Psychopharmacology

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability...

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RATIONALE: Alcopop beverages are generally the first alcoholic beverage that young females drink which contain high levels of sugar and alcohol. The over-consumption of these drinks may encourage alcohol co-administration with methamphetamine (METH) impacting on drinking behaviour and glial function. AIMS: The aims of this study were to evaluate the effect of adolescent binge alcohol exposure on consumption level, anxiety-like behaviour, cross-sensitization with METH and on astrocyte expression in reward related brain regions...

RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward...

RATIONALE: Methamphetamine addiction is a persistent and intractable pathological learning and memory, whereas no approved therapeutics is available. However, few attentions have been paid to how associative learning participates in the formation of intractable memory related to drug addiction OBJECTIVES AND METHODS: To investigate the role of associative learning in methamphetamine addiction and the underlying neurobiological mechanism, methamphetamine self-administration, oral sucrose self-administration, chemogenetic neuromanipulation, and fiber photometry in mice were performed in this study...

RATIONALE: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. OBJECTIVES: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective...

RATIONALE: Treatments with the serotonergic psychedelic psilocybin are being investigated for multiple neuropsychiatric disorders. Because many patients with these disorders use selective serotonin reuptake inhibitors (SSRIs), understanding interactions between psilocybin and SSRIs is critical for evaluating the safety, efficacy, and scalability of psilocybin-based treatments. Current knowledge about these interactions is limited, as most clinical psilocybin research has prohibited concomittant SSRI use...

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention...

RATIONALE/OBJECTIVES: Targeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice. METHODS: Mice received escalating doses of oxycodone (9-33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9...

RATIONALE: Patients with schizophrenia with second-generation antipsychotics (SGAs) treatment have shown an increased risk of bone fragility and susceptibility to fracture; however, it is still unclear whether this risk is derived from the effect of antipsychotics on balance of bone metabolism. OBJECTIVES: We investigated the changes of two bone turnover biomarkers (BTMs) concentrations in people with schizophrenia receiving SGAs: procollagen type I aminoterminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) as BTMs of osteogenesis and bone resorption, respectively, to explore how antipsychotics contribute to bone fragility...

RATIONALE AND OBJECTIVE: Avoidance of opioid withdrawal plays a key role in human opioid addiction. Here, we present a procedure for studying operant negative reinforcement in rats that was inspired by primate procedures where opioid-dependent subjects lever-press to prevent naloxone infusions. METHODS: In Experiment 1, we trained rats (n = 30, 15 females) to lever-press to escape and then avoid mild footshocks (0.13-0.27 mA) for 35 days (30 trials/d)...

RATIONALE: Major Depressive Disorder (MDD) significantly impairs the quality of life for those affected. While the exact causes of MDD are not fully understood, the deficit of monoamines, especially serotonin and noradrenaline, is widely accepted. Resistance to long-term treatments and adverse effects are often observed, highlighting the need for new pharmacological therapies. Synthetic organic compounds containing selenium have exhibited pharmacological properties, including potential antidepressant effects...

RATIONALE: Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined. OBJECTIVE: To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice...

RATIONAL: Patients experience post-stroke cognitive impairment during aging. To date, no specific treatment solution has been reported for this disorder. OBJECTIVE: The purpose of this study was to evaluate the effects of exercise training and coenzyme Q10 supplementation on middle cerebral artery occlusion (MCAO) induced behavioral impairment, long-term potentiation inhibition and cerebral infarction size in aging rats. METHODS: Fifty aging male rats underwent MCAO surgery and were randomly distributed in to the following groups: 1-Sham, 2- control, 3- Coenzyme Q10, 4- Exercise training and 5- Exercise training with Q10 supplementation (Ex + Q10)...

RATIONALE: The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. OBJECTIVES: To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials...

RATIONALE: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. OBJECTIVES: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. METHODS: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC)...

RATIONALE: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown...

RATIONALE: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects...

RATIONALE: In 2018, the International Classification of Diseases (ICD-11) classified Gaming Disorder (GD) as a mental disorder. GD mainly occurs among adolescents, who, after developing addiction, show psychopathological traits, such as social anxiety, depression, social isolation, and attention deficit. However, the different studies conducted in humans so far show several limitations, such as the lack of demographic heterogeneity and equal representation of age, differences in the type of game and in the follow-up period...

RATIONALE: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. OBJECTIVES: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. METHODS: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA...