Localizations and Projections of Brain Stress Systems?Dynorphin

Dynorphin has long been hypothesized to mediate negative emotional states. κ receptor agonists produce place aversions (Shippenberg et al., 2007) and depression and dysphoria in humans (Pfeiffer et al., 1986). The activation of dynorphin systems in the nucleus accumbens has long been associated with activation of the dopamine systems by cocaine and amphetamine. Activation of dopamine D₁ receptors stimulates a cascade of events that ultimately leads to cAMP response-element binding protein (CREB) phosphorylation and subsequent alterations in gene expression, notably the activation of expression of protachykinin and prodynorphin mRNA. The subsequent activation of dynorphin systems could contribute to the dysphoric syndrome associated with cocaine dependence and also feedback to decrease dopamine release (Nestler, 2005). Activation of dynorphin systems also may mediate a dysphoric component of stress (Land et al., 2008; McLaughlin et al., 2003).

The evidence for a role of the dynorphin/κ opioid system in the neuroadaptive actions of other drugs of abuse is based both on biochemical and antagonist studies. Substantial evidence suggests that dynorphin peptide and gene expression are activated in the striatum, ventral striatum, and amygdala during acute and chronic administration of cocaine and alcohol (Spangler et al., 1993; Daunais et al., 1993; Lindholm et al., 2000). Chronic binge patterns of cocaine administration increase μ and κ opioid receptor density in the nucleus accumbens, cingulate cortex, and basolateral amygdala (Unterwald et al., 1994).

A highly selective κ agonist, when administered chronically via minipump, potentiated the alcohol deprivation effect in rats with long-term ethanol experience, but acute injection of a κ antagonist had no effect, suggesting the possibility that ethanol drinking may be an attempt to overcome the aversive effects of κ agonists (Holter et al., 2000). Direct support for the hypothesis that dynorphin is part of the negative emotional systems recruited in dependence is the observation that nor-binaltorphimine, when injected intracerebroventricularly or systemically, blocked ethanol self-administration in dependent but not in non-dependent animals (Walker and Koob, 2008; B.M. Walker and G.F.K., unpublished data). κ knockout mice also drank less ethanol in a two-bottle choice test using escalating doses of ethanol (Kovacs et al., 2005).

Opiate withdrawal has been shown to increase dynorphin levels in the amygdala (Rattan et al., 1992) and nucleus accumbens (Turchan et al., 1997). Animals with a history of heroin self-administration showed increased levels of dynorphin A and -B in the striatum at a time point just before the next scheduled self-administration session (Cappendijk et al., 1999). Intracerebroventricular dynorphin A treatment decreased heroin-stimulated dopamine release and significantly increased heroin self-administration in daily 5 hr sessions, whereas a κ antagonist had the opposite effects (Xi et al., 1998).

Stress increases dynorphin activity, suggesting a potential interaction with CRF systems. Blockade of dynorphin activity, either via κ receptor antagonism or prodynorphin gene disruption, blocked stress-induced reinstatement of cocaine-induced place preference in mice (McLaughlin et al., 2003) and blocked stress-induced reinstatement of cocaine-seeking behavior (Beardsley et al., 2005). Forced swim stress and inescapable footshock produced place aversions in mice that were blocked by a κ antagonist and dynorphin knockout, and here, CRF was hypothesized to produce its aversive effect via a CRF₂ receptor-dynorphin interaction (Land et al., 2008). Evidence also exists showing that reinstatement of drug-seeking behavior via activation of κ opioid receptors is mediated by CRF, and κ agonist-induced reinstatement of cocaine seeking was blocked by a CRF₁ antagonist (Valdez et al., 2007). Thus, the dynorphin/κ system mimics stressor administration in animals in producing aversive effects and inducing drug-seeking behavior, and this aversive response may involve reciprocal interactions with nucleus accumbens dopamine and the brain extrahypothalamic CRF system.

Orexin

Orexin (also known as hypocretin)-containing neurons derive exclusively from the lateral hypothalamus and project widely throughout the brain (Peyron et al., 1998), with a dense innervation of anatomical sites involved in regulating arousal, motivation, and stress states (Baldo et al., 2003) (Figure 6) (see Supplemental Data). Orexin A and orexin B have actions that are mediated by two G protein-coupled receptors, OX₁ and OX₂ (also referred to as hypocretin 1 and -2, respectively, but orexin A, orexin B, OX₁, and OX₂ are the accepted International Union of Pharmacology nomenclature). OX₁ has higher affinity for orexin A, and OX₂ has equal affinity for both orexin A and -B (Sakurai et al., 1998). The orexin neuropeptides orexin A and orexin B interact with noradrenergic, cholinergic, serotonergic, histaminergic, and dopaminergic systems, in addition to the HPA axis, to mediate sleep-wake regulation, energy homeostasis, and motivational, neuroendocrine, and cardiovascular functions (Sutcliffe and de Lecea, 2002).

Figure 6

Localizations and Projections of Brain Stress Systems?Orexin (Hypocretin)

A role for the orexin systems in the neuroadaptive processes linked to dependence have been hypothesized based on a brain arousal-stress function. Orexin neurons have been implicated in drug seeking. Orexin neurons in the lateral hypothalamus are activated by cues associated with rewards, such as food or drugs, and exogenous stimulation of lateral hypothalamic orexin neurons reinstates extinguished drug-seeking behavior in rodents (Harris et al., 2005). Injection of an OX₁ antagonist decreased the place preference produced by morphine (Narita et al., 2006).

Using an intravenous cocaine self-administration model, administration of orexin A reinstated previously extinguished cocaine-seeking behavior, but rather than potentiating reward, orexin A induced a long-lasting brain reward deficit (Boutrel et al., 2005). The reinstatement of cocaine-seeking behavior by orexin also was blocked by noradrenergic or CRF receptor antagonists. Antagonism of OX₁ receptors prevented footshock-induced reinstatement of cocaine-seeking behavior in rats (Boutrel et al., 2005). Additionally, footshock stress elicited a selective effect on activation of orexin neurons in the perifornical-dorsomedial hypothalamus, leading to the hypothesis that orexin neurons in the lateral hypothalamus mediate reward activation/arousal, whereas orexin neurons in the perifornical-dorsomedial hypothalamus mediate stress activation/arousal/memory (Harris and Aston-Jones, 2006). Orexin A, possibly from the perifornical-dorsomedial hypothalamus, activates CRF-expressing neurons in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala (Sakamoto et al., 2004). CRF neurons innervate orexin neurons, possibly from the extended amygdala (Winsky-Sommerer et al., 2004), suggesting a novel reciprocal stress-activation system. Overall, these results suggest a dynamic relationship between orexin and reward/stress pathways in regulating the reinstatement of previously extinguished drug-seeking behaviors. Studies on the role of specific orexin peptide receptors and specific brain sites on the motivational aspects of drug dependence remain to be explored.

Vasopressin

The neurohypophysial peptide vasopressin has actions in the central nervous system in addition to its classic role as an antidiuretic hormone derived from the posterior pituitary (see Supplemental Data). Vasopressin is widely distributed in the brain outside of the hypothalamus, and the highest vasopressin concentrations are in the suprachiasmatic and supraoptic nuclei, but substantial levels also have been observed in the septum and locus coeruleus (Figure 7). Vasopressin neurons innervating the extended amygdala are hypothesized to derive from cell bodies in the medial bed nucleus of the stria terminalis (de Vries and Miller, 1998). Vasopressin binds to three different G protein-coupled receptor subtypes: V_1a, V_1b, and V₂. The V₂ receptor is expressed almost exclusively in the kidney, where it mediates the antidiuretic action of vasopressin. The V_1a and V_1b receptors are localized to the brain, and the distribution of vasopressin receptor binding is prominent in the rat extended amygdala, with high concentrations in the lateral and supracapsular bed nucleus of the stria terminalis, the central nucleus of the amygdala, and the shell of the nucleus accumbens (Veinante and Freund-Mercier, 1997).

Figure 7

Date: 2016-06-12; view: 291