Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats.

Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats.

Effects of Alcohol Withdrawal on Sleep Macroarchitecture and Microarchitecture in Female and Male Rats.

The prevalence of sleep disruptions is higher among people with alcohol use disorder (AUD), particularly during alcohol withdrawal, compared to non-AUD individuals. Although women generally have a higher risk of developing sleep disorders, few studies have investigated sex differences in sleep disruptions following chronic alcohol exposure. The present study examined sleep macroarchitecture (time spent asleep or awake and sleep onset latency) and microarchitecture (bout rate and duration and sleep spindle characterization) prior to alcohol vapor exposure (baseline), during acute withdrawal, and through protracted abstinence in female and male rats.

Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.

The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration.

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.

Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential.

Compulsive-Like Sufentanil Vapor Self-Administration in Rats.

Opioid misuse is at historically high levels in the United States, with inhalation (ie, smoking and vaping) being one of the most common routes of consumption. We developed and validated a novel preclinical model of opioid self-administration by inhalation that does not require surgery and reliably produces somatic and motivational signs of dependence. Rats were trained to perform an operant response (nosepoke) to receive 10 s of vaporized sufentanil, a potent opioid, in 2 h daily sessions.

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors.

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE.

Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats.

Background: Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA).

Norepinephrine at the nexus of arousal, motivation and relapse.

Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α1- and β-noradrenergic receptors within a distributed network of subcortical regions.

Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking.

Amphetamine acts within the lateral hypothalamic area to elicit affectively neutral arousal and reinstate drug-seeking.

Psychostimulants, including amphetamine (AMPH), exert robust arousal-enhancing, reinforcing and locomotor-activating effects. These behavioural actions involve drug-induced elevations in extracellular norepinephrine (NE) and dopamine (DA) within a variety of cortical and subcortical regions. The lateral hypothalamic area (LHA), including the lateral hypothalamus proper, perifornical area and adjacent dorsomedial hypothalamus, is implicated in appetitive- and arousal-related processes.

Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction.

Background: Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA).

Methods: We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1-hour (short access [ShA]) or 6-hour (long access [LgA]) sessions induced plasticity at CeA gamma-aminobutyric acid (GABA)ergic synapses or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (norbinaltorphimine [norBNI]).

Addiction as a stress surfeit disorder.

Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state.

Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants.

Low doses of psychostimulants, including methylphenidate (MPH), are highly effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). At these doses, psychostimulants improve prefrontal cortex (PFC)-dependent function. Recent evidence indicates that low and clinically relevant doses of psychostimulants target norepinephrine (NE) and dopamine (DA) signaling preferentially in the PFC.

Wake-promoting actions of noradrenergic α1 - and β-receptors within the lateral hypothalamic area.

Central norepinephrine exerts potent wake-promoting effects, in part through the actions of noradrenergic α1 - and β-receptors located in the medial septal and medial preoptic areas. The lateral hypothalamic area (LHA), including the lateral hypothalamus, perifornical area and adjacent dorsomedial hypothalamus, is implicated in the regulation of arousal and receives a substantial noradrenergic innervation. To date the functional significance of this innervation is unknown.

A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder.

Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants.

Noradrenergic modulation of wakefulness/arousal.

The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus noradrenergic neurons has long-suggested a role of this system in the induction of an alert waking state. Work over the past two decades provides unambiguous evidence that the locus coeruleus, and likely other noradrenergic nuclei, exert potent wake-promoting actions via an activation of noradrenergic β- and α₁-receptors located within multiple subcortical structures, including the general regions of the medial septal area, the medial preoptic area and, most recently, the lateral hypothalamus.

Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons.

The hypocretin/orexin (HCRT) neuropeptide system modulates behavioral state and state-dependent processes via actions on multiple neuromodulatory transmitter systems. Recent studies indicate that HCRT selectively increases dopamine (DA) neurotransmission within the prefrontal cortex (PFC) and the shell subregion of the nucleus accumbens (NAs), but not the core subregion of the nucleus accumbens (NAc). The circuitry underlying the differential actions of HCRT across distinct DA systems is unclear.

Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.

Background: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD.