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Review
, 59 (1), 11-34

A Role for Brain Stress Systems in Addiction

Affiliations
Review

A Role for Brain Stress Systems in Addiction

George F Koob. Neuron.

Abstract

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.

Figures

Figure 1
Figure 1. Localizations and Projections of Brain Stress Systems—Corticotropin-Releasing Factor
(A) The major CRF-stained cell groups (dots) and fiber systems in the rat brain. Most of the immunoreactive cells and fibers appear to be associated with systems that regulate the output of the pituitary and the autonomic nervous system and with cortical interneurons. Most of the longer central fibers course either ventrally through the medial forebrain bundle and its caudal extension in the reticular formation, or dorsally through a periventricular system in the thalamus and brainstem central gray. The direction of fibers in these systems is unclear because they appear to interconnect regions that contain CRF-stained cell bodies. Three adjacent CRF-stained cell groups—laterodorsal tegmental nucleus, locus coeruleus, parabrachial nucleus—lie in the dorsal pons. Uncertain is which of these cell groups contributes to each of the pathways shown, and which of them receives inputs from the same pathways. Modified with permission from Swanson et al. (1983). ac, anterior commissure; BST, bed nucleus of the stria terminalis; cc, corpus callosum; CeA, central nucleus of the amygdala; CG, central gray; DR, dorsal raphe; DVC, dorsal vagal complex; HIP, hippocampus; LDT, laterodorsal tegmental nucleus; LHA, lateral hypothalamic area; ME, median eminence; mfb, medial forebrain bundle; MID THAL, midline thalamic nuclei; MPO, medial preoptic area; MR, median raphe; MVN, medial vestibular nucleus; PB, parabrachial nucleus; POR, perioculomotor nucleus; PP, peripeduncular nucleus; PVN, paraventricular nucleus; SEPT, septal region; SI, substantia innominata; st, stria terminalis. (B) Role of corticotropin-releasing factor in dependence.
Figure 2
Figure 2. Effects of Drug Withdrawal on CRF Levels in the Amygdala
(A) Effects of ethanol withdrawal on CRF-like immunoreactivity in the rat amygdala determined by microdialysis. Dialysate was collected over four 2 hr periods regularly alternated with nonsampling 2 hr periods. The four sampling periods corresponded to the basal collection (before removal of ethanol), and 2–4 hr, 6–8 hr, and 10–12 hr after withdrawal. Fractions were collected every 20 min. Data are represented as mean ± SEM (n = 5 per group). ANOVA confirmed significant differences between the two groups over time (p < 0.05). Taken with permission from Merlo-Pich et al. (1995). (B) Mean (±SEM) dialysate CRF concentrations collected from the central nucleus of the amygdala of rats during baseline, 12 hr cocaine self-administration, and a subsequent 12 hr withdrawal period (Cocaine group, n = 5). CRF levels in rats with the same history of cocaine self-administration training and drug exposure but not given access to cocaine on the test day (Control group, n = 6). Data are expressed as percentages of basal CRF concentrations. Dialysates were collected over 2 hr periods alternating with 1 hr nonsampling periods shown by the timeline at the top. During cocaine self-administration, dialysate CRF concentrations in the cocaine group were decreased by about 25% compared with control animals. In contrast, termination of access to cocaine resulted in a significant increase in CRF release, which began ~5 hr post-cocaine and reached about 400% of presession baseline levels at the end of the withdrawal session. *p < 0.05, **p < 0.01, ***p < 0.001. Simple effects after overall mixed-factorial analysis of variance. Taken with permission from Richter and Weiss (1999). (C) Effects of cannabinoid CB1 antagonist SR 141716A (3 mg/kg) on CRF release from the central nucleus of the amygdala in rats pretreated for 14 days with cannabinoid CB1 agonist HU-210 (100 mg/kg). Cannabinoid withdrawal induced by SR 141716A was associated with increased CRF release (*p < 0.005, n = 5–8). Vehicle injections did not alter CRF release (n = 5–7). Data were standardized by transforming dialysate CRF concentrations into percentages of baseline values based on averages of the first four fractions. Data are shown as mean ± SEM. Taken with permission from Rodriguez de Fonseca et al. (1997). (D) Effects of morphine withdrawal on CRF release in the central nucleus of the amygdala. Withdrawal was precipitated by administration of naltrexone (0.1 mg/kg) in rats prepared with chronic morphine pellet implants. Data are shown as mean ± SEM. Taken with permission from Weiss et al. (2001). (E) Effect of mecamylamine (1.5 mg/kg, i.p.) precipitated nicotine withdrawal on CRF release in the central nucleus of the amygdala measured by in vivo microdialysis in chronic nicotine pump-treated (nicotine-dependent, n = 7) and chronic saline pump-treated (nondependent, n = 6) rats. *p < 0.05 compared with non-dependent. Data are shown as mean ± SEM. Taken with permission from George et al. (2007).
Figure 3
Figure 3. Effect of CRF1 Receptor Antagonist on Alcohol and Nicotine Self-Administration in Dependent Rats
(A) The effect of small-molecule CRF1 receptor antagonist MPZP on operant self-administration of alcohol (g/kg) in dependent and nondependent rats. Testing was conducted when dependent animals were in acute withdrawal (6–8 hr after removal from vapors). Dependent animals self-administered significantly more alcohol than nondependent animals. MPZP significantly reduced alcohol self-administration only in dependent animals. MPZP had no effect on alcohol self-administration in nondependent animals. *p < 0.05 compared with nondependent controls. #p < 0.05 compared with vehicle (0 mg/kg MPZP). Data are shown as mean ± SEM (n = 8 per vapor treatment group). Taken with permission from Richardson et al. (2008). (B) The effect of small-molecule CRF1 receptor antagonist MPZP on nicotine self-administration during the active period in rats given extended access to nicotine (*p < 0.05 versus baseline, #p < 0.05 versus post abstinence vehicle treatment, n = 8). Data are shown as mean ± SEM. Taken with permission from George et al. (2007). (C) The effect of small-molecule CRF1 receptor antagonist MPZP on cocaine intake in short-access (ShA) and long-access (LgA) rats. MPZP dose-dependently reduced cocaine intake, achieving a maximal reduction of ~20%, with a greater effect in LgA compared to ShA rats. A main effect for Access (*p < 0.05), a main effect for MPZP dose (p < 0.001), and a significant access × MPZP dose interaction (+p < 0.05) were observed. Data are expressed as mean (+SEM) cocaine intake (mg/kg). Taken with permission from Specio et al. (2008).
Figure 4
Figure 4. Localizations and Projections of Brain Stress Systems—Norepinephrine
(A) Origin and distribution of central noradrenergic pathways in the rat brain. Note noradrenergic cell groups A1–A7, including the locus coeruleus (A6). Modified with permission from Robbins and Everitt (1995). PFC, prefrontal cortex; Sept, septum; NAc, nucleus accumbens; MFB, medial fore-brain bundle; Hypo, hypothalamus; DNAB, dorsal noradrenergic ascending bundle; VNAB, ventral noradrenergic ascending bundle; CTT, central tegmental tract. (B) Role of norepinephrine in dependence.
Figure 5
Figure 5. Localizations and Projections of Brain Stress Systems—Dynorphin
(A) Schematic representation of the distribution of prodynorphin-derived peptides in the rat central nervous system determined by immunohistochemistry. Prodynorphin codes for several active opioid peptides containing the sequence of [Leu]enkephalin, including dynorphin A, dynorphin B, and α-neoendorphin. This precursor is distributed in neuronal systems found at all levels of the neuraxis. Like their proenkephalin counterparts, the prodynorphin neurons form both short-and long-tract projections often found in parallel with the proenkephalin systems. Neuronal perikarya are shown as solid circles, and fibers-terminals as short curved lines and dots. Modified with permission from Khachaturian et al. (1985). AA, anterior amygdala; ABL, basolateral nucleus of amygdala; AC, anterior commissure; ACB, nucleus accumbens; ACE, central nucleus of the amygdala; ACO, cortical nucleus of amygdala; AD, anterodorsal nucleus of thalamus; AL, anterior lobe of pituitary; AM, anteromedial nucleus of thalamus; AMB, nucleus ambiguus; AME, medial nucleus of the amygdala; AON, anterior olfactory nucleus; ARC, arcuate nucleus; AV, anteroventral nucleus of thalamus; BST, bed nucleus of the stria terminalis; CC, corpus callosum; CGX, cingulate cortex; CM, central-medial nucleus of thalamus; COCH, cochlear nuclear complex; CPU, caudate-putamen; CST, corticospinal tract; DH, dorsal horn of spinal cord; DG, dentate gyrus; DM, dorsomedial nucleus of hypothalamus; DNV, dorsal motor nucleus of vagus; DTN, dorsal tegmental nucleus; ENT, entorhinal cortex; FN, fastigial nucleus of cerebellum; FRX, frontal cortex; GL, glomerular layer of olfactory bulb; GP, globus pallidus; HM, medial habenular nucleus; HPC, hippocampus; IC, inferior colliculus; IL, intermediate lobe of pituitary; IP, interpeduncular nuclear complex; LC, nucleus locus coeruleus; LG, lateral geniculate nucleus; LHA, lateral hypothalamic area; LRN, lateral reticular nucleus; MF, mossy fibers of hippocampus; MFN, motor facial nucleus; MG, medial geniculate nucleus; ML, medial lemniscus; MM, medial mammillary nucleus; MNT, mesencephalic nucleus of trigeminal; MVN, medial vestibular nucleus; NCU, nucleus cuneatus; NCX, neocortex; NDB, nucleus of diagonal band; NL, neural lobe of pituitary; NRGC, nucleus reticularis gigantocellularis; NRPG, nucleus reticularis paragigantocellularis; NTS, nucleus tractus solitarius; OCX, occipital cortex; OT, optic tract; OTU, olfactory tubercle; PAG, periaqueductal gray; PAX, periamygdaloid cortex; PBN, parabrachial nucleus; PC, posterior commissure; PIR, piriform cortex; PN, pons; POA, preoptic area; PP, perforant path; PV, periventricular nucleus of thalamus; PVN(M), paraventricular nucleus (pars magnocellularis); PVN(P), paraventricular nucleus (pars parvocellularis); RD, nucleus raphe dorsalis; RE, nucleus reuniens of thalamus; RF, reticular formation; RM, nucleus raphe magnus; RME, nucleus raphe medianus; SC, superior colliculus; SCP, superior cerebellar peduncle; SM, stria medullaris thalami; SNC, substantia nigra (pars compacta); SNR, substantia nigra (pars reticulata); SNT, sensory nucleus of trigeminal (main); SON, supraoptic nucleus; SPT, septal nuclei; STN, spinal nucleus of trigeminal; SUB, subiculum; VM, ventromedial nucleus of hypothalamus; VP, ventral pallidum; ZI, zona incerta. (B) Role of dynorphin in dependence.
Figure 6
Figure 6. Localizations and Projections of Brain Stress Systems—Orexin (Hypocretin)
(A) Dots indicate the relative location of orexin-immunoreactive neurons, with arrows pointing toward some of the more prominent terminal fields. Modified with permission from Nambu et al. (1999). AP, area postrema; cc, cerebral cortex; CeG, central gray; Flo, flocculus; Hip, hippocampus; Hypo, hypothalamus; IC, inferior colliculus; LC; locus coeruleus; MB, midbrain; MO, medulla oblongata; OB, olfactory bulb; PN, parabrachial nucleus; SC, superior colliculus; Sept, septum; SFO, subfornical organ. (B) Role of orexin in dependence.
Figure 7
Figure 7. Localizations and Projections of Brain Stress Systems—Vasopressin
Schematic of the most prominent vasopressin-immunoreactive projections. Modified with permission from de Vries and Miller (1998). AMB, ambiguus nucleus; BST, bed nucleus of the stria terminalis; CG, midbrain central gray; DM, dorsomedial nucleus of the hypothalamus; DR, dorsal raphe nucleus; DVC, dorsal vagal complex; Hip, ventral hippocampus; LC, locus coeruleus; LH; lateral habenular nucleus; LS; lateral septum; MA, medial nucleus of the amygdala; MP; medial preoptic area; OT, olfactory tubercle; ovlt; organum vasculosum laminae terminalis; PB, parabrachial nucleus; PV, periventricular nucleus of the hypothalamus; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SON, supraoptic nucleus; VSA, ventral septal area. (B) Role of vasopressin in dependence.
Figure 8
Figure 8. Localizations and Projections of Brain Antistress Systems—Neuropeptide Y
(A) NPY pathways hypothesized to be involved in NPY effects related to stress and emotionality. Modified with permission from Heilig (2004). ARC, arcuate nucleus; Hipp, hippocampus; LC, locus coeruleus; LSdc, lateral septum-dorsocaudal; LSv, lateral septum-ventral; NAc, nucleus accumbens; PAG, periaqueductal gray matter. (B) Role of NPY in dependence.
Figure 9
Figure 9. Localizations and Projections of Brain Antistress Systems—Nociceptin/Orphanin FQ
(A) Schematic representation of the distribution of nociceptin peptide in the rat central nervous system determined by immunohistochemistry and in situ hybridization. Neuronal perikarya are shown as solid circles, and fibers-terminals as short curved lines and dots. Data from Neal et al. (1999); very similar results were reported by Anton et al. (1996). AA, anterior amygdala; ABL, basolateral nucleus of amygdala; AC, anterior commissure; ACB, nucleus accumbens; ACE, central nucleus of the amygdala; ACO, cortical nucleus of amygdala; AD, anterodorsal nucleus of thalamus; AL, anterior lobe of pituitary; AM, anteromedial nucleus of thalamus; AMB, nucleus ambiguus; AME, medial nucleus of the amygdala; AON, anterior olfactory nucleus; ARC, arcuate nucleus; AV, anteroventral nucleus of thalamus; BST, bed nucleus of the stria terminalis; CC, corpus callosum; CGX, cingulate cortex; CM, central-medial nucleus of thalamus; COCH, cochlear nuclear complex; CPU, caudate-putamen; CST, corticospinal tract; DH, dorsal horn of spinal cord; DG, dentate gyrus; DM, dorsomedial nucleus of hypothalamus; DNV, dorsal motor nucleus of vagus; DTN, dorsal tegmental nucleus; ENT, entorhinal cortex; FN, fastigial nucleus of cerebellum; FRX, frontal cortex; GL, glomerular layer of olfactory bulb; GP, globus pallidus; HM, medial habenular nucleus; HPC, hippocampus; IC, inferior colliculus; IL, intermediate lobe of pituitary; IP, interpeduncular nuclear complex; LC, nucleus locus coeruleus; LG, lateral geniculate nucleus; LHA, lateral hypothalamic area; LRN, lateral reticular nucleus; MF, mossy fibers of hippocampus; MFN, motor facial nucleus; MG, medial geniculate nucleus; ML, medial lemniscus; MM, medial mammillary nucleus; MNT, mesencephalic nucleus of trigeminal; MVN, medial vestibular nucleus; NCU, nucleus cuneatus; NCX, neocortex; NDB, nucleus of diagonal band; NL, neural lobe of pituitary; NRGC, nucleus reticularis gigantocellularis; NRPG, nucleus reticularis paragigantocellularis; NTS, nucleus tractus solitarius; OCX, occipital cortex; OT, optic tract; OTU, olfactory tubercle; PAG, periaqueductal gray; PAX, periamygdaloid cortex; PBN, parabrachial nucleus; PC, posterior commissure; PIR, piriform cortex; PN, pons; POA, preoptic area; PP, perforant path; PV, periventricular nucleus of thalamus; PVN(M), paraventricular nucleus (pars magnocellularis); PVN(P), paraventricular nucleus (pars parvocellularis); RD, nucleus raphe dorsalis; RE, nucleus reuniens of thalamus; RF, reticular formation; RM, nucleus raphe magnus; RME, nucleus raphe medianus; SC, superior colliculus; SCP, superior cerebellar peduncle; SM, stria medullaris thalami; SNC, substantia nigra (pars compacta); SNR, substantia nigra (pars reticulata); SNT, sensory nucleus of trigeminal (main); SON, supraoptic nucleus; SPT, septal nuclei; STN, spinal nucleus of trigeminal; SUB, subiculum; VM, ventromedial nucleus of hypothalamus; VP, ventral pallidum; ZI, zona incerta. (B) Role of nociceptin in dependence.
Figure 10
Figure 10. The Extended Amygdala and Its Afferent and Major Efferent Connections and Modulation via Brain Arousal-Stress Systems
Horizontal section through a rat brain depicting the extended amygdala and its afferent and major efferent connections and modulation via brain arousal-stress systems. (Top) Central division of the extended amygdala with the central nucleus of the amygdala and lateral bed nucleus of the stria terminalis and a transition area in the shell of the nucleus accumbens highlighted. (Bottom) Enlargement of the hypothesized interaction of the brain stress systems and the extended amygdala. Note that dynorphin may activate CRF neurons or be activated by CRF neurons, that norepinephrine and CRF are hypothesized to be involved in a feed-forward circuit, and that vasopressin for the central nucleus of the amygdala is hypothesized to derive from the bed nucleus of the stria terminalis. NPY and nociceptin are not depicted in this figure but may act either via modulation of the CRF system or independently, directly on the output of the central nucleus of the amygdala (to be determined).

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