Cocaine abuse and midbrain circuits: Functional anatomy of hypocretin/orexin transmission and therapeutic prospect

Abstract

Cocaine abuse remains a pervasive public health problem, and treatments thus far have proven ineffective for long-term abstinence maintenance. Intensive research on the neurobiology underlying drug abuse has led to the consideration of many candidate transmitter systems to target for intervention. Among these, the hypocretin/orexin (hcrt/ox) neuropeptide system holds largely untapped yet clinically viable therapeutic potential. Hcrt/ox originates from the hypothalamus and projects widely across the mammalian central nervous system to produce neuroexcitatory actions via two excitatory G-protein coupled receptor subtypes. Functionally, hcrt/ox promotes arousal/wakefulness and facilitates energy homeostasis. In the early 2000s, hcrt/ox transmission was shown to underlie mating behavior in male rats suggesting a novel role in reward-seeking. Soon thereafter, hcrt/ox neurons were shown to respond to drug-associated stimuli, and hcrt/ox transmission was found to facilitate motivated responding for intravenous cocaine. Notably, blocking hcrt/ox transmission using systemic or site-directed pharmacological antagonists markedly reduced motivated drug-taking as well as drug-seeking in tests of relapse. This review will unfold the current state of knowledge implicating hcrt/ox receptor transmission in the context of cocaine abuse and provide detailed background on animal models and underlying midbrain circuits. Specifically, attention will be paid to the mesoaccumbens, tegmental, habenular, pallidal and preoptic circuits. The review will conclude with discussion of recent preclinical studies assessing utility of suvorexant - the first and only FDA-approved hcrt/ox receptor antagonist - against cocaine-associated behaviors.

Keywords: Addiction; Cocaine; Dopamine; Hypocretin/orexin; Midbrain; Psychostimulant(s); Reward; Ventral tegmental area.

Figure 1.

(A) Hcrt/ox mRNA and two mature protein products (hcrt-1/OX-A and hcrt-2/OX-B). (B) Mechanisms through which hcrt/ox exerts neuroexcitatory actions. (C) Origin and projections of hypothalamic orexin neurons with relative quantitative distribution of receptors derived from in situ hybridization study and pathway intensity from fiber innervation using studies immunofluorescence. Amy – amygdala, BNST – bed nucleus of stria terminalis, Cb – cerebellum, Ctx – cortex, DRN – dorsal raphe nucleus, Hp – hippocampus, Hy – hypothalamus, LC – locus coeruleus, NAcc – nucleus accumbens, OB – olfactory bulb, POA – preoptic area, VTA – ventral tegmental area. (D) Immunohistochemical characterization of the orexin field within rat hypothalamus. Atlas image adapted from Brain Maps: Structure of the Rat Brain, Third Edition (Swanson 2004). IIIv – third ventricle, fx – fornix, mtt – mammillothalamic tract. Figure originally contained within and adapted from Gentile et al. 2017a.

Figure 2.

Timeline depicting notable discoveries relating hcrt/ox transmission in the context of pscyhostimulant abuse. Studies in magenta text are of particular interest to the topic of this review. (a) Gautvik et al. 1996, (b) de Lecea et al. 1998, (c) Sakurai et al. 1998, (d) van den Pol et al. 1998, (e) Peyron et al. 1998, (f) Chemelli et al. 1999, (g) Lin et al. 1999, (h) Smart 2000, (i) Marcus et al. 2001, (j) Estabrooke et al. 2001, (k) Fadel and Deutch 2002, (l) Korotkova et al. 2003, (m) Gulia et al. 2003, (n) Harris et al. 2005, (o) Boutrel et al. 2005, (p) Narita et al. 2006, (q) Borgland et al. 2006, (r) Muschamp et al. 2007, (s) Wang et al. 2009, (t) Whitman et al. 2009, (u) Borgland et al. 2009, (v) Hollander et al. 2012, (w) Yang 2014, (x) NCT02785406, (y) Gentile et al. 2018, (z) Steiner et al. 2018.

Figure 3.

Circuit schematic of neurochemically-defined midbrain pathways participating in the facilitation (reward) of constraint (aversion) of motivated behaviors. *indicates pathways of hypothesized but untested function. Hyp – hypothalamus, LHb – lateral habenula, NAcc – nucleus accumbens, POA – preoptic area, RMTg – rostromedial tegmentum, VP – ventral pallidum, VTA – ventral tegmental area.

Figure 4.

Effects of suvorexant on (A.i) motivated cocaine-taking and (A.ii) cocaine-evoked DA response in ventral striatum. All panels of (A) are adapted from Gentile et al. 2018. Additionally, we observe that suvorexant decreases cocaine-elicited impulsivity when injected systemically (B.i) as well as when deposited bilaterally into the VTA (B.ii). All panels of (B) are adapted from Gentile et al. 2017b.