No abstract

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. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction.

The locus coeruleus-noradrenergic systems 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. Conversely, global blockade of β- and α1-receptors or suppression of norepinephrine release results in profound sedation. The wake-promoting action of central noradrenergic neurotransmission has clinical implications for treatment of sleep/arousal disorders, such as insomnia and narcolepsy, and clinical conditions associated with excessive arousal, such as post-traumatic stress disorder.

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. The current study examined whether HCRT preferentially activates PFC- and NAs-projecting relative to NAc-projecting DA neurons within the VTA. One week after infusion of the retrograde tracer fluorogold (FG) into the medial PFC, NAc or NAs, animals received a ventricular infusion of HCRT-1. Subsequent analyses conducted across the rostral-caudal extent of the VTA determined the degree to which: (i) Fos-immunoreactivity (ir) was observed within tyrosine hydroxylase (TH)-ir neurons; (ii) TH-ir was observed within FG-ir neurons; and (iii) Fos-ir was observed within FG-ir neurons. HCRT significantly increased Fos-ir in VTA DA (TH-ir) neurons, primarily in a restricted population of small-to-medium-sized DA neurons located within the caudomedial VTA. Furthermore, within this region of the VTA, PFC- and NAs-projecting TH-ir neurons were more likely to contain Fos-ir than were NAc-projecting TH-ir neurons. These results provide novel evidence that HCRT selectively activates PFC- and NAs-projecting DA neurons within the VTA, and suggest a potential role for HCRT in PFC- and NAs-dependent cognitive and/or affective processes. Moreover, these and other observations suggest that the dysregulation of HCRT–DA interactions could contribute to cognitive/affective dysfunction associated with a variety of behavioral disorders.

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. Rats readily and concentration-dependently self-administered vaporized sufentanil. Rats exhibited a significant increase in responding for sufentanil when given the preferential μ-opioid receptor inverse agonist naloxone, suggesting the participation of μ-opioid receptors in the reinforcing properties of sufentanil vapor. Serum sufentanil concentrations significantly correlated with the number of sufentanil vapor deliveries. Rats that were given long access (LgA; 12 h/day) but not short access (ShA; 1 h/day) to vaporized sufentanil escalated their drug intake over time and exhibited both naloxone-precipitated somatic signs of opioid withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. After 6 months of forced drug abstinence, LgA rats returned to pre-escalation baseline levels of responding for sufentanil and mechanical sensitivity. Upon subsequent re-escalation (ie, after the return to extended access to sufentanil vapor), LgA rats again developed naloxone-precipitated somatic signs of withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. These findings demonstrate that the operant sufentanil vapor self-administration model has both face and construct validity and therefore will be useful for investigating the neurobiological basis of opioid addiction.