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Rita A Fuchs - One of the best experts on this subject based on the ideXlab platform.

  • role of the agranular insular cortex in contextual control over cocaine seeking Behavior in rats
    Psychopharmacology, 2017
    Co-Authors: Amy A Arguello, Matthew A Hodges, Rong Wang, Jessica A Higginbotham, Carey M Lyons, Rita A Fuchs
    Abstract:

    Rationale Environmental stimulus control over drug relapse requires the retrieval of context-response-cocaine associations, maintained in long-term memory through active reconsolidation processes. Identifying the neural substrates of these phenomena is important from a drug addiction treatment perspective.

  • role of a lateral orbital frontal cortex basolateral amygdala circuit in cue induced cocaine seeking Behavior
    Neuropsychopharmacology, 2017
    Co-Authors: Amy A Arguello, Matthew A Hodges, Garret D. Stuber, Ben D Richardson, Jacob L Hall, Rong Wang, Marshall P Mitchell, David J Rossi, Rita A Fuchs
    Abstract:

    Role of a Lateral Orbital Frontal Cortex-Basolateral Amygdala Circuit in Cue-Induced Cocaine-Seeking Behavior

  • requisite role of basolateral amygdala glucocorticoid receptor stimulation in drug context induced cocaine seeking Behavior
    The International Journal of Neuropsychopharmacology, 2016
    Co-Authors: Rita A Fuchs, Sierra J Stringfield, Jessica A Higginbotham
    Abstract:

    Background: Exposure to cocaine-associated stimuli triggers a robust rise in circulating glucocorticoid levels. Glucocorticoid receptors are richly expressed in the basolateral amygdala, a brain region that controls the reinstatement of Cocaine-Seeking Behavior upon exposure to a previously cocaine-paired environmental context. In the present study, we investigated whether glucocorticoid receptor stimulation in the basolateral amygdala is integral to drug context-induced motivation to seek cocaine in a rat model of drug relapse. Methods: Rats were trained to lever press for cocaine reinforcement in a distinct environmental context and were then given daily extinction training sessions in a different context. At test, the rats received bilateral glucocorticoid receptor antagonist (mifepristone; 3 or 10ng/hemisphere) or vehicle microinfusions into either the basolateral amygdala or the overlying posterior caudate-putamen (anatomical control region). Immediately thereafter, drug-seeking Behavior (i.e., nonreinforced lever presses) was assessed in the previously cocaine-paired context and locomotor activity was assessed in a novel context. Results: Intra-basolateral amygdala, but not intra-posterior caudate-putamen, mifepristone dose-dependently attenuated drug context-induced Cocaine-Seeking Behavior relative to vehicle, such that responding was similar to that observed in the extinction context. In contrast, mifepristone treatment did not alter locomotor activity. Conclusions: These findings suggest that basolateral amygdala glucocorticoid receptor stimulation is necessary for drug context-induced motivation to seek cocaine.

  • contribution of an sfk mediated signaling pathway in the dorsal hippocampus to cocaine memory reconsolidation in rats
    Neuropsychopharmacology, 2016
    Co-Authors: Audrey M. Wells, Amy A Arguello, Xiaohu Xie, Jessica A Higginbotham, Kati L Healey, Megan Blanton, Rita A Fuchs
    Abstract:

    Environmentally induced relapse to cocaine seeking requires the retrieval of context–response–cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental Cocaine-Seeking Behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced Cocaine-Seeking Behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2—as well as PEAQX—attenuated subsequent drug context-induced Cocaine-Seeking Behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over Cocaine-Seeking Behavior.

  • contribution of a mesocorticolimbic subcircuit to drug context induced reinstatement of cocaine seeking Behavior in rats
    Neuropsychopharmacology, 2014
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Amy A Arguello, Matthew A Hodges, Rita A Fuchs
    Abstract:

    Cocaine-Seeking Behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)–basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of Cocaine-Seeking Behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated Cocaine-Seeking Behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced Cocaine-Seeking Behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC–BLA functional interactions. Thus, a VTA–OFC–BLA neural circuit promotes drug context-induced motivated Behavior.

Heather C Lasseter - One of the best experts on this subject based on the ideXlab platform.

  • contribution of a mesocorticolimbic subcircuit to drug context induced reinstatement of cocaine seeking Behavior in rats
    Neuropsychopharmacology, 2014
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Amy A Arguello, Matthew A Hodges, Rita A Fuchs
    Abstract:

    Cocaine-Seeking Behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)–basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of Cocaine-Seeking Behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated Cocaine-Seeking Behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced Cocaine-Seeking Behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC–BLA functional interactions. Thus, a VTA–OFC–BLA neural circuit promotes drug context-induced motivated Behavior.

  • subregion specific role of glutamate receptors in the nucleus accumbens on drug context induced reinstatement of cocaine seeking Behavior in rats
    Addiction Biology, 2012
    Co-Authors: Xiaohu Xie, Audrey M. Wells, Heather C Lasseter, Donna R Ramirez, Kaicee L Ponds, Rita A Fuchs
    Abstract:

    The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual Cocaine-Seeking Behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of Cocaine-Seeking Behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-Seeking Behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual Cocaine-Seeking Behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this Behavior. The manipulations failed to alter instrumental Behavior in the extinction context, general motor activity, or food-reinforced instrumental Behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

  • interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context induced cocaine seeking Behavior in rats
    Learning & Memory, 2011
    Co-Authors: Audrey M. Wells, Heather C Lasseter, Xiaohu Xie, Kate E Cowhey, Andrew M Reittinger, Rita A Fuchs
    Abstract:

    Contextual stimulus control over instrumental drug-seeking Behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of Cocaine-Seeking Behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced Cocaine-Seeking Behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced Cocaine-Seeking Behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of Cocaine-Seeking Behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger Cocaine-Seeking Behavior and contributing to the incubation of Cocaine-Seeking Behavior.

  • Interaction of the Basolateral Amygdala and Orbitofrontal Cortex is Critical for Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats
    Neuropsychopharmacology, 2011
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Xiaohu Xie, Rita A Fuchs
    Abstract:

    The basolateral amygdala (BLA) and lateral orbitofrontal cortex (OFC) are critical elements of the neural circuitry that regulates drug context-induced reinstatement of Cocaine-Seeking Behavior. Given the existence of dense reciprocal anatomical connections between these brain regions, this study tested the hypothesis that serial information processing by the BLA and OFC is necessary for drug context-induced Cocaine-Seeking Behavior. Male Sprague–Dawley rats were trained to lever press for un-signaled cocaine infusions (0.15 mg/infusion, i.v.) in a distinct environment (cocaine-paired context) then underwent extinction training in a different environment (extinction context). During four subsequent test sessions, rats were re-exposed to the cocaine-paired and extinction contexts in order to assess Cocaine-Seeking Behavior (non-reinforced active lever responding). Immediately before each test session, rats received microinfusions of the GABA_A/GABA_B agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle unilaterally into the BLA plus the contralateral or ipsilateral OFC, or unilaterally into the OFC alone. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished Cocaine-Seeking Behavior. BM-induced unilateral OFC inactivation failed to alter this Behavior, similar to the effect of unilateral BLA inactivation in our previous study ( Fuchs et al, 2007 ). Conversely, neural inactivation of the BLA plus the contralateral or ipsilateral OFC equally attenuated drug context-induced cocaine seeking without altering food-reinforced instrumental responding, relative to vehicle pretreatment. These findings suggest that the BLA and OFC co-regulate drug context-induced motivation for cocaine either through sequential information processing via intra- and interhemispheric connections or by providing converging input to a downstream brain region.

  • sub region specific contribution of the ventral hippocampus to drug context induced reinstatement of cocaine seeking Behavior in rats
    Neuroscience, 2010
    Co-Authors: Heather C Lasseter, Xiaohu Xie, Donna R Ramirez, Rita A Fuchs
    Abstract:

    Abstract The ventral hippocampus (VH) plays critical roles in cue-induced and cocaine-primed reinstatement of cocaine seeking [Rogers JL, See RE (2007) Neurobiol Learn Mem 87:688–692]. Subregions of the VH make distinct projections to elements of the brain relapse circuitry that mediate drug context-induced reinstatement. Thus, the VH may also critically contribute to this form of cocaine seeking in a subregion-specific manner. Accordingly, this study evaluated the hypothesis that functional inactivation of the ventral hippocampus proper (VHp)—but not of the dentate gyrus (DG)—impairs cocaine seeking elicited by re-exposure to a drug-paired environmental context. Rats were trained to lever press for un-signaled i.v. cocaine infusions (0.15 mg/infusion) in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different context (extinction context). Subsequently, Cocaine-Seeking Behavior (i.e., non-reinforced active lever responding) was assessed in either the previously cocaine-paired context or the extinction context. Rats received bilateral microinfusions of the GABA agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle into the VHp, DG, or the posterior dorsal hippocampus (pDH; extra-VH control) immediately before each test session. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished Cocaine-Seeking Behavior following vehicle pretreatment. BM pretreatment administered into the VHp, but not the DG or pDH, significantly attenuated drug context-induced cocaine seeking. These results indicate that the VH contributes to drug context-induced cocaine seeking in a subregion-specific manner, with the functional integrity of the VHp being necessary for memory or motivational aspects of drug-paired environmental stimuli that sustain stimulus control over goal-directed Behavior.

Xiaohu Xie - One of the best experts on this subject based on the ideXlab platform.

  • contribution of an sfk mediated signaling pathway in the dorsal hippocampus to cocaine memory reconsolidation in rats
    Neuropsychopharmacology, 2016
    Co-Authors: Audrey M. Wells, Amy A Arguello, Xiaohu Xie, Jessica A Higginbotham, Kati L Healey, Megan Blanton, Rita A Fuchs
    Abstract:

    Environmentally induced relapse to cocaine seeking requires the retrieval of context–response–cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental Cocaine-Seeking Behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced Cocaine-Seeking Behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2—as well as PEAQX—attenuated subsequent drug context-induced Cocaine-Seeking Behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over Cocaine-Seeking Behavior.

  • subregion specific role of glutamate receptors in the nucleus accumbens on drug context induced reinstatement of cocaine seeking Behavior in rats
    Addiction Biology, 2012
    Co-Authors: Xiaohu Xie, Audrey M. Wells, Heather C Lasseter, Donna R Ramirez, Kaicee L Ponds, Rita A Fuchs
    Abstract:

    The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual Cocaine-Seeking Behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of Cocaine-Seeking Behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-Seeking Behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual Cocaine-Seeking Behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this Behavior. The manipulations failed to alter instrumental Behavior in the extinction context, general motor activity, or food-reinforced instrumental Behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

  • interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context induced cocaine seeking Behavior in rats
    Learning & Memory, 2011
    Co-Authors: Audrey M. Wells, Heather C Lasseter, Xiaohu Xie, Kate E Cowhey, Andrew M Reittinger, Rita A Fuchs
    Abstract:

    Contextual stimulus control over instrumental drug-seeking Behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of Cocaine-Seeking Behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced Cocaine-Seeking Behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced Cocaine-Seeking Behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of Cocaine-Seeking Behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger Cocaine-Seeking Behavior and contributing to the incubation of Cocaine-Seeking Behavior.

  • Interaction of the Basolateral Amygdala and Orbitofrontal Cortex is Critical for Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats
    Neuropsychopharmacology, 2011
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Xiaohu Xie, Rita A Fuchs
    Abstract:

    The basolateral amygdala (BLA) and lateral orbitofrontal cortex (OFC) are critical elements of the neural circuitry that regulates drug context-induced reinstatement of Cocaine-Seeking Behavior. Given the existence of dense reciprocal anatomical connections between these brain regions, this study tested the hypothesis that serial information processing by the BLA and OFC is necessary for drug context-induced Cocaine-Seeking Behavior. Male Sprague–Dawley rats were trained to lever press for un-signaled cocaine infusions (0.15 mg/infusion, i.v.) in a distinct environment (cocaine-paired context) then underwent extinction training in a different environment (extinction context). During four subsequent test sessions, rats were re-exposed to the cocaine-paired and extinction contexts in order to assess Cocaine-Seeking Behavior (non-reinforced active lever responding). Immediately before each test session, rats received microinfusions of the GABA_A/GABA_B agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle unilaterally into the BLA plus the contralateral or ipsilateral OFC, or unilaterally into the OFC alone. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished Cocaine-Seeking Behavior. BM-induced unilateral OFC inactivation failed to alter this Behavior, similar to the effect of unilateral BLA inactivation in our previous study ( Fuchs et al, 2007 ). Conversely, neural inactivation of the BLA plus the contralateral or ipsilateral OFC equally attenuated drug context-induced cocaine seeking without altering food-reinforced instrumental responding, relative to vehicle pretreatment. These findings suggest that the BLA and OFC co-regulate drug context-induced motivation for cocaine either through sequential information processing via intra- and interhemispheric connections or by providing converging input to a downstream brain region.

  • sub region specific contribution of the ventral hippocampus to drug context induced reinstatement of cocaine seeking Behavior in rats
    Neuroscience, 2010
    Co-Authors: Heather C Lasseter, Xiaohu Xie, Donna R Ramirez, Rita A Fuchs
    Abstract:

    Abstract The ventral hippocampus (VH) plays critical roles in cue-induced and cocaine-primed reinstatement of cocaine seeking [Rogers JL, See RE (2007) Neurobiol Learn Mem 87:688–692]. Subregions of the VH make distinct projections to elements of the brain relapse circuitry that mediate drug context-induced reinstatement. Thus, the VH may also critically contribute to this form of cocaine seeking in a subregion-specific manner. Accordingly, this study evaluated the hypothesis that functional inactivation of the ventral hippocampus proper (VHp)—but not of the dentate gyrus (DG)—impairs cocaine seeking elicited by re-exposure to a drug-paired environmental context. Rats were trained to lever press for un-signaled i.v. cocaine infusions (0.15 mg/infusion) in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different context (extinction context). Subsequently, Cocaine-Seeking Behavior (i.e., non-reinforced active lever responding) was assessed in either the previously cocaine-paired context or the extinction context. Rats received bilateral microinfusions of the GABA agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle into the VHp, DG, or the posterior dorsal hippocampus (pDH; extra-VH control) immediately before each test session. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished Cocaine-Seeking Behavior following vehicle pretreatment. BM pretreatment administered into the VHp, but not the DG or pDH, significantly attenuated drug context-induced cocaine seeking. These results indicate that the VH contributes to drug context-induced cocaine seeking in a subregion-specific manner, with the functional integrity of the VHp being necessary for memory or motivational aspects of drug-paired environmental stimuli that sustain stimulus control over goal-directed Behavior.

Barry J Everitt - One of the best experts on this subject based on the ideXlab platform.

  • the basolateral amygdala to nucleus accumbens core circuit mediates the conditioned reinforcing effects of cocaine paired cues on cocaine seeking
    Biological Psychiatry, 2021
    Co-Authors: Mickael Puaud, Barry J Everitt, Alejandro Higueramatas, Paul Brunault, David Belin
    Abstract:

    Abstract Background Individuals addicted to cocaine spend much of their time foraging for the drug. Pavlovian drug-associated conditioned stimuli exert a major influence on the initiation and maintenance of drug seeking often long into abstinence, especially when presented response-contingently, acting as conditioned reinforcers that bridge delays to drug use. The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the nucleus accumbens core (NAcC). However, the precise neuronal circuits underlying the acquisition of cue-controlled Cocaine-Seeking Behavior have not been elucidated. Methods Here, we used a projection-specific Cre-dependent DREADD (designer receptor exclusively activated by designer drugs)-mediated causal approach to test the hypothesis that the direct projections from the BLA to the NAcC are required for the acquisition of cue-controlled Cocaine-Seeking Behavior. Results In Sprague Dawley rats with Cre-mediated expression of the inhibitory DREADD hM4D(Gi) in the NAcC-projecting BLA neurons, treatment with clozapine N-oxide, but not vehicle, selectively prevented the impact of cocaine-associated conditioned reinforcers on cocaine seeking under a second-order schedule of reinforcement. This effect was attributable to the chemogenetic inhibition of the NAcC-projecting BLA neurons, as it was reversible, and it was absent in clozapine N-oxide–treated rats expressing an empty control virus. In contrast, chemogenetic inhibition of the anterior insula, which receives collateral projections from NAcC-projecting BLA neurons, was without effect. Conclusions These data demonstrate that the acquisition of cue-controlled cocaine seeking that depends on the conditioned reinforcing effects of cocaine cues requires activity in the direct projections from the BLA to the NAcC.

  • 2012a) Double dissociation of the dorsomedial and dorsolateral striatal control over the acquisition and performance of cocaine seeking
    2016
    Co-Authors: Jennifer E Murray, David Belin, Barry J Everitt
    Abstract:

    The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early- and late-stage performance of Cocaine-Seeking Behavior. Rats were trained to self-administer cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of a-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule [FI15(FR10:S)] so that Cocaine-Seeking performance became well established. At this stage, intra-aDLS, but not pDMS, a-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. a-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of Cocaine-Seeking Behavior, supporting the theory o

  • double dissociation of the dorsomedial and dorsolateral striatal control over the acquisition and performance of cocaine seeking
    Neuropsychopharmacology, 2012
    Co-Authors: Barry J Everitt, Jennifer E Murray, David Belin
    Abstract:

    The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early- and late-stage performance of Cocaine-Seeking Behavior. Rats were trained to self-administer cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of α-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule [FI15(FR10:S)] so that Cocaine-Seeking performance became well established. At this stage, intra-aDLS, but not pDMS, α-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. α-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of Cocaine-Seeking Behavior, supporting the theory of dynamic shifts in the striatal control over cocaine seeking between goal-directed and habitual performance.

  • the orbital prefrontal cortex and drug addiction in laboratory animals and humans
    Annals of the New York Academy of Sciences, 2007
    Co-Authors: Barry J Everitt, Jeffrey W Dalley, Daniel M Hutcheson, Karen D Ersche, Yann Pelloux, Trevor W Robbins
    Abstract:

    In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of Cocaine-Seeking Behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.

  • disrupting reconsolidation of drug memories reduces cocaine seeking Behavior
    Neuron, 2005
    Co-Authors: Jonathan L C Lee, Patricia Di Ciano, Kerrie L Thomas, Barry J Everitt
    Abstract:

    Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new Cocaine-Seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking.

Audrey M. Wells - One of the best experts on this subject based on the ideXlab platform.

  • contribution of an sfk mediated signaling pathway in the dorsal hippocampus to cocaine memory reconsolidation in rats
    Neuropsychopharmacology, 2016
    Co-Authors: Audrey M. Wells, Amy A Arguello, Xiaohu Xie, Jessica A Higginbotham, Kati L Healey, Megan Blanton, Rita A Fuchs
    Abstract:

    Environmentally induced relapse to cocaine seeking requires the retrieval of context–response–cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental Cocaine-Seeking Behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced Cocaine-Seeking Behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2—as well as PEAQX—attenuated subsequent drug context-induced Cocaine-Seeking Behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over Cocaine-Seeking Behavior.

  • contribution of a mesocorticolimbic subcircuit to drug context induced reinstatement of cocaine seeking Behavior in rats
    Neuropsychopharmacology, 2014
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Amy A Arguello, Matthew A Hodges, Rita A Fuchs
    Abstract:

    Cocaine-Seeking Behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)–basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of Cocaine-Seeking Behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated Cocaine-Seeking Behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced Cocaine-Seeking Behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC–BLA functional interactions. Thus, a VTA–OFC–BLA neural circuit promotes drug context-induced motivated Behavior.

  • subregion specific role of glutamate receptors in the nucleus accumbens on drug context induced reinstatement of cocaine seeking Behavior in rats
    Addiction Biology, 2012
    Co-Authors: Xiaohu Xie, Audrey M. Wells, Heather C Lasseter, Donna R Ramirez, Kaicee L Ponds, Rita A Fuchs
    Abstract:

    The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual Cocaine-Seeking Behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of Cocaine-Seeking Behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-Seeking Behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual Cocaine-Seeking Behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this Behavior. The manipulations failed to alter instrumental Behavior in the extinction context, general motor activity, or food-reinforced instrumental Behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

  • interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context induced cocaine seeking Behavior in rats
    Learning & Memory, 2011
    Co-Authors: Audrey M. Wells, Heather C Lasseter, Xiaohu Xie, Kate E Cowhey, Andrew M Reittinger, Rita A Fuchs
    Abstract:

    Contextual stimulus control over instrumental drug-seeking Behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of Cocaine-Seeking Behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced Cocaine-Seeking Behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced Cocaine-Seeking Behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of Cocaine-Seeking Behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger Cocaine-Seeking Behavior and contributing to the incubation of Cocaine-Seeking Behavior.

  • Interaction of the Basolateral Amygdala and Orbitofrontal Cortex is Critical for Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats
    Neuropsychopharmacology, 2011
    Co-Authors: Heather C Lasseter, Audrey M. Wells, Xiaohu Xie, Rita A Fuchs
    Abstract:

    The basolateral amygdala (BLA) and lateral orbitofrontal cortex (OFC) are critical elements of the neural circuitry that regulates drug context-induced reinstatement of Cocaine-Seeking Behavior. Given the existence of dense reciprocal anatomical connections between these brain regions, this study tested the hypothesis that serial information processing by the BLA and OFC is necessary for drug context-induced Cocaine-Seeking Behavior. Male Sprague–Dawley rats were trained to lever press for un-signaled cocaine infusions (0.15 mg/infusion, i.v.) in a distinct environment (cocaine-paired context) then underwent extinction training in a different environment (extinction context). During four subsequent test sessions, rats were re-exposed to the cocaine-paired and extinction contexts in order to assess Cocaine-Seeking Behavior (non-reinforced active lever responding). Immediately before each test session, rats received microinfusions of the GABA_A/GABA_B agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle unilaterally into the BLA plus the contralateral or ipsilateral OFC, or unilaterally into the OFC alone. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished Cocaine-Seeking Behavior. BM-induced unilateral OFC inactivation failed to alter this Behavior, similar to the effect of unilateral BLA inactivation in our previous study ( Fuchs et al, 2007 ). Conversely, neural inactivation of the BLA plus the contralateral or ipsilateral OFC equally attenuated drug context-induced cocaine seeking without altering food-reinforced instrumental responding, relative to vehicle pretreatment. These findings suggest that the BLA and OFC co-regulate drug context-induced motivation for cocaine either through sequential information processing via intra- and interhemispheric connections or by providing converging input to a downstream brain region.