Toni Shippenberg, Ph.D. - US grants
Affiliations: | National Institute on Drug Abuse |
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According to our matching algorithm, Toni Shippenberg is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2007 — 2011 | Shippenberg, Toni | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Descending Modulation of Nerve Injury and Injury-Evoked Pain @ National Institute On Drug Abuse Neuroimaging techniques have provided effective tools for investigating the influence of pain on CNS function. Human imaging studies have identified a pain matrix composed of brain regions that are activated by nociceptive stimuli. Activation is observed in the secondary somatosensory and insular regions, the anterior cingulate as well as the primary somatosensory area and thalamus. More limited evidence indicates decreased activity in a network that includes the inferior parietal lobule, and the medial prefrontal cortex. These regions are thought to subserve discriminative sensory pain transmission and to process affective-motivational components of pain. MRI investigations in chronic neuropathic pain indicate brain neurodegeneration and decreased gray matter volume and density in patients with chronic back pain, phantom pain, or fibromyalgia, although degree and regional distribution varies. Chronic back pain patients show activation of the prefrontal cortex during spontaneous pain, the same area that shows a reduction in gray matter density, as well as disruption in resting functional connectivity of widespread cortical areas. The nature of structural changes remains to be determined, whether neurodegeneration is causal and if analgesics prevent these changes. A difficulty in human research is assembling a homogenous patient cohort with matched symptoms, disease duration, medication history and age distribution. Since subjects are not tested prior to pain onset, individual differences that may predispose pain vulnerability can not be assessed. Importantly, the response to nerve injury and to different treatments varies among patients with comparable pain syndromes and not all patients exhibit neuropathic pain behavior after a demonstrable nerve injury. For these reasons, human functional imaging has not yet provided reproducible findings specific to the disease or a pathophysiological basis for symptomology. Prior to the advent of small animal imaging, preclinical studies could not directly measure spontaneous pain, a limitation in their utility as models of neuropathic pain. However, procedural advances now allow quantification of alterations in resting state connectivity and stimulus-evoked activity. The coupling of imaging to animal models of neuropathic pain allows longitudinal study of the development of pain and its expression. Changes in brain function that occur during spontaneous and stimulus-evoked pain can be assessed as a function of pain duration: grey matter volume and white matter integrity can be assessed over time. Using MRI and MRS techniques and the spared nerve injury (SNI) model of neuropathic pain in rats, ongoing studies seek to: i) identify changes in brain structure, function and metabolism that occur in the pain matrix as a function of the duration of neuropathic pain;ii) determine whether individuals differ in vulnerability to SNI-evoked pain and whether these differences are associated with differences in brain function and iii) determine whether a manipulation that we have shown to prevent the development of or reverse the expression of SNI-evoked allodynia and hyperalgesia (see below) reduces SNI-evoked alterations in spontaneous and evoked brain activity, functional connectivity, concentrations of biochemical compounds, grey matter volume and white matter integrity. Using advanced MRI and MRS techniques developed within the IRP, we expect to identify maladaptive brain plasticity at a systems level in the SNI rats, and to correlate brain plasticity with behavioral pain measures. The proposed translational studies will enable identification of a disease-modifying strategy aimed at both preventing maladaptive plasticity and identifying intrinsic risk individuals The rostral ventromedial medulla (RVM) constitutes the efferent component of pain-control systems that descend from the brain to the spinal cord. Considerable evidence has emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. The RVM normally exerts an inhibitory influence on dorsal horn neurons However, persistent noxious stimulation triggers time-related alterations in RVM synaptic activity. In inflammatory pain models, descending facilitation transiently increases reducing the net effect of inhibition. Over time, descending inhibition increases resulting in decreased nocifensive behavior. After nerve injury, RVM plasticity leads to facilitation of spinal cord nociceptive output, exacerbation of primary hyperalgesia and enhanced sensory input from adjacent regions (secondary hyperalgesia). AMPA receptor activation in the RVM has been shown to inhibit spinal nociceptive transmission and nocifensive behavior. Increased AMPA receptor function in the RVM is implicated in the activity-dependent plasticity that occurs in response to persistent pain produced by tissue inflammation. Targeting and synaptic clustering of AMPA receptors is essential for efficient excitatory transmission. Neuronal pentraxin 1 (NP1) is a member of the pentraxin family of proteins that is expressed exclusively in neurons and facilitates AMPA receptor clustering. Given the postulated role of NP1 in excitatory synaptic transmission and AMPA receptor systems in pain processing, we have used gene deletion and viral-mediated transfer techniques to examine whether manipulations that target this protein can affect the expression of persistent pain. To determine the contribution of NP1 to nerve-injury evoked pain, we assessed mechanical hypersensitivity in wild type and NP1 knock out mice following spared nerve injury. Nerve injury led to marked mechanical hypersensitivity of the injured limb. This enhanced nociception is significantly inhibited in NP1 knockout mice. In order to probe the specific involvement of RVM NP1 in mediating the attenuated response of NP1 knockout mice, we infused a lentiviral vector which drives expression of functional NP1 protein directly into the RVM. Selective rescue of RVM NP1 expression in knockout mice restores allodynia produced by nerve injury. Consistent with the data obtained in NP1 knockout mice, silencing NP1 expression in the RVM of rats prior to nerve injury inhibits allodynia. Furthermore, it decreases mechanical hyperalgesia. These findings are consistent with the observation that descending facilitatory systems arising in the RVM are necessary for the maintenance of neuropathic pain and identify NP1 in the RVM as a critical element in the descending facilitation of nerve-injury evoked pain. Together, these data suggest that targeting NP1 may be a novel therapeutic strategy for reversing persistent pain of diverse etiologies. On-going studies examining the role of NP1 in other conditions including those associated with AIDS antiretroviral therapy and peripheral inflammation indicate a key role of this protein in the development of persistent pain. Preliminary studies examining the contribution of another pentraxin, pentraxin 3 suggest a global role of the pentraxin family of proteins in the pathogenesis of nerve injury, neuropathic and inflammatory pain. |
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2007 — 2011 | Shippenberg, Toni | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Discovery of Novel Molecular Targets For Endogenous and Synthetic Cannabinoids @ National Institute On Drug Abuse The neurotransmitter, dopamine, modulates excitatory and inhibitory neurotransmission in brain regions that control movement, emotion, and reward. Dysregulation of DA transmission is implicated in the etiology of several pathological conditions including Parkinsons disease, drug addiction, and schizophrenia. The dopamine transporter (DAT) is an integral membrane protein that is a member of the Na+- and Cl-- dependent cotransporter gene family. It serves a key role in terminating dopamine transmission by clearing dopamine released into the extracellular space. Systemic administration of the endocannabinoid, anandamide, increases extracellular dopamine concentrations in the nucleus accumbens, a brain region implicated in mediating the abuse liability of various psychoactive drugs. Increased dopamine concentrations are also observed in response to synthetic cannabinoid agonists. Although these effects have been attributed to alterations in release, evidence that anandamide and other cannabinoids inhibit transporter-mediated dopamine uptake in native tissue and heterologous expression systems has been presented. Such findings are noteworthy in that they suggest that endocannabinoids may modulate dopamine transmission by regulating DAT function. The cellular mechanisms mediating the interaction of anandamide with DAT are unclear. Although there is evidence that it may modulate DAT function by a CB1 independent mechanism, whether the effect of anandamide is mediated by the activation of other cannabinoid receptors such as CB2 and GPR55 that are expressed in the brain is unclear. In addition, although prolonged incubation of cells or synaptosomes decreases dopamine uptake, the time course and the cellular mechanisms of this effect have not been assessed. We previously demonstrated that use of the fluorescent, high affinity DAT substrate, ASP+ 4-(4-(dimethylamino)styrl)-N-methylpyridinium))in combination with confocal microscopy enables real-time, spatially resolved analysis of transporter function in heterologous expression systems. Analysis of ASP+ accumulation not only permits resolution of substrate binding and uptake in the same cell but enables quantification of rapid (e.g. 1 min) changes in DAT function (see: Bolan et al., 2007, Zapata et al 2007). Using this technique we have investigated the effect of anandamide on the function of human DAT (hDAT) expressed in the EM4 HEK 293 cell line which does not endogenously express known cannabinoid receptors. In parallel studies, biochemical and confocal imaging techniques were employed to assess the role of transporter trafficking in mediating anandamide-evoked alterations in DAT function. Addition of anandamide to EM4 cells transiently transfected to express fluorescently tagged hDAT produced a concentration-dependent inhibition of ASP+ accumulation. This effect was rapid occurring within 1 min after anandamide addition. Increased DAT function was long-lasting. A significant inhibition of ASP+ accumulation was still apparent 10 min after anandamide addition. Incubation of cells with pertussis toxin did not attenuate the effects of anandamide suggesting a mechanism independent of Gi/Go coupled receptors. The amidohydrolase inhibitor, phenylmethylsulfonyl fluoride, failed to alter the effects of anandamide. No change in ASP+ accumulation was observed in response to arachidonic acid suggesting that the effects of anandamide are not mediated by its metabolic products. The downregulation of DAT function was associated with a significant redistribution of hDAT from the membrane to the cytosol as measured using both confocal microscopy and biotinylation techniques. These results demonstrate that anandamide modulates DAT function via a cannabinoid receptor-independent mechanism. Furthermore, they suggest that endocannabinoids may increase extracellular dopamine, in part, by increasing DAT internalization. The serotonin type three (5-HT3) receptor, a member of the ligand-gated ion channel family, mediates rapid and transient membrane depolarizing effect of 5-HT in the central and peripheral nervous system. An involvement of 5-HT3 receptors in pain transmission, mood disorders, and drug abuse has been reported. Furthermore, 5-HT3 receptor antagonists are effective therapeutic agents for the treatment of chemotherapy-induced nausea and vomiting. Earlier studies showed that 5-HT3-receptor antagonists and cannabinoids produce similar pharmacological effects such as non-opioid receptor-mediated analgesia and antiemesis. In fact, synthetic Δ-tetrahydrocannabinol (THC), dronabinol, and THC analogs such as nabilone are approved by the US Food and Drug Administration for use in chemotherapy-induced nausea and vomiting refractory to conventional antiemetic therapy. The limitation of the therapeutic utility of THC and the above-mentioned chemical analogs is that they can produce psychoactive effects through the cannabinoid 1 receptor (CB1) Cannabidiol (CBD) is one of the most abundant cannabinoids of Cannabis sativa with reported antioxidant, anti-inflammatory, and antiemetic effects. It is well tolerated and is without side effects when chronically administered to humans. Furthermore, CBD is devoid of psychoactive properties due to a low affinity for the CB1 and CB2 receptors. Thus, pharmaceutical interest in this compound has increased significantly in recent years. Although the effects of THC, synthetic cannabinoid receptor agonists (e.g., WIN55,212- 2, CP55,940, and JWH-015), and the endocannabinoid, anandamide, on the functional properties of 5-HT3-receptors were demonstrated in in-vitro studies, whether CBD, a nonpsychotropic cannabinoid affects 5-HT3A-receptor function is unknown. This issue was addressed by assessing the effects of CBD on the function of 5-HT3A receptors expressed in Xenopus oocytes using two-electrode voltage clamp techniques. CBD reversibly inhibited 5-HT (1 μM)-evoked currents in a concentration-dependent manner (IC50=0.6μM). CBD did not alter specific binding of the 5-HT3A antagonist 3HGR65630. In the presence of CBD, the maximum 5-HT-induced currents were also inhibited. The EC50 values were 1.2 μM and 1.4 μM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 receptors. Neither intracellular BAPTA injection nor pertussis toxin pretreatment altered the CBD-evoked inhibition of 5-HT-induced currents. CBD inhibition was inversely correlated with 5-HT3A expression levels and mean 5-HT3 receptor current density. Pretreatment with actinomycin D, which inhibits protein transcription, decreased the mean 5-HT3 receptor current density and increased the magnitude of CBD inhibition. These data demonstrate that CBD is an allosteric inhibitor of 5-HT3 receptors expressed in Xenopus oocytes. They further suggest that allosteric inhibition of 5-HT3 receptors by CBD may contribute to its physiological role in the modulation of nociception and emesis. |
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2007 — 2011 | Shippenberg, Toni | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Neurobiology of Alcohol and Inhalant Abuse @ National Institute On Drug Abuse Dopaminergic afferents arising from the ventral tegmental (VTA) area and projecting to the nucleus accumbens (ACb)are key elements of brain circuits that subserve arousal, motivation, and reinforcement. Increased dopamine neurotransmission within this mesoaccumbal pathway has been implicated in the mediation of the reinforcing effects of psychostimulants, alcohol, and other drugs of abuse. [unreadable] [unreadable] Previous studies have shown toluene inhalation produces reinforcing effects in animal models and is abused by humans. Although acute exposure of rats to toluene increases dopamine release in the dorsal striatum similar effects have not been reported in the ACb. These findings have led to the hypothesis that a dopamine-independent mechanism mediates the abuse liability of toluene and other inhalants. Anatomical studies, however, have shown that the ACb consists of two sub-regions termed the shell and the core. Heterogeneity of the VTA and in the responsiveness of VTA dopamine neurons to several drugs of abuse has been reported. [unreadable] [unreadable] We conducted a series of studies to determine whether there are sub-region-specific effects of toluene on neuronal activity in the VTA and ACb. Using in-vitro electrophysiology, we have now shown that behaviorally relevant concentrations of toluene directly stimulates dopamine neurons in the VTA but not in surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-dopamine containing neurons, the magnitude of VTA dopamine neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in-vivo microdialysis to monitor dopamine release, we show that perfusion of toluene directly into the VTA increases dopamine concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACb. The magnitude of the dopamine response to toluene also varied as a function of the VTA sub-region evaluated. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA dopamine neurons, thereby enhancing dopamine transmission in the ACb. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA dopamine neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse. Importantly, they suggest that the mesoaccumbal pathway may also contribute to the abuse of toluene and other inhalants. [unreadable] [unreadable] We previously demonstrated the existence of a tonically active kappa-opioid receptor (KOPr) system located in the ACb that inhibits the basal activity of dopamine neurons in the ACb. This same opioid system is up-regulated in response to the repeated use of alcohol and psychostimulants suggesting that this neuroadaptation may underlie alterations in behavior and mesolimbic dopamine transmission that occur following repeated drug use. We have tested this hypothesis using in-vivo microdialysis in conjunction with pharmacological and gene targeting techniques Our studies have revealed that acute alcohol exposure increases dopamine concentrations in the Acb and that this effect is enhanced in animals lacking KOPr. These findings demonstrate that inhibition of KOPR is associated with increased sensitivity of an individual to the dopamine-releasing effects of ethanol. They are particularly interesting in that they may provide a neurochemical basis for the recent demonstration that variations in the genes encoding both KOPr and its endogenous ligand, dynorphin, are associated with the risk for alcohol dependence in human subjects. [unreadable] [unreadable] We have gone on to examine the influence of KOPr blockade on alcohol self-administration and extracellular dopamine concentrations in the Acb. Microdialysis revealed a transient elevation of dopamine concentration within 5 min of ethanol access in controls that was abolished by KOPr blockade. Despite these neurochemical changes, KOPr blockade did not alter operant responding or ethanol intake, suggesting that the KOPr is not involved in ethanol-reinforced behavior under the limited conditions we studied. However, fundamental questions exist as to whether behavioral interactions of KOPr ligands with alcohol are observed following longer access to alcohol and/or with administration paradigms that result in the development of alcohol dependence. [unreadable] [unreadable] Preliminary studies conducted with our collaborators at the Karolinska Instituute (NIH and Karolinska Institute Collaborative Program In Postgraduate Education) have shown that expression of dynorphin, the endogenous ligand for the KOPr, is altered in the hippocampus of human alcoholics. KOPr is located on glutamatergic neurons in the hippocampus and has been implicated in the modulation of long-term depression (LTD). On-going studies are seeking to determine whether KOPr regulate glutamate transmission in the hippocampus and whether dysregulation of this opioid system contributes to the neurotoxic effects of alcohol on hippocampal function. Our preliminary data suggest that KOPr antagonist can not only prevent cognitive deficits produced by repeated high dose alcohol exposure but also prevent alterations in glutamatergic neurotransmission that occurs in the hippocampus following alcohol exposure. On-going studies are determining the mechanisms by which KOPr antagonism produces neuroprotection. |
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2007 — 2011 | Shippenberg, Toni | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Neurobiology of Psychostimulant and Opiate Addiction @ National Institute On Drug Abuse Psychostimulants increase extracellular concentration of the neurotransmitter, dopamine, in the nucleus accumbens and other brain regions comprising the prefrontal-cortico-striatal loop. Dysregulation of this system has been implicated in the transition from casual to compulsive drug use and to the preservative behavior that characterizes addiction. Psychostimulants increase dopamine concentrations by binding to and inhibiting the dopamine transporter, a membrane bound protein that clears dopamine released into the synaptic cleft. This action mediates the abuse liability of these agents as well as their psychomotor stimulant effects. We and others have shown that D2 and D3 receptors, members of the D2 family of G-protein coupled receptors, regulate extracellular dopamine concentrations in the nucleus accumbens and striatum. Extracellular dopamine concentrations are decreased in response to D2/D3 receptor agonists and increased in response to receptor antagonists. Our in-vivo and in-vitro studies provided evidence that D2/D3 receptors regulate dopamine transmission presynaptically by two distinct mechanisms. They affect transporter mediated dopamine re-uptake and they affect release. Due, however, to the lack of ligands selective for these receptor sub-types and the presence of both D2 and D3 receptors in the brain regions examined, the role of each in the regulation of dopamine dynamics could not be delineated.[unreadable] [unreadable] Using a recently developed live-cell imaging technique, our studies have provided the first direct demonstration that D2 receptors regulate the activity of the dopamine transporter. For these studies, human embryonic kidney (HEK) cells and a neuronally-derived cell line were co-transfected with the human D2 receptor and the human dopamine transporter. Dopamine transporter function was monitored in real time using the high affinity, fluorescent dopamine transporter substrate, 4-(4-diethylaminostyryl)-N-methylpyridinium iodide (ASP+). Addition of the D2/D3 agonist, quinpirole to cells co-expressing these proteins induced a rapid and concentration-dependent increase in ASP+ accumulation. The structurally dissimilar D2/D3 agonist, PD128907 also increased ASP+ accumulation. Increases in accumulation was pertussis toxin-sensitive and only apparent in transfected cells. D2 receptor stimulation induced phosphorylation of extracellular related kinase (ERK1/2) and Akt, a major target of phosphoinositide 3-kinase (PI3K), confirming that the D2 receptor signals through these kinase cascades. Pretreatment of cells with the ERK 1/2 inhibitor, PD 98059, prevented the quinpirole-evoked increase in ASP+ accumulation. PI-3 kinase inhibition was without effect indicating that D2 receptor stimulation upregulates DAT function in mammalian cell lines via an ERK1/2-dependent and PI3K-independent mechanism. Co-immunoprecipitation and bioluminescence resonance energy transfer (BRET) techniques revealed that the dopamine transporter and D2 receptor are in close proximity providing a cellular basis for the interaction of these two proteins. [unreadable] [unreadable] In subsequent studies we have used the ASP+ technique to determine whether dopamine transporter function is regulated by D3 receptors. In cells co-expressing D3 receptors and the dopamine transporter, we observed that D3 receptor activation rapidly increased ASP+ uptake. Similar effects were observed using a conventional radioligand binding assay. D3 receptor stimulation, like D2 receptor stimulation, activated ERK 1/2 and PI3-K. In contrast, however, to D2 receptor stimulation, the inhibition of either kinase prevented the increase in uptake evoked by D3 receptor activation. Using biotinylation techniques to quantify the intracellular and membrane expression of the dopamine transporter, we have shown that D3 receptor activation differentially affected transporter subcellular distribution depending on the duration of agonist exposure. The rapid increase in transporter function is associated with increased transporter cell surface expression and decreased intracellular transporter. In contrast, following prolonged D3 receptor activation, dopamine transporter function is down-regulated and transporter cell surface expression is reduced. Amphetamine and other transporter substrates promote redistribution of the dopamine transporter from the plasma membrane to the cytosol where they are unable to regulate uptake. Therefore, increased intracellular transporter accumulation would result in an elevation of extracellular dopamine concentrations. This effect appears paradoxical since decreased cell surface transporter expression decreases dopamine clearance from the extracellular fluid and high extracellular DA concentrations are neurotoxic. Our results suggest that if dopamine is available to transiently stimulate D2 or D3 receptors, transporter internalization will decrease in the vicinity of these receptors, resulting in rapid clearance of extracellular dopamine and prevention of prolonged receptor activation. On-going studies are determining the role of D2/D3 regulation of the dopamine transporter in mediating alterations in dopamine transmission produced by amphetamine and other transporter substrates. [unreadable] [unreadable] Kappa opioid receptor agonists decrease extracellular dopamine concentrations in the nucleus accumbens and dorsal striatum. Our recent studies have shown that acute administration of the potent kappa opioid receptor agonist, salvinorin A, an alkaloid found in the mint leaf and used by Indian tribes for its psychotomimetic actions, produces similar effects. Since kappa opioid receptors are apposed to dopamine transporters in dopamine nerve terminals in the nucleus accumbens we have initiated studies to determine whether this G-protein coupled receptor regulates dopamine transmission by affecting the activity of the dopamine transporter. Our studies in native tissue and heterologous expression systems have revealed that salvinorin, dynorphin, the endogenous kappa opioid receptor ligand, as well as synthetic agonists modulate extracellular dopamine concentrations, at least in part, by facilitating dopamine uptake. Furthermore, the interaction of kappa opioid receptors with the dopamine transporter, like that of D2 and D3 receptors is ERK 1/2- dependent. These findings suggest that the previously documented cocaine-antagonist-like effects of kappa opioid receptor agonists may result, at least, in part, from the ability of kappa opioid receptors to regulate the dopamine transporter. [unreadable] [unreadable] Cocaine binds with high affinity to the dopamine transporter as well as other monoamine transporters. Studies, currently in progress, are examining the role of kappa opioid receptors in regulating the activity of these monoamine transporters. The contribution of kappa- and other opioid receptor types to the regulation of amino acid transporter function will also be assessed in view of our recent findings indicating the involvement of endogenous opioid system in regulating in glutamate and GABA homeostasis in-vivo. |
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2010 — 2011 | Shippenberg, Toni | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Modeling Goal-Oriented Versus Habitual Drug-Seeking and Taking in Rodents @ National Institute On Drug Abuse Habit learning processes are implicated in the transition from recreational drug use to the compulsive drug seeking that characterizes addiction. Lesions of the dorsal striatum, an area necessary for habit learning, attenuate cue controlled drug seeking and nigrostriatal dopamine lesions disrupt habit formation. Moreover, prior repeated psychostimulant administration facilitates habitual responding for food reinforcers suggesting that their self-administration accelerates habit development. Studies assessing the development of habitual drug seeking are limited. Using outcome devaluation procedures by satiation or pairing of oral reinforcers with sickness induced by a drug (e.g. lithium), two laboratories demonstrated habitual drug seeking of orally administered drug reinforcers. However, studies of intravenous drug administration have been hampered by difficulties inherent in adapting standard devaluation procedures for natural reinforcers to intravenous administered drug. In contrast to natural reinforcers, this route of administration is not associated with an obvious consummatory response and psychostimulants such as cocaine have unconditioned, behaviorally activating effects, that can affect responding. To circumvent these issues, we have used a heterogenous chained schedule of intravenous cocaine administration in which habitual cocaine-seeking is tested by devaluing the final link of a drug seeking/taking chained schedule. In this procedure, responding on the designated drug seeking lever provides access to a drug taking lever, rather than to cocaine itself. Responses on the drug taking lever result in a cocaine infusion. The effects of devaluation of the drug taking link (by extinction) is assessed once performance under the chained schedule has stabilized. Decreased responding during the drug seeking link is indicative of behavior that is goal-oriented. Responding that is insensitive to devaluation is evidential of the development of habitual drug-seeking. Other rats underwent the same protocol except that after completing the cocaine seeking test, an additional 36 sessions were conducted to provide an extended drug seeking history. Given the documented role of the dorsolateral striatum in stimulus-response associations, the influence of inactivation of this brain area was assessed in animals with a prolonged history of cocaine seeking and taking. In rats with limited cocaine access, devaluation of the outcome of the drug seeking link by extinction significantly decreased drug seeking indicating that behavior is goal-oriented rather than habitual. Importantly, however, examination of each animals data revealed that whereas drug seeking was clearly attenuated by outcome devaluation in eight animals, responding of six animals after devaluation was greater than 80% of that under the revalued condition, indicating poor sensitivity to devaluation in these animals. Thus, in this subset of animals, cocaine seeking was not goal-oriented but already habitual in nature. With, however, more prolonged drug experience, all animals transitioned to habitual cocaine seeking. Thus, cocaine-seeking became insensitive to outcome devaluation. Moreover, when the dorsolateral striatum, an area implicated in habit learning, was transiently inactivated, outcome devaluation was again effective in decreasing drug-seeking indicating that responding was no longer habitual but had reverted to control by the goal-oriented system. These studies provide direct evidence that cocaine seeking becomes habitual with prolonged drug experience and describe a rodent model with which to study the neural mechanisms underlying the transition from goal-oriented to habitual drug-seeking. On-going studies are using this model to examine the role of the dynorphin/k-opioid receptor system (see: DA000538-04) in modulating the transition from goal-directed to habitual cocaine seeking. Stimuli associated with drug use not only contribute to the maintenance of habitual drug seeking but their presentation precipitates relapse in abstinent subjects. Second order schedules of drug self administration have been used extensively to study control of drug seeking by drug associated stimuli. In this schedule, responses on the drug lever are maintained for prolonged periods of time by discrete presentations of a cocaine associated stimulus before any drug is infused. Responding during the first component of the schedule, before the first drug infusion, provides a measure of drug seeking exclusively under the control of drug-associated stimuli. As such, it is not confounded by the unconditioned effects of a drug. Responses during the second and subsequent components reflect control of behavior by both the conditioned and unconditioned effects of a drug. Furthermore, in contrast to fixed ratio schedules of drug self-administration, the extended training required for acquisition of behavior in a second order schedule is thought to promote the transition from goal-oriented to habitual (stimulus-response) drug seeking. During the past year, we have established this procedure for cocaine. Furthermore, we have begun to examine whether drugs currently under evaluation for the treatment of cocaine addiction affect drug-seeking under the control of conditioned stimuli. Our studies have focused on kappa opioid receptor antagonists since kappa opioid receptor antagonists are in Phase I testing for preventing stress-induced relapse to cocaine addiction. We found that in rats actively taking drug, the selective and long-acting kappa opioid receptor antagonist, nor-binaltorphimine, exacerbates cocaine-seeking maintained by a conditioned stimulus. In contrast, cocaine-taking is unaltered. Kappa opioid receptor blockade does not affect taking or seeking of a natural reinforcer (e.g. sucrose). Furthermore, it does not attenuate the spontaneous reinstatement of cocaine taking and seeking that occurs in animals in which self-administration was terminated several weeks prior to testing. Kappa opioid receptor antagonists attenuate stress-induced potentiation of cocaine place conditioning and stress induced reinstatement of cocaine seeking in abstinent animals. These effects have been attributed to blockade of increased kappa opioid receptor activation resulting from stress-evoked increases in dynorphin. We previously reported that kappa opioid receptor antagonists do not prevent (or even potentiate) relapse to drug seeking induced by a cocaine priming injection;and enhance behavioral sensitization to cocaine. These findings and those regarding their effects on cocaine-seeking maintained by conditioned stimuli suggests that the utility of these agents for preventing relapse in abstinent addicts may depend on the predominant factor (i.e. context, stress, unconditioned drug effects, etc) which precipitate drug-seeking and taking in a particular individual. Furthermore, they suggest that kappa opioid receptor blockade may promote drug seeking in non-abstinent individuals by increasing the ability of conditioned stimuli to control drug seeking. Future studies seek to delineate the role of the kappa opioid receptor/dynorphin system during various stages of the addiction cycle and in modulating processes within the brain that underlie control of behavior by conditioned stimuli. |
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