Stress-related neuropeptides and addictive behaviors: beyond the usual suspects.

Ucn circuitry potentially impacting addiction-related behaviorsEWcp is the main site of Ucn1 production in brain. Ucn1 projections (blue) from this structure to the lateral septum (LS) and dorsal raphe (DR), two structures that mediate behavioral stress responses, are well established. Ucn1-immunoreactive fibers are, however, widely distributed, and the number of Ucn1-innervated brain regions is likely much greater than depicted. Projections from Ucn2 cell bodies (red) largely await characterization, while much of the forebrain Ucn3 circuitry has been mapped, and is indicated (green). Ucn1 activates both CRF1 and CRF2, receptors, while Ucn2 and 3 are CRF2R selective (see main text). CRF1R are widely distributed in the brain and are not shown; areas indicated in the figure as targets of Ucn peptides all contain CRF2 receptors to various degrees. Endogenous Ucn1 pathways originating from the EWcp mediate positively reinforcing effects of alcohol, although exogenous Ucn1 administration inhibits alcohol intake. The latter effect presumably reflects actions on targets that are innervated by endogenous Ucn2 or Ucn3 pathways, since exogenous administration of the latter two peptides inhibits alcohol intake. Endogenous Ucn2 or Ucn3 positively regulate the acute locomotor response to methamphetamine, a response that involves amygdala neurons.

SP / NK1R circuitry potentially impacting addiction-related behaviorsBrain regions that receive SP projections and contain NK1Rs to varying degrees are shown. SP and NK1Rs have been shown to regulate the activity of brainstem and midbrain monoamine nuclei (NE neurons of LC, DA neurons of VTA, 5-HT neurons of DR), which have widespread projections to forebrain regions; some of these, relevant for addiction-related behaviors, are included in the current schematic. Some 5-HT neurons of the DR co-express SP, but target regions of this subset are not established; the projections that contain 5-HT potentially co-localized with SP are shown in gray. The amygdala (AMG) and hypothalamus (HYP), which regulate behavioral, autonomic and endocrine stress responses contain intrinsic SP circuits that modulate their output. The pathway from the prefrontal cortex (PFC) to the nucleus accumbens (NAC; core subregion) to the ventral pallidum (VP) is part of a proposed “final common pathway” for reinstatement of drug seeking (see main text). Medium spiny neurons (MSNs) of the nucleus accumbens (NAC) that project to the ventral pallidum (VP) and substantia nigra (SN) contain SP and activate NK1R and/or NK3R in these regions. These SP containing GABAergic projections are shown in red. Not shown is the habenula, an NK1R containing structure recently postulated to mediate important anti-reward processes; a role of SP and NK1R in these has not yet been evaluated.

NPS / NPSR circuitry potentially impacting addiction-related behaviorsNPS is expressed in about 500 cells located between the Peri-LC (locus coeruleus), the lateral parabrachial nucleus and the principal sensory trigeminal nucleus, where it is largely co-expressed with Glu and CRF, respectively. NPS cells project (red arrows) to three main target clusters: the hypothalamus (HYP; grey), which regulates, basic physiological functions such as feeding and arousal; the thalamus (light brown), which integrates somatosensory imputs, as well as endocrine and autonomic responses; and a third cluster (light blue) composed of the Subiculum (SUB), Basolateral Amygdala (BLA) and Lateral Entorhinal Cortex (LEnt), involved in emotional memory. The thalamus sends non-NPS projections (black arrows) to several brain regions, including central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), that are involved in emotional aspects of stress responses. The CeA as well as the nucleus accumbens (NAC) also receive heavy non-NPS projection from the basolateral amygdala (BLA) and cortical areas (not depicted in this schematic) that integrate cognitive function with emotional stress and reward processing. NPS neurotransmission is located upstream of these pathways, and can therefore have complex effects on drug seeking and taking, that impact both negatively and positively reinforced aspects of these behaviors.

An integrated viewKey nodes in circuitry that drives drug seeking and self-administration [adapted from (Koob and Volkow, 2010)] modulated by Ucn family peptides and CRF2R, SP and NK1R, NPS and NPSR, and N/OFQ and NOPR systems. Nodes at which modulation is likely to occur through effects on stress-reactivity and negative emotionality are shown in red; those at which modulation is likely to influence appetitive or approach-related mechanisms are depicted in green. The figures shows that the systems discussed in this review can impact addiction-related behaviors at multiple sites. Their impact is likely to vary with genetic factors that influence the functional activity of the respective system, as well as drug exposure history of the individual, and concomitant neuroadaptations. Although many effects on drug seeking and taking have been described following manipulation of these systems, their complexity suggests that extensive research will be required to properly assess their potential as therapeutic targets, and to define patient characteristics most likely predictive of efficacy.