Eye-Movement sleep. These behavioral dysfunctions are associated with altered serotonergic and noradrenergic neurotransmissions. Several studies indicate that the MT1, rather than MT2, receptor is implicated in circadian rhythm regulation. The involvement of MT1 receptors in Alzheimer's and Huntington diseases has also been proposed. Postmortem studies in depressed patients have further confirmed the possible involvement of MT1 receptors in depression. Overall, there is substantial evidence indicating a role for MT1 receptor in modulating brain function and mood. Consequently, this MLT receptor subtype deserves to be further examined as a novel target for neuropsychopharmacological drug development.