The anxiogenic drug yohimbine is a reinforcer in male and female rats.

The indole alkaloid yohimbine is an anxiogenic drug that activates stress-responsive systems in the brain. However, because yohimbine also elicits approach behaviors, this study employed male and female Sprague-Dawley rats to explore its potential reinforcing effects. Thus, it was first determined if intravenous (IV) infusions of yohimbine (0.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

Introduction: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, , , , and , and its effect on these outcomes.

Methods: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole.

Adolescent restraint stress enhances adult nicotine reinforcement in male and female rats.

Adolescent stress is a risk factor for the initiation of nicotine use, but whether adolescent stress can enhance nicotine reinforcement when it is initiated later in adulthood is unknown, and it is unclear whether males and females are equally impacted. Therefore, this study assessed physiological responses (body weight and blood serum corticosterone - CORT) to restraint stress (RS) during adolescence (P28-55) or during adulthood (P70-96) in male and female Sprague-Dawley rats. When all subjects reached adulthood (P69 or 110; 2 weeks after termination of stress exposure), they were tested on sucrose preference and intravenous single-dose nicotine (0.

Influence of , , and Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

Objectives: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, and , and the transmembrane efflux pump, P-glycoprotein (i.e.

Role of dopamine D1 receptor in the modulation of memory consolidation by passive and self-administered heroin and associated conditioned stimuli.

It has been proposed that opiates modulate memory consolidation, but recent work has indicated that this effect may be mediated by how the drug is experienced (i.e., passive injections vs.

Enhancement of memory consolidation by an avoidance conditioned stimulus: Modulation by the D3 receptor.

Conditioned stimuli (CS) paired with foot-shock can enhance memory consolidation. Because the dopamine D3 receptor (D3R) has been implicated in mediating various responses to CSs, the current study explored its potential role in modulation of memory consolidation by an avoidance CS. Male Sprague-Dawley rats trained to avoid foot-shocks in a two-way signalled active avoidance task (8 sessions, 30 trials per session, 0.

Double dissociation of perirhinal nicotinic acetylcholine receptors and dopamine D2 receptors in modulation of object memory consolidation by nicotine, cocaine and their conditioned stimuli.

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.

ABCB1 Gene Variants and Antidepressant Treatment Outcomes: A Systematic Review and Meta-Analysis Including Results from the CAN-BIND-1 Study.

The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta-analysis to investigate the association between six ABCB1 single-nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN-BIND-1) cohort. For the CAN-BIND-1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels.

Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study.

Cytochrome P450 drug-metabolizing enzymes may contribute to interindividual differences in antidepressant outcomes. We investigated the effects of CYP2C19 and CYP2D6 gene variants on response, tolerability, and serum concentrations. Patients (N = 178) were treated with escitalopram (ESC) from weeks 0-8 (Phase I), and at week 8, either continued ESC if they were responders or were augmented with aripiprazole (ARI) if they were non-responders (<50% reduction in Montgomery-Åsberg Depression Rating Scale from baseline) for weeks 8-16 (Phase II).

Conditioned anti-immobility by ketamine: A comparison to escitalopram and bupropion.

This study was designed to explore the clinical belief that "set and setting" play an important role in favorable responses to psychedelic agents such as ketamine (KET). In fact, there is evidence in animals that the antidepressant effect of this drug may involve drug-environment interactions in which a context paired with its effects acquires the ability to influence behavior. Therefore, it was investigated in male Sprague-Dawley rats whether exposure to a context paired with the effects of KET, or with the effects of the common antidepressant medications bupropion (BUP) and escitalopram (ESC), could produce an antidepressant-like conditioned response.

Clinical and Preclinical Assessments of Anhedonia in Psychiatric Disorders.

Anhedonia is a prevalent symptom across many psychiatric disorders. The contemporary scope of anhedonia across various models includes interest, reward anticipation, motivation, effort expenditure, reward valuation, expectation, pleasure, satiation, and learning. In order to further elucidate the impact of anhedonia on treatment outcomes, quality of life, as well as brain function, validated tools to probe the various facets of anhedonia are necessary.

Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in -Oleoylglycine and -Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators.

The endocannabinoidome mediators, -Oleoylglycine (OlGly) and -Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses. To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats. Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5).

Extended amygdala, conditioned withdrawal and memory consolidation.

Opioid withdrawal can be associated to environmental cues through classical conditioning. Exposure to these cues can precipitate a state of conditioned withdrawal in abstinent subjects, and there are suggestions that conditioned withdrawal can perpetuate the addiction cycle in part by promoting the storage of memories. This review discusses evidence supporting the hypothesis that conditioned withdrawal facilitates memory consolidation by activating a neurocircuitry that involves the extended amygdala.

Effect of ketamine on the physiological responses to combined hypoglycemic and psychophysical stress.

There is evidence that hypoglycemic stress can interact with other stressors, and that ketamine can mitigate the impact of these stressors on behavior and physiology. The current study in male Sprague-Dawley rats investigated whether pre-treatment with 0, 10, or 20 mg/kg ketamine could modulate the interaction between hypoglycemia induced by 0 or 300 mg/kg 2-deoxy-D-glucose (2-DG) and the psychophysical stress of forced swimming (FSS; 6 sessions, 10 min/session) on serum concentrations of corticosterone (CORT) and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α. It was found that 2-DG enhanced the CORT response to an initial session of FSS, and this effect dissipated after multiple sessions.

Effects of inescapable stress on responses to social incentive stimuli and modulation by escitalopram.

Rationale: Stress is a well-known risk factor for anhedonia, and its impacts on social reward functions may be mitigated by its controllability. Moreover, there are questions about the effectiveness of selective serotonin reuptake inhibitors (SSRIs) on improving social hedonic functioning deficits characteristic of major depression.

Objectives: The current study in male Sprague-Dawley rats investigated the effects of uncontrollable stress on responses to social incentive stimuli and possible modulation by the SSRI escitalopram (ESC).

Memory enhancing effects of nicotine, cocaine, and their conditioned stimuli; effects of beta-adrenergic and dopamine D2 receptor antagonists.

Background: There is evidence that post-training exposure to nicotine, cocaine, and their conditioned stimuli (CS), enhance memory consolidation in rats. The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation.

Methods: Males Sprague-Dawley rats tested on the spontaneous object recognition task received post-sample exposure to 0.

High fructose corn syrup alters behavioural and neurobiological responses to oxycodone in rats.

There are indications that sugars in the diet can play a role in vulnerability to opioid abuse. The current study examined a range of neuro-behavioural interactions between oxycodone (OXY) and high fructose corn syrup (HFCS). Male Sprague-Dawley rats had access to HFCS (0 or 50%) over 26 days in their home cages and were subsequently tested on place conditioning induced by 0, 0.

Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence.

Anhedonia is one of the core symptoms of major depressive disorder (MDD), which is often inadequately treated by traditional antidepressants. The modern framework of anhedonia extends the definition from impaired consummatory pleasure or interest in rewards to a broad spectrum of deficits that impact functions such as reward anticipation, approach motivation, effort expenditure, reward valuation, expectation, and reward-cue association learning. Substantial preclinical and clinical research has explored the neural basis of reward deficits in the context of depression, and has implicated mesocorticolimbic reward circuitry comprising the nucleus accumbens, ventral pallidum, ventral tegmental area, amygdala, hippocampus, anterior cingulate, insula, orbitofrontal cortex, and other prefrontal cortex regions.

Analysis of memory modulation by conditioned stimuli.

Conditioned stimuli (CS) have multiple psychological functions that can potentially contribute to their effect on memory formation. It is generally believed that CS-induced memory modulation is primarily due to conditioned emotional responses, however, well-learned CSs not only generate the appropriate behavioral and physiological reactions required to best respond to an upcoming unconditioned stimulus (US), but they also serve as signals that the US is about to occur. Therefore, it is possible that CSs can impact memory consolidation even when their ability to elicit conditioned emotional arousal is significantly reduced.

Evidence of hypoglycemic anhedonia and modulation by bupropion in rats.

Background: Disorders characterized by dysfunction of glucose metabolism are often comorbid with depression. The current study investigated whether a hypoglycemic state caused by 2-deoxy-d-glucose (2-DG) can result in anhedonic behaviors responsive to stimulation of monoamine activity.

Methods: In experiment 1, male Sprague-Dawley rats were tested for maintenance of intra-oral self-administration (IOSA) of a sweet solution after pre-treatment with 300 or 500 mg/kg 2-DG, a blocker of glucose metabolism.

Impact of impaired glucose metabolism on responses to a psychophysical stressor: modulation by ketamine.

Rationale: There is evidence that hypoglycemia, a metabolic stressor, can negatively impact mood and motivation, and can interact with other stressors to potentiate their effects on behavior and physiology.

Objectives/methods: The current study in male Sprague-Dawley rats explored the interaction between impaired glucose metabolism induced by 0, 200, or 300 mg/kg 2-deoxy-D-glucose (2-DG) and a psychophysical stressor induced by forced swimming stress (FSS; 6 sessions, 10 min/session). The endpoints of interest were blood glucose levels, progressive behavioral immobility, and saccharin preference (2-bottle choice test).

Dietary -6/-3 Ratio Influences Brain Fatty Acid Composition in Adult Rats.

There is mounting evidence that diets supplemented with polyunsaturated fatty acids (PUFA) can impact brain biology and functions. This study investigated whether moderately high-fat diets differing in -6/-3 fatty acid ratio could impact fatty acid composition in regions of the brain linked to various psychopathologies. Adult male Sprague Dawley rats consumed isocaloric diets (35% kcal from fat) containing different ratios of linoleic acid (-6) and alpha-linolenic acid (-3) for 2 months.

Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats.

Rationale: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal.

Objectives: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats.