The clinical utility of combinatorial pharmacogenomic testing for patients with depression: a meta-analysis.

To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions for patients with major depressive disorder (MDD). The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model. Overall, 1556 patients were included from four studies, with outcomes evaluated at week 8 or week 10.

Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking.

The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 × 6 h/d) but not short-access (ShA; 14 × 2 h/d) self-administration showed robust shock-induced cocaine seeking.

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances.

Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances.

Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex.

Background: Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL).

Methods: We have established a rat model for these stage-setting effects of stress.

The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective.

The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components.

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3.

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF.

CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats.

Rationale: Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Stress-induced cocaine seeking requires a beta-2 adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis that regulates CRF actions in the ventral tegmental area.

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs).

Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice.

Rationale: Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF).

Objectives: The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice.

Neurobiological mechanisms that contribute to stress-related cocaine use.

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors.

Corticosterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking.

Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction.

β-adrenergic receptor mediation of stress-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: roles for β1 and β2 adrenergic receptors.

Stress can trigger the relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that may involve norepinephrine release and β-adrenergic receptor activation. The present study examined the role of β-adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg i.p.

Adrenal activity during repeated long-access cocaine self-administration is required for later CRF-Induced and CRF-dependent stressor-induced reinstatement in rats.

Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.

Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats.

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats.

Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats.

Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine.

Involvement of noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: role for β-2 adrenergic receptors.

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.