COMMENTARY COMMENTARY Opposing roles of cotransmission of dynorphin and hypocretin on reward and motivation Xuan Li1, Nathan J. Marchant, and Yavin Shaham1 Behavioral Neuroscience Research Branch, Intramural Research Program, Department of A Brain stimulation Cocaine self- reward administration Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baseline Impulsive behavior Baltimore, MD 21224 Hypocretin Dynorphin

In PNAS, Muschamp et al. (1) report that sleep homeostasis (12), and—most relevant HCRTR1 antagonist: KOR signal dominates hypocretin and dynorphin are coexpressed in to the present study—the rewarding effects the same synaptic vesicles of hypothalamic of cocaine and other rewards via its action neurons. Their data from behavioral, phar- on VTA dopamine neurons (13, 14).

macological, and electrophysiological studies In 2001, Chou et al. (15) reported that HCRTR1 antagonist + KOR antagonist: Balance restored suggest that hypocretin and dynorphin are hypocretin and dynorphin colocalize in the coreleased, and that they play opposing roles same hypothalamic neurons (15). In 2006, Li in cocaine self-administration, brain stimula- and van den Pol (16) extended these findings ’ tion reward, and impulsivity. The authors and provided electrophysiological data in- B Ventral tegmental area: data also suggest that the critical brain site for dicating that inhibitory dynorphin and ex- these opposing effects of coreleased hypocre- citatory hypocretin are simultaneously tin and dynorphin is the ventral tegmental coreleased after stimulation of hypothalamic area (VTA), the cell body region of the hypocretin neurons. The functional signifi- mesolimbic dopamine reward system (2). cance of hypocretin/dynorphin corelease is un- Fig. 1 provides a summary of the main find- known, because despite the above-mentioned ings from the study. anatomical and physiological findings, investi- In 1979, Avram Goldstein et al. discovered gators typically study in isolation the role of the third endogenous opioid peptide, termed hypocretin and dynorphin in stress responses, dynorphin (3). Dynorphin is widely distrib- reward processes, and motivated behavior. Fig. 1. (A) Summary of the behavioral findings. Selective uted in the brain and its physiological and Muschamp et al. (1) have elegantly addressed blockade of HCRTR1 reveals KOR signaling, which de- behavioral effects are a result of selective ac- this important gap in the current literature. creases brain stimulation reward, decreases impulsive tivation of kappa-opioid receptors (KORs) They used neuroanatomical, electrophysiolog- behavior, and decreases cocaine self-administration. (4). Activation of KORs induces stress-like ical, neuropharmacological, and behavioral However, concurrent blockade of both HCRTR1 and KOR reverses these effects, returning the behavior negativepsychologicalandphysiologicalstates, procedures to characterize the role of hypo- in all three tests to the baseline condition. (B)Sum- and blockade of KORs decreases stress- cretin and dynorphin corelease on electrical mary of the electrophysiological findings in the VTA. induced responses (5, 6). The dynorphin/KOR brain stimulation reward (BSR), intravenous Lateral hypothalamus (LH) projections to the VTA con- system also plays a complicated role in cocaine cocaine self-administration, cocaine-induced tain hypocretin and dynorphin in the same vesicles. reward (5, 7). During initial cocaine self- impulsivity, and VTA dopamine synaptic Dopamine neurons in the VTA express both HCRTR1 and KORs; activation of KORs inhibits and activation administration activation of KORs decreases physiology. of HCRTR1 activates the dopamine cells. Saturation of drug intake, during extended cocaine access At the neuroanatomical level, Muschamp both receptors produces no net effect on dopamine blockade of these receptors decreases drug et al. (1) used an immunofluorescence assay cells. Hypocretin may act together with excitatory glu- intake, and after extinction of cocaine self- and replicated the previous finding (15) that tamate input to overcome the inhibitory effect of dynophin and GABA transmission onto dopamine cells. administration activation of KORs reinstates hypocretin and dynorphin are coexpressed in dyn, dynorphin; glu, glutamate; MOR, mu-opioid receptor; drug seeking, while their blockade decreases the lateral, perifonical, and dorsomedial nu- orx, hypocretin. stress-induced reinstatement of cocaine seek- clei of the mouse hypothalamus. Using elec- ing (5, 7, 8). tron microscopy, they then examined the At the behavioral level, the authors first In 1998, two independent groups discov- subcellular localization of hypocretin and explored the role of the interaction be- ered hypocretin/orexin (9, 10). Hypocretin dynorphin and observed colocalization of tween the dynorphin and hypocertin in BSR, neurons are located in the tuberal hypo- hypocretin and dynorphin in the same thalamus and have extensive projections synaptic vesicles, which were distributed throughout the neuraxis, including the VTA along both axons and dendrites. This find- Author contributions: X.L., N.J.M., and Y.S. wrote the paper. (11). Hypocretin binds to G protein-coupled ing suggests that neuronal activity could The authors declare no conflict of interest. hypocretin 1 and 2 receptors (HCRTR1/2) lead to corelease of these seemingly func- See companion article 10.1073/pnas.1315542111. (10), and the peptide plays an important role tionally opposing peptides, and subse- 1To whom correspondence may be addressed. E-mail: anna.li@nih. in promoting arousal (9, 10), maintaining quent studies tested this idea. gov or [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1403603111 PNAS Early Edition | 1of2 Downloaded by guest on October 2, 2021 where mice lever-press for rewarding lateral to hypocretin and dynorphin, and coad- innervated by hypothalamic hypocretin hypothalamus electrical stimulation. Once the ministration of both peptides caused no neurons, such as the nucleus accumbens mice were self-stimulating at a reliable rate, net change in firing rate in these neurons. shell (11) or paraventricular thalamus (17). they received systemic or VTA injections Based on the results described above and Interestingly, hypocretin neurons them- of the HCRTR1 antagonist SB334867. Both other findings described in the paper, selves seem to be more sensitive to KOR manipulations caused a dose-dependent ele- Muschamp et al. (1) reached three major activation than HCRTR1 activation (16). vation of BSR threshold, which indicates a re- conclusions: (i) Hypocretin and dynorphin Another fascinating question derived from duced efficacy for the simulation to produce are copackaged in the same synaptic vesicles this study is whether the balance of the reward. Critically, the effect of SB334867 on of hypothalamic neurons, and therefore coreleased peptides is changed by experience, BSR was reversed by systemic or intra-VTA likely act as cotransmitters; (ii) under certain such as exposure to stress or drugs of abuse. injections of nor-binaltorphimine (norBNI), conditions, one of the main functions of For example, after a significant event do the a long-lasting KOR antagonist. In a second hypocretin signaling is to counteract the hypocretin hypothalamic neurons change experiment, the authors examined the role effects of activation of the KORs by dynor- their peptide expression profile? Or, do the of hypocretin and dynorphin cotransmis- phin; (iii) the opposing roles of hypocretin postsynaptic neurons change their receptor sion in impulsivity using the five-choice and dynorphin in drug and nondrug rewards balance (HCRTR1 vs. KOR) to fine-tune serial reaction task (5-CSRTT) in rats. Sys- are because of their effects on VTA dopa- their responsiveness to the coreleased pep- temic blockade of HCRTR1 with SB334867 mine neurons, the cell body region of the tides? Such data are critically important from decreased spontaneous premature responses mesolimbic dopamine reward system. the perspective of future medication devel- (the operational measure of impulsivity This elegant multidisciplinary study of opment for psychiatric disorders, as sug- in the task). Once again, blockade of both Muschamp et al. (1) raises several questions gested by the authors. HCRTR1 and KOR restored the behavior for future research and also has some more Finally, from a “big picture” perspective, of the rat to the baseline condition. A rela- general implications for the study of the role perhaps the largest contribution of the paper tionship between the HCRTR1 system and of neuropeptides in normal and pathologi- for future research in neuroscience and psy- cocaine was then demonstrated, whereby cal behaviors. Perhaps the most important chiatry is not the particular findings reported systemic blockade of HCRTR1 reversed question is under what physiological condi- in it, but the realization that to fully under- cocaine-induced impulsivity. tionsthenetimpactonbehaviorandphysi- stand the physiological and behavioral role In the third behavioral experiment, the ology of one peptide dominates over the other of a given peptide, it is critical to take into authors followed up on the relationship peptide. This question was not addressed in account the entire peptide and neurotrans- between hypocretin and cocaine-induced the present study in which the conclusions mitter profile of the neuronal population impulsivity to assess whether hypocretin were primarily based on classic ex vivo elec- under study. This is a daunting prospect, but and dynorphin cotransmission plays a role trophysiological recording and pharmacol- it holds the potential to significantly increase in the rewarding effects of cocaine. Using ogical receptor blockade. the likelihood of effective psychiatric med- the drug self-administration procedure, they Another question relates to the anatomical ications, as well as giving us a greater ap- found that HCRTR1 knockout mice self- specificity of the putative cotransmission preciation of the complexity of the central administered less cocaine than wild-type of hypocretin and dynorphin. The authors nervous system. mice. Surprisingly, they found that systemic studied a potential role of cotransmission injections of the KOR antagonist norBNI, at of the peptides on VTA-mediated behaviors. ACKNOWLEDGMENTS. The authors are supported by a dose that decreased cocaine self-adminis- Thus, a question for future research is the National Institute on Drug Abuse, Intramural Re- search Program. N.J.M. received support from Early tration in wild-type mice, partially restored whether the opposite actions of the two Career Fellowship 1053308 by the National Health and the reduced cocaine intake in the knockout peptides also occur in other brain areas Medical Research Council. mice. These data represent one of the first demonstrations that a behavioral effect in the mouse induced by deleting one type of 1 Muschamp JW, et al. (2014) Hypocretin (orexin) facilitates reward 9 de Lecea L, et al. (1998) The hypocretins: Hypothalamus-specific receptor can be ameliorated by pharma- by attenuating the antireward effects of its cotransmitter dynorphin in peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95(1): ventral tegmental area. Proc Natl Acad Sci USA, 10.1073/ 322–327. cological blockade of a different receptor. pnas.1315542111. 10 Sakurai T, et al. (1998) Orexins and orexin receptors: A family Finally, the authors reported that in rats 2 Wise RA (2004) Dopamine, learning and motivation. Nat Rev of hypothalamic neuropeptides and G protein-coupled receptors Neurosci 5(6):483–494. that regulate feeding behavior. Cell 92(4):573–585. the VTA injections of SB334867 decreased 3 Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L 11 Peyron C, et al. (1998) Neurons containing hypocretin (orexin) cocaine self-administration and that this (1979) Dynorphin-(1-13), an extraordinarily potent opioid project to multiple neuronal systems. J Neurosci 18(23):9996–10015. effect was reversed by VTA injections peptide. Proc Natl Acad Sci USA 76(12):6666–6670. 12 Sutcliffe JG, de Lecea L (2000) The hypocretins: Excitatory 4 Chavkin C, Goldstein A (1981) Demonstration of a specific neuromodulatory peptides for multiple homeostatic systems, of norBNI. dynorphin receptor in guinea pig ileum myenteric plexus. Nature including sleep and feeding. J Neurosci Res 62(2):161–168. At the synaptic level, the authors assessed 291(5816):591–593. 13 Aston-Jones G, et al. (2010) Lateral hypothalamic orexin/hypocretin the effect of hypocretin and dynorphin on 5 Bruchas MR, Land BB, Chavkin C (2010) The dynorphin/kappa neurons: A role in reward-seeking and addiction. Brain Res 1314:74–90. opioid system as a modulator of stress-induced and pro-addictive 14 Borgland SL, et al. (2009) Orexin A/hypocretin-1 selectively promotes cell firing of VTA dopamine neurons of mice behaviors. Brain Res 1314:44–55. motivation for positive reinforcers. 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