Basic Neurobiology of Addiction

Corticotropin Releasing Factor

Stress is a major factor in drug relapse, and corticotropin-releasing factor (CRF) is key to the body’s stress response. A large, 41-amino-acid polypeptide with a wide distribution throughout the brain, CRF cell bodies are prominent in the paraventricular nucleus of the hypothalamus, basal forebrain (notably the extended amygdala), and brainstem (Figure 2.14). When CRF is administered directly into rodents, it mimics behavioral activation and the stress response, and CRF receptor antagonists generally have anti-stress effects.

Two major CRF receptors have been identified: CRF1 and CRF2. CRF1 receptor activation is associated with activation of the hypothalamic–pituitary–adrenal (HPA) axis neuroendocrine response to stress and increased stress responsiveness at the behavioral and physiological (autonomic) extrahypothalamically (outside the HPA axis). The HPA axis is a term that describes the relationship between direct releasing factor/hormonal actions and feedback between the hypothalamus, pituitary gland, and adrenal gland. CRF2 receptor activation is associated with decreased feeding behavior and decreased stress responsiveness, although there is some controversy in this area. Both CRF receptor subtypes belong to a subfamily of G-protein-coupled receptors. CRF itself has preferential affinity for CRF1 rather than CRF2 receptors. Other CRF-related neuropeptides include urocortins, and some of these preferentially bind CRF2 receptors. The distribution of CRF1 receptors in the brain is highly consistent across mammalian species in stress-responsive brain regions, including the neocortex, central division of the extended amygdala, medial septum, hippocampus, hypothalamus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei. This receptor distribution, concordant with its natural ligand CRF, is consistent with the role for CRF1 receptors outside the HPA axis in behavioral and physiological (autonomic) stress responses.

Figure 2.13 Dynorphin localization. Schematic representation of the distribution of prodynorphin-derived peptides in the rat’s 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 fiber-terminals are shown as short curved lines and dots. 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. [Modified with permission from Khachaturian H, Lewis ME, Schafer MKH, Watson SJ. Anatomy of the CNS opioid systems. Trends in Neurosciences, 1985, (8), 111-119.]

Figure 2.14 Corticotropin-releasing factor localization. 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 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. It is uncertain which of these cell groups contributes to each of the pathways shown and which of them receives inputs from the same pathways. 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. [Modified with permission from Swanson LW, Sawchenko PE, Rivier J, Vale W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology, 1983, (36), 165-186.]

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