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The Journal of Neuroscience, April 15, 2003, 23(8):3106
BRIEF COMMUNICATION
Involvement of the Lateral Hypothalamic Peptide Orexin in
Morphine Dependence and Withdrawal
Dan
Georgescu1,
Venetia
Zachariou1,
Michel
Barrot1, 3,
Michihiro
Mieda2,
Jon T.
Willie2,
Amelia J.
Eisch1,
Masashi
Yanagisawa2,
Eric J.
Nestler1, and
Ralph J.
DiLeone1
1 Department of Psychiatry, and
2 Department of Molecular Genetics and Howard Hughes
Medical Institute, University of Texas Southwestern Medical Center,
Dallas, Texas 75390-9070, and 3 Unité Mixte de
Recherche 7519, Centre National de la Recherche Scientifique,
University Louis Pasteur, 67084 Strasbourg, France
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ABSTRACT |
The lateral hypothalamus (LH) is implicated in the behavioral
actions of drugs of abuse, but the cellular and molecular basis of this
role is unclear. Recent identification of neuropeptides localized in LH
neurons has allowed for more specific studies of LH function. The
LH-specific peptide orexin (hypocretin) has been shown to be important
in arousal and sleep regulation. However, orexin cells of the LH
project broadly throughout the brain such that orexin may influence
other behaviors as well. In this study, we show that orexin neurons,
and not nearby LH neurons expressing melanin-concentrating hormone
(MCH), have µ-opioid receptors and respond to chronic morphine
administration and opiate antagonist-precipitated morphine withdrawal.
cAMP response element-mediated transcription is induced in a
subset of orexin cells, but not MCH cells, after exposure to chronic
morphine or induction of withdrawal. Additionally, c-Fos and the
orexin gene itself are induced in orexin cells in the LH during
morphine withdrawal. Finally, we show that orexin knock-out mice
develop attenuated morphine dependence, as indicated by a less severe
antagonist-precipitated withdrawal syndrome. Together, these studies
support a role for the orexin system in molecular adaptations to
morphine, and demonstrate dramatic differences in molecular responses
among different populations of LH neurons.
Key words:
µ-opioid receptor; CREB; c-Fos; melanin-concentrating hormone; opiate withdrawal; drug addiction
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Introduction |
Lesion and intracranial
self-stimulation (ICSS) studies have suggested an important role for
the lateral hypothalamus (LH) in feeding, arousal, and reward (Anand
and Brobeck, 1951 ; Olds and Milner, 1954). Compared with other brain
regions, ICSS in the LH is the most robust (Gallistel et al., 1981) and
can be modulated by opiates and several other drugs of abuse or their antagonists (Adams et al., 1972; Goodall and Carey, 1975; Bozarth et
al., 1980). Opiates, such as morphine, are also self-administered directly into the LH (Olds and Williams, 1980; Cazala et al., 1987).
The target of these self-stimulation and self-administration studies is
a subregion of the LH that is crossed by the medial forebrain bundle
(MFB). Besides the passing fibers that connect limbic structures from
the basal forebrain with the midbrain, the MFB also contains axons of
intrinsic LH neurons (Millhouse, 1969). Moreover, previous studies have
shown that ibotenic acid lesions of the LH, which destroy cell bodies
but leave the passing MFB fibers intact, decrease ICSS in the LH
(Velley et al., 1983). However, little is known about the specific
neuronal cell types in the LH that contribute to these behaviors.
Recently, several neuropeptides have been shown to be highly enriched
in the LH. Two neuropeptides, orexin (also called hypocretin) and
melanin-concentrating hormone (MCH), are expressed in nonoverlapping populations of LH neurons (Peyron et al., 1998). Knock-out and transgenic overexpression studies have shown that MCH is important in
feeding (Ludwig et al., 1998; Shimada et al., 1998), whereas orexin is
important in arousal and sleep (Chemelli et al., 1999). However, there
is evidence that orexin neurons may regulate other behaviors, such as
stress responses (Ida et al., 2000) and feeding (Edwards et al., 1999;
Haynes et al., 1999). This is consistent with the fact that orexin
neurons project to many brain areas. Among these orexin projection
regions are several that are implicated in behavioral responses to
drugs of abuse, such as the locus ceruleus, nucleus accumbens, and
ventral tegmental area (Peyron et al., 1998; Fadel and Deutch, 2002).
However, little is known about the function of orexin neurons in
influencing responses to drugs of abuse. In this study, we use cAMP
response element (CRE) reporter mice, orexin gene reporter
mice, and orexin knock-out mice to demonstrate a role for
orexin in regulating morphine dependence and withdrawal.
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Materials and Methods |
Transgenic mouse lines. We used CRE-LacZ
reporter (line 37), orexin knock-out (Impey et al., 1998),
and orexin reporter (orexin- -LacZ) mice (Chemelli et al.,
1999) that had all been backcrossed more than five times to a C57BL/6
background. Animals were bred and maintained under a 12 hr dark/light
cycle with food and water available ad libitum and were used
at 8-12 weeks of age; littermates were used as controls in all experiments.
Behavioral scoring. Homozygous male orexin
knock-out mice and wild-type littermates were implanted with a 25 mg
morphine base pellet subcutaneously, or received sham surgery (no
pellet), under light isofluorane anesthesia. Two days later, mice
received naloxone (1 mg/kg, s.c.), and withdrawal symptoms (jumps, wet
dog shakes, backwards walking, paw tremor, tremor, diarrhea, ptosis,
and weight loss) were monitored for 25 min (Shaw-Lutchman et al.,
2002). A global withdrawal score was calculated by multiplying
withdrawal signs by a constant and adding the scores for each sign. A
separate set of mice was exposed to an open field, and activity and
locomotion were recorded for 3 hr before the onset of the dark cycle.
Immunohistochemical studies. Orexin--LacZ and CRE-LacZ
mice were implanted subcutaneously on day 1 with a 25 mg morphine pellet or received sham surgery. An identical procedure was performed on day 3. On day 6, mice received saline or naltrexone (100 mg/kg, s.c.), a dose required for maximal, sustained levels of withdrawal (Shaw-Lutchman et al., 2002). Four hours later (to permit reporter gene
expression), animals were injected with an overdose of pentobarbital and perfused transcardially with 1× PBS followed by 4%
paraformaldehyde. The brains were postfixed for 12 hr in 4%
paraformaldehyde and then cryoprotected in 20% glycerol for 6 hr.
Brains were sectioned at 40 µm intervals and collected in 1× PBS
plus 0.05% sodium azide.
Double-labeling immunohistochemistry was performed as described
previously (Shaw-Lutchman et al., 2002) using goat polyclonal anti- -galactosidase (-gal) antibody (1:5000;
Biogenesis, Poole, UK), rabbit polyclonal anti-orexin
antibody (1:400; Chemicon, Temecula, CA), rabbit
polyclonal anti-MCH antibody (1:5000; gift from W. Vale, Salk
Institute, La Jolla, CA), goat polyclonal anti-c-Fos antibody
(1:500; Santa Cruz Biotechnology, Santa Cruz, CA), goat polyclonal anti-FosB antibody (1:500; Santa Cruz
Biotechnology), or rabbit polyclonal anti-µ-opioid receptor
(anti-MOR; 1:4000; ImmunoStar, Hudson, WI). Quantification and
localization of -gal, c-Fos, or FosB expression with orexin or MCH
were performed using fluorescent light microscopy by an investigator
blinded to treatment conditions.
Triple-labeling immunocytochemistry used mouse anti-orexin (1:500; R&D
Systems, Minneapolis, MN), goat anti-c-Fos (1:500) or goat anti--gal
(1:5000), and rabbit anti-µ-opioid receptor (1:4000).
Secondary antibodies were added sequentially: first, the Cy-2 donkey
anti-goat (1:200) and Cy-5 donkey anti-mouse antibodies in 1× PBS for
4 hr, followed by biotinylated goat anti-rabbit antibody (1:400) in 1×
PBS for 1 hr. An avidin-biotin complex (ABC) reaction (Vectastain Elite
kit; Vector Laboratories, Burlingame, CA) was performed
for 10 min followed by a 10 min tyramide signal amplification (TSA Plus
Fluorescence Systems kit; PerkinElmer Life Sciences,
Boston, MA). Each of the four components of the amplification reaction
was omitted as a control. Analysis of triple-labeling was performed by
confocal microscopy (LSM 510; Zeiss, Oberkochen, Germany) at 630× magnification. Sections were optically sliced in the z-plane at 0.4 µm intervals.
Analysis of -gal expression. Perfused brains of
orexin--LacZ mice were cut as 40 µm coronal sections, and
5-bromo-4-chloro-3-indolyl--D-galactopyranoside histochemistry was performed as described previously (Min et al., 1994). For quantification, images of brain sections were captured at
200× magnification, and densitometry was performed on
anteroposteriorly matched sections using NIH Image software, as
described previously (Min et al., 1996). For every mouse used (six per
group), the density of all cell bodies (5-15 per section) from three
adjacent, anatomically matched sections was measured and averaged.
Statistical analysis. Results were expressed as mean ± SEM. Statistical significance was estimated using the t test
or one-way ANOVA followed by the Tukey post hoc test when
appropriate. A p value of <0.05 was considered significant.
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Results |
Orexin neurons are regulated by chronic morphine and
morphine withdrawal
To better understand the effects of morphine on the LH, we
evaluated molecular responses to chronic morphine and morphine withdrawal precipitated by the opioid receptor antagonist naltrexone. CRE-LacZ transgenic mice were used as a reporter of CRE-mediated transcription (Impey et al., 1998), which is known to be regulated by
morphine in several other brain regions (Shaw-Lutchman et al., 2002).
In these mice, the LacZ gene is induced with activation of CRE-binding
protein (CREB) or a CREB family protein (Montminy et al., 1990; Sheng
et al., 1990; Van Nguyen et al., 1990). We used double-labeling
immunohistochemistry to colocalize CRE activity (i.e., LacZ expression)
with orexin or MCH neurons. Chronic administration of morphine caused
an ~10-fold induction of CRE activity in orexin cells (Fig.
1A,B)
(F(3,23) = 49.93; p < 0.05). Precipitation of withdrawal tended to produce a larger induction
of CRE activity, although this was not statistically significant.
Naltrexone by itself, in morphine-naive animals, produced a much
smaller induction of CRE activity in orexin neurons (Fig.
1C,D). Under all three experimental conditions
(chronic morphine, morphine withdrawal, or naltrexone alone), there was
virtually no induction seen in MCH neurons (Fig.
1A,B). This is in contrast to the
selective activation of CRE-LacZ in MCH neurons after starvation (data
not shown), indicating that the CRE-LacZ reporter can be activated in
both cell types. Interestingly, only a subset of orexin cells showed
responses to morphine: 25% of orexin cells were activated after
chronic morphine and 33% during withdrawal (Fig.
1B). Moreover, orexin neurons accounted for only
approximately one-half of the -gal-positive neurons observed,
indicating that induction of CRE activity also occurs in a population
of orexin-negative and MCH-negative neurons.
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Figure 1.
Chronic morphine (Morph) and withdrawal
selectively affect orexin (OX) neurons. Confocal microscopy shows
double-label immunohistochemistry for orexin or MCH with -gal
(A) or c-Fos (C). The data
were quantified and summarized for CRE-LacZ (B)
and for c-Fos (D) (n = 6 per
group). Nal, Naltrexone. *p < 0.05.
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As a second measure of response to morphine treatments, we studied the
induction of c-Fos in wild-type C57BL/6 mice. c-Fos induction has been
used as a marker of neuronal activation during opiate withdrawal
(Hayward et al., 1990; Georges et al., 2000; Gracy et al., 2001).
Whereas chronic morphine treatment, or naltrexone administration to
morphine-naive animals, did not induce c-Fos in orexin or MCH cells,
precipitation of morphine withdrawal significantly induced c-Fos
immunoreactivity in orexin cells, with no response seen in MCH cells
(Fig. 1C,D)
(F(3,20) = 15.79; p < 0.05). Levels of the Fos family protein FosB, which is also induced by
morphine treatments in some brain regions (Nye and Nestler, 1996), were also analyzed. However, we found very little induction of FosB in the
LH, with no induction seen in orexin or MCH cells (data not shown).
Morphine withdrawal induces orexin gene expression
To assess the impact of chronic morphine and precipitated
withdrawal on orexin gene expression, we used a new line of
orexin--LacZ reporter mice, where the -LacZ cassette was knocked
into the endogenous orexin locus. The fusion between -gal and in
these mice makes it possible to visualize neuronal processes in
addition to cell bodies. As an initial test of the reporter, one group of mice was deprived of food for 24 hr, and a control group had normal
access to food. Food restriction induced a robust increase in the
density of LacZ staining in the LH compared with controls (data not
shown). Similar increases in orexin mRNA levels have been
demonstrated in the LH with food deprivation (Sakurai et al., 1998; Cai
et al., 1999; Lopez et al., 2000), indicating that regulation of the
reporter gene follows the normal pattern of orexin expression. We
subsequently examined the effect of chronic morphine and morphine
withdrawal on different groups of orexin--LacZ mice. No change in
LacZ staining was detected in response to chronic morphine or to
naltrexone in morphine-naive mice (Fig.
2). However, precipitation of morphine
withdrawal caused a 56% increase in LacZ staining
(F(3,19) = 5.78; p < 0.01). The increase in LacZ staining during withdrawal was particularly
apparent in cellular processes, which demonstrates the utility of the
-LacZ reporter.
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Figure 2.
Withdrawal induces orexin gene expression in
orexin--LacZ mice. A, A representative image showing
-gal staining in the LH after sham plus naltrexone (Nal; left) or
morphine (Morph) plus naltrexone (right). B, Mean
optical densities are indicated (n = 5 per group).
ROD, Relative optical density.
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Morphine-responsive orexin neurons express the
µ-opioid receptor
To investigate the possibility of a direct effect of morphine on
orexin cells, we used double-labeling immunofluorescence to examine the
presence of MORs on orexin cells in the LH. Examination by
conventional and confocal microscopy revealed that ~50% of orexin
cells display high levels of MOR immunoreactivity. Because only a
subset of orexin cells respond with CRE-LacZ or c-Fos activation, we
performed confocal analysis on triple-immunostained LH sections from
animals during precipitated withdrawal. This analysis confirmed that
all orexin cells that respond with CRE-LacZ or c-Fos also express MORs,
suggesting a direct mode of action. In addition, nonorexin cells that
express CRE-LacZ or c-Fos also express MORs (Fig.
3).
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Figure 3.
Triple immunostaining showing orexin (orx)
cells expressing MOR and LacZ (top) or c-Fos (bottom) as responses to
morphine withdrawal. Arrowheads indicate triple positive staining
shown on the far right (Merge). Also present are nonorexin
cells showing LacZ or c-Fos.
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Orexin knock-out mice display attenuated
morphine withdrawal
The above molecular studies indicated that orexin neurons and the
orexin gene are regulated by morphine treatment. To investigate the
possible behavioral significance of this regulation, we studied morphine withdrawal in orexin knock-out mice. Precipitation
of withdrawal in wild-type littermates induced classic behavioral signs of withdrawal (Fig. 4). Several but
not all of these signs were markedly attenuated in the
orexin knock-outs, and the overall withdrawal score was
significantly decreased (wild-type mice, 99.44 ± 15.76; knock-out
mice, 42.02 ± 5.38; p < 0.05; n = 8 per group). In contrast, orexin mutant mice showed
normal open-field locomotor activity (Fig.
4G,H) and stereotypy (data not shown), and
no other general behavioral abnormalities were observed.
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Figure 4.
Morphine withdrawal is attenuated in orexin
knock-out mice. Orexin knock-outs (gray bars) are compared
with their wild-type littermates (white bars) for jumps
(A), tremor (B), diarrhea
(C), weight loss (D), paw
tremor (E), and wet dog shakes (WDS;
F) (n = 8;
*p < 0.01). Open-field locomotor time course
(G) and cumulative distance for the first 30 min
in a separate set of animals (H) are also
shown. ACSF, Artificial CSF.
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Discussion |
Previous ICSS and self-administration studies support the
involvement of the LH in behavioral responses to morphine and other opiates (Bozarth et al., 1980; Gallistel et al., 1981). Regions of LH
that support morphine self-administration correspond to optimal ICSS
sites, which are located in the MFB, a bundle of fibers that connects
mesencephalic regions (e.g., the ventral tegmental area) with
forebrain structures (e.g., the nucleus accumbens). Although the fibers
are known to be important for ICSS, cells intrinsic to the LH also seem
to be involved (Velley et al., 1983). The studies reported here are the
first to directly implicate orexin neurons in morphine action.
Interestingly, endogenous opioids are needed for orexin-induced feeding
(Clegg et al., 2002), suggesting multiple points of interaction between
orexin and opioids.
Using CRE-LacZ reporter mice, we demonstrate induction of CRE-mediated
transcription in the LH by chronic morphine administration, with no
additional activation observed during precipitation of withdrawal. A
significant fraction of this induction occurs in orexin neurons,
whereas virtually no induction is seen in MCH neurons. The fact that
CRE activity is seen in the chronic morphine-treated state, without
induction of withdrawal, suggests that morphine exposure is sufficient
to induce molecular changes that may reflect neural plasticity in
response to drug exposure. We also examined induction of c-Fos by
chronic morphine and precipitated withdrawal. In contrast to CRE
activity, c-Fos was not induced by chronic morphine but was robustly
induced during withdrawal. This response, like the induction of CRE
activity, was seen in orexin cells but not in MCH cells. These findings
suggest that morphine withdrawal produces acute activation of orexin
cells. In addition to these changes in transcription factors, morphine
withdrawal also induced the orexin gene itself, as seen in
orexin--LacZ reporter mice. Together, these studies demonstrate the
regulation of orexin cells by chronic morphine and morphine withdrawal.
However, it is important to note that orexin neurons account for only a
portion of cells in the LH that show induction of CRE activity and
c-Fos in response to chronic morphine or morphine withdrawal.
Identification of the other cell types will help to delineate the
heterogeneous neuronal populations found in the LH.
The attenuation of morphine withdrawal seen in orexin
knock-out mice implies that the orexin system serves an important
functional role in modulating responses to morphine. The broad
projections of orexin neurons and their potential interactions with
dopaminergic systems (Nakamura et al., 2000), adrenergic systems (Hagan
et al., 1999; Horvath et al., 1999; Bourgin et al., 2000), and the hypothalamic-pituitary-adrenal axis (Kuru et al., 2000) suggest that
multiple modes of action may be implicated in orexin modulation of
morphine withdrawal. Although orexin knock-out mice also
display narcolepsy and cataplexy, we did not observe sleep attacks
during the 25 min testing period, and locomotor activity was normal. This is expected, because we performed these studies during the light
phase, when sleep attacks are infrequent (Chemelli et al., 1999).
Although MORs have been detected previously in the LH (Mansour et al.,
1987; Delfs et al., 1994; Mansour et al., 1994; Briski and Sylvester,
2001), the cellular identity of these neurons was unknown. We show in
this study that a subset (~50%) of orexin neurons expresses MORs,
and that most of these cells respond to morphine by induction of CRE
activity or c-Fos. The data also suggest, not surprisingly, that orexin
cells are not a homogeneous population. Indeed, it has been
demonstrated that amphetamine and antipsychotic drugs induce c-Fos in
subsets of orexin neurons (Fadel et al., 2002). It is notable that all
cells, both orexin and nonorexin, that show molecular responses to
morphine express MORs.
The induction of CRE activity and c-Fos in orexin cells that express
the MOR suggests that regulation of the cells by chronic morphine and
morphine withdrawal is mediated via direct actions of morphine on these
cells. Chronic morphine upregulates the cAMP pathway in many regions of
the central and peripheral nervous systems, where it has been shown to
be an important mechanism underlying opiate dependence and withdrawal
(Nestler, 2001). The expression of MORs on orexin neurons and the
activation of CRE-mediated transcription in these cells after chronic
morphine treatment suggest that a similar upregulation of the cAMP
pathway may occur in these LH neurons. Although additional work is
needed to identify the target genes of the cAMP cascade in orexin
neurons, the orexin gene itself does not appear to be one of
them, because chronic morphine did not increase orexin gene
expression in the orexin--LacZ reporter mice. It is also notable
that orexin cells express the endogenous opioid peptide dynorphin (Chou
et al., 2001); it remains to be determined whether this colocalization
has functional implications for mechanisms of morphine withdrawal.
The data presented in this study begin to define, on a molecular and
cellular level, the relationship between the LH and drug addiction.
Multiple lines of evidence implicate orexin neurons in behavioral
responses to morphine. Specifically, induction of c-Fos suggests that
orexin neurons are activated during precipitated morphine withdrawal,
with the induction of orexin gene expression possibly
representing a response to restore orexin levels after a period of
increased neural activity. The attenuated withdrawal syndrome seen in
orexin knock-out mice suggests that such regulation of
orexin neurons may be an important contributor to morphine physical
dependence and to the expression of withdrawal. Additional studies are
now needed to assess a role for the orexin system in other behavioral
actions of morphine, in particular those actions related to ICSS and
self-administration.
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FOOTNOTES |
Received Dec. 18, 2002; revised Jan. 30, 2003; accepted Feb. 4, 2003.
This study was supported by grants from the National Institutes of
Health to E.J.N. M.Y. is an investigator of the Howard Hughes
Medical Institute. We thank Chitra Mandyam and Linda Perrotti for
advice on antibody staining and Wylie Vale for the gift of anti-MCH antibody.
Correspondence should be addressed to Dr. Ralph DiLeone,
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. E-mail: ralph.dileone{at}utsouthwestern.edu.
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References |
-
Adams WJ,
Lorens SA,
Mitchell CL
(1972)
Morphine enhances lateral hypothalamic self-stimulation in the rat.
Proc Soc Exp Biol Med
140:770-771[Medline].
-
Anand BK,
Brobeck JR
(1951)
Hypothalamic control of food intake in rats and cats.
Yale J Biol Med
24:123-140[ISI][Medline].
-
Bourgin P,
Huitron-Resendiz S,
Spier AD,
Fabre V,
Morte B,
Criado JR,
Sutcliffe JG,
Henriksen SJ,
de Lecea L
(2000)
Hypocretin-1 modulates rapid eye movement sleep through activation of locus ceruleus neurons.
J Neurosci
20:7760-7765[Abstract/Free Full Text].
-
Bozarth MA,
Gerber GJ,
Wise RA
(1980)
Intracranial self-stimulation as a technique to study the reward properties of drugs of abuse.
Pharmacol Biochem Behav
13:245-247.
-
Briski KP,
Sylvester PW
(2001)
Co-distribution of Fos- and mu opioid receptor immunoreactivity within the rat septopreoptic area and hypothalamus during acute glucose deprivation: effects of the mu receptor antagonist CTOP.
Neurosci Lett
306:141-144[Medline].
-
Cai XJ,
Widdowson PS,
Harrold J,
Wilson S,
Buckingham RE,
Arch JR,
Tadayyon M,
Clapham JC,
Wilding J,
Williams G
(1999)
Hypothalamic orexin expression: modulation by blood glucose and feeding.
Diabetes
48:2132-2137[Abstract].
-
Cazala P,
Darracq C,
Saint-Marc M
(1987)
Self-administration of morphine into the lateral hypothalamus in the mouse.
Brain Res
416:283-288[Medline].
-
Chemelli RM,
Willie JT,
Sinton CM,
Elmquist JK,
Scammell T,
Lee C,
Richardson JA,
Williams SC,
Xiong Y,
Kisanuki Y,
Fitch TE,
Nakazato M,
Hammer RE,
Saper CB,
Yanagisawa M
(1999)
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Cell
98:437-451[ISI][Medline].
-
Chou TC,
Lee CE,
Lu J,
Elmquist JK,
Hara J,
Willie JT,
Beuckmann CT,
Chemelli RM,
Sakurai T,
Yanagisawa M,
Saper CB,
Scammell TE
(2001)
Orexin (hypocretin) neurons contain dynorphin.
J Neurosci
21:RC168[Abstract/Free Full Text](1-6).
-
Clegg DJ,
Air EL,
Woods SC,
Seeley RJ
(2002)
Eating elicited by orexin-A, but not melanin-concentrating hormone, is opioid mediated.
Endocrinology
143:2995-3000[Abstract/Free Full Text].
-
Delfs JM,
Kong H,
Mestek A,
Chen Y,
Yu L,
Reisine T,
Chesselet MF
(1994)
Expression of mu opioid receptor mRNA in rat brain: an in situ hybridization study at the single cell level.
J Comp Neurol
345:46-68[ISI][Medline].
-
Edwards CM,
Abusnana S,
Sunter D,
Murphy KG,
Ghatei MA,
Bloom SR
(1999)
The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin.
J Endocrinol
160:R7-R12[Abstract].
-
Fadel J,
Deutch AY
(2002)
Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area.
Neuroscience
111:379-387[ISI][Medline].
-
Fadel J,
Bubser M,
Deutch AY
(2002)
Differential activation of orexin neurons by antipsychotic drugs associated with weight gain.
J Neurosci
22:6742-6746[Abstract/Free Full Text].
-
Gallistel CR,
Shizgal P,
Yeomans JS
(1981)
A portrait of the substrate for self-stimulation.
Psychol Rev
88:228-273[ISI][Medline].
-
Georges F,
Stinus L,
Le Moine C
(2000)
Mapping of c-fos gene expression in the brain during morphine dependence and precipitated withdrawal, and phenotypic identification of the striatal neurons involved.
Eur J Neurosci
12:4475-4486[Medline].
-
Goodall EB,
Carey RJ
(1975)
Effects of D- versus L-amphetamine, food deprivation, and current intensity on self-stimulation of the lateral hypothalamus, substantia nigra, and medial frontal cortex of the rat.
J Comp Physiol Psychol
89:1029-1045[Medline].
-
Gracy KN,
Dankiewicz LA,
Koob GF
(2001)
Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion.
Neuropsychopharmacology
24:152-160[Medline].
-
Hagan JJ,
Leslie RA,
Patel S,
Evans ML,
Wattam TA,
Holmes S,
Benham CD,
Taylor SG,
Routledge C,
Hemmati P,
Munton RP,
Ashmeade TE,
Shah AS,
Hatcher JP,
Hatcher PD,
Jones DN,
Smith MI,
Piper DC,
Hunter AJ,
Porter RA
(1999)
Orexin A activates locus coeruleus cell firing and increases arousal in the rat.
Proc Natl Acad Sci USA
96:10911-10916[Abstract/Free Full Text].
-
Haynes AC,
Jackson B,
Overend P,
Buckingham RE,
Wilson S,
Tadayyon M,
Arch JR
(1999)
Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat.
Peptides
20:1099-1105[ISI][Medline].
-
Hayward MD,
Duman RS,
Nestler EJ
(1990)
Induction of the c-fos proto-oncogene during opiate withdrawal in the locus coeruleus and other regions of rat brain.
Brain Res
525:256-266[Medline].
-
Horvath TL,
Peyron C,
Diano S,
Ivanov A,
Aston-Jones G,
Kilduff TS,
van Den Pol AN
(1999)
Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system.
J Comp Neurol
415:145-159[ISI][Medline].
-
Ida T,
Nakahara K,
Murakami T,
Hanada R,
Nakazato M,
Murakami N
(2000)
Possible involvement of orexin in the stress reaction in rats.
Biochem Biophys Res Commun
270:318-323[ISI][Medline].
-
Impey S,
Smith DM,
Obrietan K,
Donahue R,
Wade C,
Storm DR
(1998)
Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning.
Nat Neurosci
1:595-601[ISI][Medline].
-
Kuru M,
Ueta Y,
Serino R,
Nakazato M,
Yamamoto Y,
Shibuya I,
Yamashita H
(2000)
Centrally administered orexin/hypocretin activates HPA axis in rats.
NeuroReport
11:1977-1980[ISI][Medline].
-
Lopez M,
Seoane L,
Garcia MC,
Lago F,
Casanueva FF,
Senaris R,
Dieguez C
(2000)
Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus.
Biochem Biophys Res Commun
269:41-45[ISI][Medline].
-
Ludwig DS,
Mountjoy KG,
Tatro JB,
Gillette JA,
Frederich RC,
Flier JS,
Maratos-Flier E
(1998)
Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.
Am J Physiol
274:E627-E633.
-
Mansour A,
Khachaturian H,
Lewis ME,
Akil H,
Watson SJ
(1987)
Autoradiographic differentiation of µ,
 , and  opioid receptors in the rat forebrain and midbrain.
J Neurosci
7:2445-2464[Abstract]. -
Mansour A,
Fox CA,
Thompson RC,
Akil H,
Watson SJ
(1994)
mu-Opioid receptor mRNA expression in the rat CNS: comparison to mu-receptor binding.
Brain Res
643:245-265[ISI][Medline].
-
Millhouse OE
(1969)
A Golgi study of the descending medial forebrain bundle.
Brain Res
15:341-363[ISI][Medline].
-
Min N,
Joh TH,
Kim KS,
Peng C,
Son JH
(1994)
5' Upstream DNA sequence of the rat tyrosine hydroxylase gene directs high-level and tissue-specific expression to catecholaminergic neurons in the central nervous system of transgenic mice.
Brain Res Mol Brain Res
27:281-289[Medline].
-
Min N,
Joh TH,
Corp ES,
Baker H,
Cubells JF,
Son JH
(1996)
A transgenic mouse model to study transsynaptic regulation of tyrosine hydroxylase gene expression.
J Neurochem
67:11-18[Medline].
-
Montminy MR,
Gonzalez GA,
Yamamoto KK
(1990)
Regulation of cAMP-inducible genes by CREB.
Trends Neurosci
13:184-188[ISI][Medline].
-
Nakamura T,
Uramura K,
Nambu T,
Yada T,
Goto K,
Yanagisawa M,
Sakurai T
(2000)
Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system.
Brain Res
873:181-187[ISI][Medline].
-
Nestler EJ
(2001)
Molecular basis of long-term plasticity underlying addiction.
Nat Rev Neurosci
2:119-128[ISI][Medline].
-
Nye HE,
Nestler EJ
(1996)
Induction of chronic Fos-related antigens in rat brain by chronic morphine administration.
Mol Pharmacol
49:636-645[Abstract].
-
Olds J,
Milner P
(1954)
Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.
J Comp Physiol Psychol
47:419-427[ISI][Medline].
-
Olds ME,
Williams KN
(1980)
Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites.
Brain Res
194:155-170[ISI][Medline].
-
Peyron C,
Tighe DK,
van den Pol AN,
de Lecea L,
Heller HC,
Sutcliffe JG,
Kilduff TS
(1998)
Neurons containing hypocretin (orexin) project to multiple neuronal systems.
J Neurosci
18:9996-10015[Abstract/Free Full Text].
-
Sakurai T,
Amemiya A,
Ishii M,
Matsuzaki I,
Chemelli RM,
Tanaka H,
Williams SC,
Richardson JA,
Kozlowski GP,
Wilson S,
Arch JR,
Buckingham RE,
Haynes AC,
Carr SA,
Annan RS,
McNulty DE,
Liu WS,
Terrett JA,
Elshourbagy NA,
Bergsma DJ
(1998)
Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.
Cell
92:573-585[ISI][Medline].
-
Shaw-Lutchman TZ,
Barrot M,
Wallace T,
Gilden L,
Zachariou V,
Impey S,
Duman RS,
Storm D,
Nestler EJ
(2002)
Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal.
J Neurosci
22:3663-3672[Abstract/Free Full Text].
-
Sheng M,
McFadden G,
Greenberg ME
(1990)
Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB.
Neuron
4:571-582[ISI][Medline].
-
Shimada M,
Tritos NA,
Lowell BB,
Flier JS,
Maratos-Flier E
(1998)
Mice lacking melanin-concentrating hormone are hypophagic and lean.
Nature
396:670-674[Medline].
-
Van Nguyen T,
Kobierski L,
Comb M,
Hyman SE
(1990)
The effect of depolarization on expression of the human proenkephalin gene is synergistic with cAMP and dependent upon a cAMP-inducible enhancer.
J Neurosci
10:2825-2833[Abstract].
-
Velley L,
Chaminade C,
Roy MT,
Kempf E,
Cardo B
(1983)
Intrinsic neurons are involved in lateral hypothalamic self-stimulation.
Brain Res
268:79-86[Medline].
Copyright © 2003 Society for Neuroscience 0270-6474/03/2383106-06$05.00/0
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TOP
ABSTRACT
Introduction
