Background
The lateral hypothalamic neuropeptide orexin (or hypocretin) is implicated in drug
addiction. Although a role for orexin has been shown in reward and dependence, the
molecular and neural mechanisms are unclear. We investigated the mechanism and neuroanatomic
basis of orexin's role in morphine withdrawal.
Methods
C57BL/6J mice received chronic morphine followed by naloxone (0 or 1 mg/kg, subcutaneous)
to precipitate withdrawal. Before naloxone, mice received SB-334867 (0 or 20 mg/kg,
intraperitoneal), an orexin 1 receptor (Ox1r) antagonist. Using immunohistochemistry,
c-Fos, a marker of cell activation, was quantified in the nucleus accumbens (Acb),
lateral hypothalamus (LH), ventral tegmental area (VTA), and locus coeruleus (LC).
Retrograde tracing with fluorogold (FG) was performed to determine whether orexin
neurons project directly to the Acb.
Results
SB-334867 before naloxone significantly attenuated withdrawal symptoms. Withdrawal
was accompanied by an increase in c-Fos expression in the Acb shell (AcbSh), which
was reduced by SB-334867 but had no effect on the VTA or the LC. Morphine withdrawal
increased c-Fos expression in the dorsomedial (DMH) and perifornical (PFA) regions
but not in the lateral region of the LH (LLH). Orexin neurons do not appear to form
direct connections with Acb neurons.
Conclusions
Altogether, these data demonstrate that orexin, acting via Ox1r, is critical for the
expression of morphine withdrawal. AcbSh activation during withdrawal is dependent
on Ox1r function and is likely mediated by indirect action of LH orexin neurons.
Key Words
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References
- The role of dopamine in locomotor activity and learning.Brain Res. 1983; 287: 173-196
- Catecholamine theories of reward: A critical review.Brain Res. 1978; 152: 215-247
- Neuropharmacological mechanisms of drug reward: Beyond dopamine in the nucleus accumbens.Crit Rev Neurobiol. 1998; 12: 37-67
- Food reward: brain substrates of wanting and liking.Neurosci Biobehav Rev. 1996; 20: 1-25
- Brain dopamine and reward.Annu Rev Psychol. 1989; 40: 191-225
- A psychomotor stimulant theory of addiction.Psychol Rev. 1987; 94: 469-492
- Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis.Pharmacol Biochem Behav. 1989; 34: 899-904
- Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence.J Neurochem. 1992; 58: 1620-1625
- Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment.Brain Res. 1991; 566: 348-350
- Dramatic depletion of mesolimbic extracellular dopamine after withdrawal from morphine, alcohol or cocaine: A common neurochemical substrate for drug dependence.Ann N Y Acad Sci. 1992; 654: 513-516
- Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine.Nature. 1978; 276: 186-188
- Noradrenergic and behavioural effects of naloxone injected in the locus coeruleus of morphine-dependent rats and their control by clonidine.Psychopharmacology. 1987; 93: 393-396
- Role of different brain structures in the expression of the physical morphine withdrawal syndrome.J Pharmacol Exp Ther. 1992; 261: 669-677
- Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal.Psychopharmacology. 1988; 96: 121-134
- Sites of action of morphine involved in the development of physical dependence in rats.Psychopharmacologia. 1976; 46: 141-147
- Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal.Psychopharmacology. 1989; 98: 530-534
- Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal.Neuroscience. 1990; 37: 767-773
- Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal.J Neurosci. 2006; 26: 6450-6457
- Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.J Comp Physiol Psychol. 1954; 47: 419-427
- Self-administration of morphine into the lateral hypothalamus in the mouse.Brain Res. 1987; 416: 283-288
- Hypothalamic substrate for the positive reinforcing properties of morphine in the rat.Brain Res. 1979; 168: 351-360
- Heroin self-administration: effects of antagonist treatment in lateral hypothalamus.Pharmacol Biochem Behav. 1987; 27: 693-700
- Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference.Brain Res. 1982; 243: 107-117
- Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal.J Neurosci. 2003; 23: 3106-3111
- Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.Cell. 1999; 98: 437-451
- Neurons containing hypocretin (orexin) project to multiple neuronal systems.J Neurosci. 1998; 18: 9996-10015
- Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.Cell. 1998; 92: 573-585
- Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems.Proc Natl Acad Sci U S A. 1999; 96: 748-753
- The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.Proc Natl Acad Sci U S A. 1998; 95: 322-327
- Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress.J Comp Neurol. 2003; 464: 220-237
- Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area.Neuroscience. 2002; 111: 379-387
- Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system.Brain Res. 2000; 873: 181-187
- Differential expression of orexin receptors 1 and 2 in the rat brain.J Comp Neurol. 2001; 435: 6-25
- Distribution of orexin receptor mRNA in the rat brain.FEBS Lett. 1998; 438: 71-75
- Interaction of the hypocretins with neurotransmitters in the nucleus accumbens.Regul Pept. 2002; 104: 111-117
- SB-334867-A antagonises orexin mediated excitation in the locus coeruleus.Neuropharmacology. 2002; 42: 127-133
- The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.Cell. 1999; 98: 365-376
- Hypocretin (orexin) deficiency in human narcolepsy.Lancet. 2000; 355: 39-40
- A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.Nat Med. 2000; 6: 991-997
- The hypocretins: setting the arousal threshold.Nat Rev Neurosci. 2002; 3: 339-349
- To eat or to sleep?.Annu Rev Neurosci. 2001; 24: 429-458
- A role for lateral hypothalamic orexin neurons in reward seeking.Nature. 2005; 437: 556-559
- Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.Proc Natl Acad Sci U S A. 2005; 102: 19168-19173
- Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.Neuron. 2006; 49: 589-601
- Morphine-induced Straub tail reaction and spinal catecholamine metabolite content: Antagonism of naloxone to morphine-induced effects in mice.Chem Pharm Bull. 1978; 26: 2615-2618
- Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions.J Pharmacol Exp Ther. 1978; 205: 536-546
- Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB.Science. 1996; 273: 657-659
- The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal.Proc Natl Acad Sci U S A. 2003; 100: 9028-9033
- The Mouse Brain in Stereotaxic Coordinates.2nd ed. Elsevier Academic Press, San Diego2004
- The orexin system regulates alcohol-seeking in rats.Br J Pharmacol. 2006; 148: 752-759
- Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement.Psychopharmacology (Berl). 2001; 153: 203-209
- Morphine withdrawal-induced morphological changes in the nucleus accumbens.Eur J Neurosci. 2005; 22: 2332-2340
- Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine.J Neurosci. 2006; 26: 398-495
- Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area.Neuropsychopharmacology. 2006; 31: 384-395
- No effect of morphine on ventral tegmental dopamine neurons during withdrawal.J Neurosci. 2006; 26: 5720-5726
- Regulation of expression of cAMP response element-binding protein in the locus coeruleus in vivo and in a locus coeruleus-like cell line in vitro.Proc Natl Acad Sci U S A. 1994; 91: 10947-10951
- CREB (cAMP response element-binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence.J Neurosci. 1997; 17: 7890-7901
- Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal.J Endocrinol. 2006; 191: 137-145
- Brain orexins and wake regulation in rats exposed to maternal deprivation.Brain Res. 2007; 1154: 163-172
- Hypocretin/orexin type 1 receptor in brain: Role in cardiovascular control and the neuroendocrine response to immobilization stress.Am J Physiol Regul Integr Comp Physiol. 2007; 292: 382-387
- Orexin axons in the rat ventral tegmental area synapse infrequently onto dopamine and gamma-aminobutyric acid neurons.J Comp Neurol. 2007; 503: 668-684
Article info
Publication history
Published online: April 23, 2008
Accepted:
March 5,
2008
Received in revised form:
March 4,
2008
Received:
August 20,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
