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ABSTRACT: The active zone protein RIM1alpha is required both for maintaining normal probability of neurotransmitter release and for long-term presynaptic potentiation at brain synapses. We now demonstrate that RIM1alpha(-/-) mice exhibit normal coordination and anxiety-related behaviors but display severely impaired learning and memory. Mice with a synaptotagmin 1 mutation, which selectively lowers release probability, and mice with Rab3A deletion, which selectively abolishes presynaptic long-term potentiation, do not exhibit this abnormality. Our data suggest that a decrease in release probability or a loss of presynaptic LTP alone is not sufficient to cause major behavioral alterations, but the combination of presynaptic abnormalities in RIM1alpha(-/-) mice severely alters learning and memory.
Neuron 05/2004; 42(1):143-53. · 14.74 Impact Factor
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ABSTRACT: Methylphenidate (MPH) is a psychomotor stimulant medication widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Given the extent of prescribed use of MPH, and because MPH interacts with the same brain pathways activated by drugs of abuse, most research has focused on assessing MPH's potential to alter an individual's risk for adult drug addiction. Data examining other potential long-term behavioral consequences of early MPH administration are lacking, however.
We investigated the long-term behavioral consequences of chronic administration of MPH (2.0 mg/kg) during pre- and periadolescent development in adult rats by assessing their behavioral reactivity to a variety of emotional stimuli.
The MPH-treated animals were significantly less responsive to natural rewards such as sucrose, novelty-induced activity, and sex compared with vehicle-treated control animals. In contrast, MPH-treated animals were significantly more sensitive to stressful situations, showed increased anxiety-like behaviors, and had enhanced plasma levels of corticosterone.
Chronic exposure to MPH during development leads to decreased sensitivity to rewarding stimuli and results in enhanced responsivity to aversive situations. These results highlight the need for further research to improve understanding of the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.
Biological Psychiatry 01/2004; 54(12):1317-29. · 8.28 Impact Factor
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ABSTRACT: Previous work has shown that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are involved in appetitive behavior. Here we show that BDNF in the ventral tegmental area-nucleus accumbens (VTA-NAc) pathway is also involved in the development of a depression-like phenotype.
Brain-derived neurotrophic factor signaling in the VTA-NAc pathway was altered in two complementary ways. One group of rats received intra-VTA infusion of vehicle or BDNF for 1 week. A second group of rats received intra-NAc injections of vehicle or adeno-associated viral vectors encoding full-length (TrkB.FL) or truncated (TrkB.T1) TrkB; the latter is kinase deficient and serves as a dominant-negative receptor. Rats were examined in the forced swim test and other behavioral tests.
Intra-VTA infusions of BDNF resulted in 57% shorter latency to immobility relative to control animals, a depression-like effect. Intra-NAc injections of TrkB.T1 resulted in and almost fivefold longer latency to immobility relative to TrkB.FL and control animals, an antidepressant-like effect. No effect on anxiety-like behaviors or locomotion was seen.
These data suggest that BDNF action in the VTA-NAc pathway might be related to development of a depression-like phenotype. This interpretation is intriguing in that it suggests a role for BDNF in the VTA-NAc that is opposite of the proposed role for BDNF in the hippocampus.
Biological Psychiatry 12/2003; 54(10):994-1005. · 8.28 Impact Factor
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ABSTRACT: Neurotrophic factor signaling pathways modulate cellular and behavioral responses to drugs of abuse. In addition, chronic exposure to morphine increases expression of phospholipase Cgamma1 (PLCgamma1) (a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of PLCgamma1, we show that overexpression of PLCgamma1 in rostral portions of the VTA (R-VTA) results in increased morphine place preference, whereas PLCgamma1 overexpression in the caudal VTA (C-VTA) results in avoidance of morphine-paired compartments. In addition, overexpression of PLCgamma1 in R-VTA causes increased preference for sucrose and increased anxiety-like behavior but does not affect responses to stress or nociceptive stimuli. In contrast, overexpression of PLCgamma1 in C-VTA decreases preference for sucrose and increases sensitivity to stress and nociceptive stimuli, although there was a tendency for increased anxiety-like behavior as seen for the R-VTA. These results show that levels of PLCgamma1 in the VTA regulate responsiveness to drugs of abuse, natural rewards, and aversive stimuli and point to the possibility that distinct topographical regions within the VTA mediate generally positive versus negative responses to emotional stimuli. Moreover, these data also support a role for drug-induced elevations in PLCgamma1 expression in the VTA in mediating long-term adaptations to drugs of abuse and aversive stimuli.
Journal of Neuroscience 09/2003; 23(20):7569-76. · 7.11 Impact Factor
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Zia Rahman,
Johannes Schwarz,
Stephen J Gold,
Venetia Zachariou,
Marc N Wein,
Kwang Ho Choi,
Abraham Kovoor,
Ching Kang Chen,
Ralph J DiLeone,
Sigrid C Schwarz,
Dana E Selley,
Laura J Sim-Selley, Michel Barrot,
Robert R Luedtke,
David Self,
Rachael L Neve,
Henry A Lester,
Melvin I Simon,
Eric J Nestler
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ABSTRACT: Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha subunits. We examined a role for RGS9-2, an RGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.
Neuron 07/2003; 38(6):941-52. · 14.74 Impact Factor
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ABSTRACT: Morphine stimulates the internalization of mu-opioid receptors (MORs) in transfected cell models to a lesser degree than opioid peptides and other analgesic drugs, such as methadone, and previous studies have reported that morphine does not produce a detectable redistribution of MORs in neural tissue after either acute or chronic administration. Nevertheless, morphine produces profound physiological effects, raising the question of whether receptor trafficking plays any role in the in vivo actions of morphine. We investigated the effects of opiate drugs on recombinant and native opioid receptors in the nucleus accumbens, which plays an important role in mediating the behavioral effects of opiate drugs. Morphine and methadone differed in their effects on the internalization of epitope-tagged MORs in cell bodies, introduced by viral gene transfer and imaged by fluorescence microscopy. A mutation of the cytoplasmic tail that confers morphine-induced internalization in cultured cells had a similar effect on receptor trafficking in nucleus accumbens cell bodies. Surprisingly, in contrast to its failure to affect MOR distribution detectably in cell bodies, acute morphine administration produced a pronounced change in MOR distribution visualized in the processes of the same neurons. A similar effect of acute morphine administration was observed for endogenously expressed MORs by immunoelectron microscopy; the acute administration of morphine increased the density of MORs associated with internal membrane structures specifically in dendrites. These results provide the first evidence that morphine regulates the distribution of MORs in neuronal processes, suggesting that "compartment-selective" membrane trafficking represents a previously unanticipated type of opioid receptor regulation contributing to the in vivo effects of opiate drugs on a physiologically relevant population of CNS neurons.
Journal of Neuroscience 06/2003; 23(10):4324-32. · 7.11 Impact Factor
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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 mu-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.
Journal of Neuroscience 05/2003; 23(8):3106-11. · 7.11 Impact Factor
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Michel Barrot,
Jocelien D A Olivier,
Linda I Perrotti,
Ralph J DiLeone,
Olivier Berton,
Amelia J Eisch,
Soren Impey,
Daniel R Storm,
Rachael L Neve,
Jerry C Yin,
Venetia Zachariou,
Eric J Nestler
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ABSTRACT: The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.
Proceedings of the National Academy of Sciences 09/2002; 99(17):11435-40. · 9.68 Impact Factor
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ABSTRACT: Chronic opiate exposure is associated with upregulation of the cAMP signaling pathway and the transcription factor cAMP response element-binding protein in the locus ceruleus (LC) and certain other brain areas. To determine whether these adaptations ultimately affect transcription mediated by the cAMP response element (CRE), we induced morphine dependence in CRE-LacZ transgenic mice and performed a regional and cellular mapping of beta-galactosidase (beta-gal) expression during naltrexone-precipitated withdrawal. Consistent with our model of opiate dependence, beta-gal expression increased in the LC, but decreased in the lateral ventral tegmental area (VTA) and dorsal raphe nucleus (DRN). In addition, withdrawal increased beta-gal expression in the continuum of the extended amygdala and nucleus accumbens, macrostructures associated with the coupling of emotional stimuli to motor and autonomic responses. At the cellular level, in the central nucleus of the amygdala, beta-gal was found in cells both with and without mu opioid receptors as well as in corticotropin-releasing factor-expressing cells. In nucleus accumbens, beta-gal was expressed in several major subpopulations of neurons. In LC, beta-gal expression was induced predominantly in tyrosine hydroxylase-expressing cells, whereas in the VTA and DRN the majority of cells expressing beta-gal were nonmonoaminergic. These results show that molecular adaptations to chronic morphine alter CRE-mediated transcription during opiate withdrawal in physiologically salient regions involved in arousal, reward, mood, and affective responses. We propose that CRE-mediated transcription serves as a functional marker for neuronal plasticity during withdrawal. CRE-mediated transcription may itself contribute to re-establishing homeostasis in the organism through target gene regulation in these regions.
Journal of Neuroscience 06/2002; 22(9):3663-72. · 7.11 Impact Factor
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ABSTRACT: Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.
Neuron 04/2002; 34(1):13-25. · 14.74 Impact Factor
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ABSTRACT: The longevity of some of the behavioral abnormalities that
characterize drug addiction has suggested that regulation of neural
gene expression may be involved in the process by which drugs of abuse
cause a state of addiction. Increasing evidence suggests that the
transcription factor ΔFosB represents one mechanism by which drugs of
abuse produce relatively stable changes in the brain that contribute to
the addiction phenotype. ΔFosB, a member of the Fos family of
transcription factors, accumulates within a subset of neurons of the
nucleus accumbens and dorsal striatum (brain regions important for
addiction) after repeated administration of many kinds of drugs of
abuse. Similar accumulation of ΔFosB occurs after compulsive running,
which suggests that ΔFosB may accumulate in response to many types of
compulsive behaviors. Importantly, ΔFosB persists in neurons for
relatively long periods of time because of its extraordinary stability.
Therefore, ΔFosB represents a molecular mechanism that could initiate
and then sustain changes in gene expression that persist long after
drug exposure ceases. Studies in inducible transgenic mice that
overexpress either ΔFosB or a dominant negative inhibitor of the
protein provide direct evidence that ΔFosB causes increased
sensitivity to the behavioral effects of drugs of abuse and, possibly,
increased drug seeking behavior. This work supports the view that
ΔFosB functions as a type of sustained “molecular switch” that
gradually converts acute drug responses into relatively stable
adaptations that contribute to the long-term neural and behavioral
plasticity that underlies addiction.
Proceedings of the National Academy of Sciences 09/2001; 98(20):11042-11046. · 9.68 Impact Factor
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ABSTRACT: Neuropathic pain is a disease caused by a lesion or dysfunction of the nervous system. Antidepressants or anticonvulsants are presently the best available treatments. The mechanism by which antidepressants relieve neuropathic pain remains poorly understood. Using pharmacological and transgenic approaches in mice, we evaluated adrenergic receptor (AR) implication in the action of the tricyclic antidepressant desipramine, the noradrenaline and serotonin reuptake inhibitor venlafaxine, and the noradrenaline reuptake inhibitor reboxetine. Neuropathy was induced by cuff insertion around the sciatic nerve. We showed that chronic antidepressant treatment suppressed cuff-induced allodynia in wild-type mice but not in β2-AR deficient mice, and/or that this antiallodynic action was blocked by intraperitoneal or intrathecal injection of the β2-AR antagonist ICI 118,551 but not by the α2-AR antagonist yohimbine. We also showed that the anticonvulsant gabapentin was still effective in β2-AR deficient mice. Our results demonstrate that β2-ARs are essential for the antiallodynic action of antidepressant drugs.
Neurobiology of Disease.
