Pharmacology, Biochemistry, and Behavior

BACKGROUND: Postpartum depression [PPD] is a prevalent and debilitating mood disorder that affects mothers in the weeks to months after childbirth. Zuranolone (Zurzuvae) is a novel pharmaceutical agent that was approved by the US FDA on 4 August 2023 for the management of PPD. This review article provides a comprehensive overview of zuranolone, focusing on its dosing, chemistry, mechanism of action, clinical trials, adverse drug reaction, and overall conclusion regarding its utility in the management of PPD...

RATIONALE: Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate...

BACKGROUND: Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction...

Addiction involves key impairments in reward sensitivity (RS). The current study explored impaired RS to natural reward as a predisposing factor to addictive-like behavior. Alcohol preferring (P) rats are selectively bred based on significantly greater ethanol consumption and preference and offer the ability to inspect differences in subjects with a positive family history of addictive-like behavior. P rat's RS was compared to RS in the well-used Sprague-Dawley (SD) strain. To assess RS in a novel manner, instrumental incentive contrast, discrimination and consumption of sucrose solution were examined...

BACKGROUND: Several studies have demonstrated that ACh modulates the dopaminergic circuit in the nucleus accumbens, and its blockade appears to be associated with the inhibition of the reinforced effect or the increase in dopamine caused by cocaine use. The objective of this study was to evaluate the effect of biperiden (a muscarinic receptor antagonist with a relatively higher affinity for the M1 receptor) on crack/cocaine use relapse compared to a control group that received placebo...

Obesity is a prevalent disease, but effective treatment options remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that central administration of the α7nAChR agonist PHA-543613 (PHA) would decrease food intake and body weight in adult male Sprague Dawley rats. Intracerebroventricular (ICV) PHA administration in chow-fed rats produced a suppression of energy intake and weight gain over 24 h...

Autism spectrum disorder (ASD) is a neurodevelopment disorder that mainly arises due to abnormalities in different brain regions, resulting in behavioral deficits. Besides its diverse phenotypical features, ASD is associated with complex and varied etiology, presenting challenges in understanding its precise neuro-pathophysiology. Pioglitazone was reported to have a fundamental role in neuroprotection in various other neurological disorders. The present study aimed to investigate the therapeutic potential of pioglitazone in the prenatal valproic acid (VPA)-model of ASD in Wistar rats...

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine...

In addition to overt somatic symptoms, cannabinoid withdrawal can also manifest as disruptions in motivation and attention. Experimental animal models using operant-conditioning approaches reveal these differences, in either antagonist-precipitated or spontaneous withdrawal models. However, these processes have yet to be characterized in the same subjects simultaneously. To differentiate between motivational and attentional processes disrupted in cannabinoid withdrawal, the current study used a response alternation task in which a fixed-ratio (FR) schedule repeatedly alternated between two spatially distinct response options throughout daily training sessions...

Gamma-aminobutyric acid (GABA) disinhibition in medial hypothalamus (MH) nuclei of rats elicits some defensive reactions that are considered panic attack-like behaviours. Recent evidence showed that the norepinephrine-mediated system modulates fear-related defensive behaviours organised by MH neurons at least in part via noradrenergic receptors recruitment on midbrain tegmentum. However, it is unknown whether noradrenergic receptors of the MH also modulate the panic attack-like reactions. The aim of this work was to investigate the distribution of noradrenergic receptors in MH, and the effects of either α1 -, α2 - or β-noradrenergic receptors blockade in the MH on defensive behaviours elaborated in hypothalamic nuclei...

Behavioral sensitization is defined as the enhanced behavioral response to drugs of abuse after repeated exposure, which can serve as a behavioral model of addiction. Our previous study demonstrated that behavioral cross-sensitization occurs between cocaine and ethanol, suggesting commonalities between these drugs. N-methyl-d-aspartate (NMDA) receptors play important roles in synaptic plasticity, learning, memory, and addiction-associated behaviors. However, little is known about whether NMDA receptor-mediated signaling regulation is a common feature following behavioral sensitizations induced by cocaine and ethanol...

Synthetic cannabinoids are associated with higher risk of dependence and more intense withdrawal symptoms than plant-derived Δ9-tetrahydrocannabinol (THC). Avoidance of withdrawal symptoms, including anxiogenic effects, can contribute to continued cannabinoid use. Adult male and female Long-Evans rats were given escalating doses of WIN 55,212-2 (WIN) via twice daily intrajugular infusions. Precipitated withdrawal was elicited with SR 141716 A (rimonabant) 4 h after the final infusion. Global withdrawal scores (GWS) were compiled by summing z-scores of observed somatic behaviors over a 30-min period with locomotor activity simultaneously collected via beam breaks...

Physical activity (PA) is very beneficial for physical and mental health. This study aims to examine the resilience-inducting effect of PA in adult male Wistar rats exposed to unpredictable chronic mild stress (UCMS). Furthermore, we analyzed the influence of PA on behavioral tasks and functional brain connectivity with cytochrome c oxidase technique. The cytochrome c oxidase (CCO) is a mitochondrial enzyme involved in oxidative phosphorylation and ATP generation. For this analysis, we included five groups: Basal (n = 10, to determine the basal level of brain activity), Behav (n = 15, subjected exclusively to behavioral tests), PA (n = 10, exposed to physical activity), UCMS (n = 15, subjected to a stress protocol) and PA + UCMS (n = 15, exposed to PA prior to stress)...

Alcohol withdrawal syndrome (AWS) is a poorly studied phenotype of alcohol use disorder. Understanding the relationship between allelic interactions and AWS-related impulsivity and aggression could have significant implications. This study aimed to investigate the main and interacting effects of ZNF804A and mTOR on impulsivity and aggression during alcohol withdrawal. 446 Chinese Han adult males with alcohol dependence were included in the study. Impulsivity and aggression were assessed, and genomic DNA was genotyped...

Along the conventional pathways, Renin-angiotensin system (RAS) plays a key role in the physiology of the CNS and pathogenesis of psychiatric diseases. RAS is a complex regulatory pathway which is composed of several peptides and receptors and comprises two counter-regulatory axes. The classical (ACE1/AngII/AT1 receptor) axis and the contemporary (ACE2/Ang (1-7)/Mas receptor) axis. The genes coding for elements of both axes have been broadly studied. Numerous functional polymorphisms on components of RAS have been identified to serve as informative disease and treatment markers...

Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in cigarettes, enhances the reinforcing value of other environmental rewards. Under some circumstances, this reward enhancement maintains nicotine consumption. Varenicline (i.e., cessation aid Chantix™) also has reward-enhancement effects via nicotinic acetylcholine receptor agonism (nAChRs) - albeit less robust than nicotine. Cotinine is the major metabolite of nicotine...

RATIONALE: Psychedelic drugs, which share in common 5-HT2A receptor agonist activity, have shown promise in treating alcohol-use disorders (AUDs). Repeated exposure to ethanol (EtOH) induces molecular and behavioural changes reflective of neuroadaptations that may contribute to addiction. Psychedelic drugs can induce neuroplasticity also, raising the possibility that their potential clinical effects in AUD may involve an action to reverse or offset effects of long-term changes induced by EtOH...

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence...

Cannabinoids have been proposed as therapeutics for pain mitigation. Therefore, the antihyperalgesic effects of a proprietary cannabis-derived mixture, Non-Euphoric Phytocannabinoid Elixir #14 (NEPE14), were examined in a persistent Complete Freund's Adjuvant (CFA)-induced model of inflammatory pain. The acute antinociceptive and operant behavioral effects of NEPE14 were then compared with single cannabinoid preparations of Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-THC, the synthetic cannabinoid (-)-CP 55,940 (CP), and cannabidiol (CBD)...

BACKGROUND: Alcohol use disorder is a chronic recurrent encephalopathy, and its pathogenesis has not been fully understood. Among possible explanations, neuroinflammation caused by the disorders of brain central immune signaling has been identified as one possible mechanism of alcohol use disorder. As the basic components of cells and important bioactive molecules, sphingolipids are essential in regulating many cellular activities. Recent studies have shown that sphingolipids-mediated neuroinflammation may be involved in the development of alcohol use disorder...