Context-induced Reinstatement Of Heroin Seeking Research Articles

Role of Glutamatergic Projections from the Ventral CA1 to Infralimbic Cortex in Context-Induced Reinstatement of Heroin Seeking

The prelimbic cortex (PL) and infralimbic cortex (IL) play a role in context-induced reinstatement of heroin seeking in an animal model of drug relapse. Both the PL and IL receive direct glutamatergic projections from the ventral CA1 (vCA1), which is also involved in context-induced reinstatement of cocaine and heroin seeking. Here we studied the role of vCA1-PL and vCA1-IL projections in context-induced reinstatement of heroin seeking by using electrophysiological, neuropharmacological, chemogenetic, and molecular methods. We showed that context-induced reinstatement of heroin seeking caused selective activation of the vCA1-IL but not vCA1-PL glutamatergic projections, decreased synaptosomal GluA2 expression in the IL, impaired basal synaptic transmission, and facilitation of long-term depression (LTD) in the vCA1-IL pathway. Additionally, chemogenetic inactivation of the vCA1-IL but not vCA1-PL pathway decreased context-induced reinstatement of heroin seeking. Inactivation of the vCA1-IL pathway also reversed synaptosomal GluA2 downregulation and basal transmission reduction, and blocked LTD induction. Taken together, our results demonstrate a critical role of the vCA1-IL glutamatergic projection in context-induced reinstatement of heroin seeking in a rat model of drug relapse.

Glutamatergic Projections from the Entorhinal Cortex to Dorsal Dentate Gyrus Mediate Context-Induced Reinstatement of Heroin Seeking

Reexposure to the context associated with heroin intake provokes relapse to drug taking after abstinence. The dorsal dentate gyrus (dDG) and entorhinal cortex (EC) have been implicated in contextual memory processing, but the underlying circuit mechanisms in context-induced relapse remain poorly understood. In this study, using a self-administration rat model, we found that activation and synaptic transmission of glutamatergic projections from the EC to the upper blade of dentate gyrus (dDGub) were significantly enhanced during context-induced reinstatement of heroin seeking. This effect was associated with increased of phosphorylation of GluN2B-containing NMDA receptors (GluN2B) at Y1472, ratio of GluN2B membrane/total protein levels, and expression of downstream extracellular signal-regulated kinase-1/2 (ERK1/2) in the dDG region. Furthermore, DREADD-mediated specific inactivation of the EC–dDG pathway or disconnection of the pathway with local postsynaptic GluN2B–ERK1/2 signaling both decreased context-induced reinstatement of heroin seeking. These experimental manipulations had no effect on saccharin-reinforced responding and general locomotor activity in rats. Our results indicate that the EC–dDG pathway mediates context-induced reinstatement of heroin seeking, via the activation of postsynaptic GluN2B–ERK1/2 signaling in the dDG.

Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats.

In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement. The ventral subiculum (vSub) sends glutamate projections to NAc shell and vmPFC. Here, we determined whether these projections contribute to context-induced reinstatement. We trained rats to self-administer heroin (0.05-0.1mg/kg/infusion) for 3h per day for 12days; drug infusions were paired with a discrete tone-light cue. Lever pressing in the presence of the discrete cue was subsequently extinguished in a different context. We then tested the rats for reinstatement in the heroin- and extinction-associated contexts under extinction conditions. We combined Fos with the retrograde tracer Fluoro-Gold (FG) to determine projection-specific activation during the context-induced reinstatement tests. We also used anatomical disconnection procedures to determine whether the vSub → NAc shell and vSub → vmPFC projections are functionally involved in this reinstatement. Exposure to the heroin but not the extinction context reinstated lever pressing. Context-induced reinstatement of heroin seeking was associated with increased Fos expression in vSub neurons, including those projecting to NAc shell and vmPFC. Anatomical disconnection of the vSub → NAc shell projection, but not the vSub → vmPFC projection, decreased this reinstatement. Our data indicate that the vSub → NAc shell glutamatergic projection, but not the vSub → vmPFC projection, contributes to context-induced reinstatement of heroin seeking.

Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking

Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking

Early initiation of alcohol and illicit drug use: Associations with psychopathology among inpatient substance users

s / Drug and Alcohol Dependence 146 (2015) e202–e284 e227 for these projections in context-induced reinstatement of heroin seeking. Financial support: NIDA/IRP. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.083 The effect of high stress on T-cell protein expression in chronic drug users: HIV implications Nawal Boukli, Sheila Lopez, Madeline Rodriguez, Eddy Rios Microbiology and Immunology, Universidad Central Del Caribe, Bayamon, United States Aims: Stress anddrugusemaywork in synergy toaffect immune response. We aim to (1) group chronic poly drug users (PDU) according to psychological, physiological and immunological characteristics, and (2) examine stress impact on plasma cytokine profile and protein expression of T-lymphocytes from HIV+ and HIV− PDUs. Methods: In non-PDU HIV−HCV− controls (n=10) and PDU samples (n=47; 20% female, age 18–35 years), stresswasmeasured by the PERI and cortisol/DHEA quantification. Cellular immune response has been evaluated by CD4/CD8 quantification. Protein expression alterations were detected through proteomics. Results: HIV−HCV− (18), HIV+HCV− (7), HIV−HCV+ (13), HIV+HCV+ (9) and non PDU HIV−HCV− control group (10). PERI scale scores were related to low and high cortisol levels. Immunologically, among 18 HIV−HCV− PDU 100% had >410 CD4 cell counts/ l; 5 of 7 HIV+HCV− PDU had high CD4 counts; all 10 non-PDU HIV−HCV− had normal CD4 cell counts. The proteomic data identified proteins showing altered expression mainly in oxidative stress, proteolytic and glycolytic enzymes, inhibitors and structural proteins in the group of PDU+ with high stress as compared to those with low stress values. Conclusions: Our findings allowed the identification of several proteinmarkers candidates for early diagnostic and/or treatment of PDU under stress. Further, the scientific processes implemented to stratify PDU+ and PDU− users according to physiological, immunological and psychologicalmeasurements are important to correlate with the protein profile of the participant groups. This will contribute to the deeper understanding of the effect of stress in the PDU and underlying mechanisms for drug of abuse prevention. Financial support: Supported by NCRR (5G12RR003035), NIMHHD (8G12MD007583), NIDA (2R24DA013335; R25DA030310). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.084 Early initiation of alcohol and illicit drug use: Associations with psychopathology among inpatient substance users Nadia Bounoua, Bina Ali, Aaron Lim, William Lechner, Julia M. Shadur, J.W. Felton, L. MacPherson, C.W. Lejuez University of Maryland, College Park, College Park,

Role of ventral subiculum in context‐induced reinstatement of heroin seeking in rats

In rats, reexposure to heroin-paired contexts after extinction of lever responding in a different context reinstates heroin seeking. Previous reports indicate that ventral hippocampus/Ca1 region plays a critical role in cocaine-, cue- and context-induced reinstatement of cocaine seeking. Here, we examined whether ventral subiculum, the output region of ventral hippocampus, is involved in context-induced reinstatement of heroin seeking. We found that reversible inactivation of ventral subiculum, but not posterior Ca1, with the gamma-aminobutyric acid agonists muscimol + baclofen decreased context-induced reinstatement of heroin seeking. Our findings, together with previous studies on cocaine seeking, indicate a critical role of ventral subiculum in context-induced relapse across drug classes.

Role of Projections from Ventral Medial Prefrontal Cortex to Nucleus Accumbens Shell in Context-Induced Reinstatement of Heroin Seeking

In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.

Craving, context and the cortex

A new study challenges the idea that the ventromedial prefrontal cortex inhibits drug relapse, by selectively inactivating a subpopulation of neurons in this brain area and showing attenuation of context-induced reinstatement of heroin seeking.

Role of dopamine D1-family receptors in dorsolateral striatum in context-induced reinstatement of heroin seeking in rats

In humans, exposure to environmental contexts previously associated with heroin intake can provoke relapse to drug use. In rats, exposure to heroin-associated contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by blockade of D(1)-family receptors in lateral or medial accumbens shell, but not accumbens core. In this study, we further characterized the role of striatal D(1)-family receptors in context-induced reinstatement by assessing the effect of dorsolateral or dorsomedial injections of the D(1)-family receptor antagonist SCH 23390 on this reinstatement. Rats were trained to self-administer heroin (0.05-0.10 mg/kg per infusion) for 12 days; drug infusions were paired with a discrete tone-light cue. Subsequently, heroin-reinforced lever pressing was extinguished in the presence of the discrete cue in a nondrug context. During reinstatement tests under extinction conditions, the D(1)-family receptor antagonist SCH 23390 (0.3-1.0 microg per side) was injected into the dorsolateral or dorsomedial striatum prior to exposure to heroin self-administration context or the nondrug (extinction) context. We then used a disconnection procedure to examine whether D(1)-family receptors in the dorsolateral striatum and lateral accumbens shell jointly or independently support context-induced reinstatement. Dorsolateral but not dorsomedial SCH 23390 injections attenuated context-induced reinstatement of heroin seeking. SCH 23390 injections into the dorsolateral striatum of one hemisphere and lateral accumbens shell of the other hemisphere were ineffective. Results indicate that dorsolateral striatum D(1)-family dopamine receptors are critical for context-induced reinstatement of heroin seeking. Results also suggest that D(1)-receptor-mediated dopamine transmission in the dorsolateral striatum and lateral accumbens shell independently support this reinstatement.

Differential Effects of Blockade of Dopamine D1-Family Receptors in Nucleus Accumbens Core or Shell on Reinstatement of Heroin Seeking Induced by Contextual and Discrete Cues

In humans, exposure to environmental contexts previously associated with heroin intake can provoke drug relapse, but the neuronal mechanisms mediating this relapse are unknown. Using a drug relapse model, we found previously that reexposing rats to heroin-associated contexts, after extinction of drug-reinforced responding in different contexts, reinstates heroin seeking. This effect is attenuated by inhibition of glutamate transmission in the ventral tegmental area and medial accumbens shell, components of the mesolimbic dopamine system. Here, we explored the role of dopamine of the accumbens in context-induced reinstatement by using the D1-family receptor antagonist SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, the heroin-reinforced lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. When tested in the original drug self-administration context, systemic and medial or lateral accumbens shell SCH 23390 injections attenuated context-induced reinstatement of heroin seeking, whereas accumbens core SCH 23390 injections were ineffective. In contrast, core but not lateral or medial shell SCH 23390 injections attenuated discrete-cue-induced reinstatement in a nondrug context after extinction of lever presses without this cue. Results indicate that activation of medial and lateral accumbens shell D1-family dopamine receptors mediate context-induced reinstatement of heroin seeking and provide the first demonstration for a role of lateral shell dopamine in conditioned drug effects. Results also demonstrate novel dissociable roles of accumbens core and shell in context- versus discrete-cue-induced reinstatement of heroin seeking.

Activation of Group II Metabotropic Glutamate Receptors in the Nucleus Accumbens Shell Attenuates Context-Induced Relapse to Heroin Seeking

Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 microg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 microg of LY379268 into the NAc core had no effect, while a higher dose (3.0 microg) decreased this reinstatement. Injections of LY379268 (3.0 microg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.

Aphagia and adipsia produced by unilateral hypothalamic lesions in rats.

ARTICLESAphagia and adipsia produced by unilateral hypothalamic lesions in ratsRM GoldRM GoldPublished Online:01 Nov 1966https://doi.org/10.1152/ajplegacy.1966.211.5.1274MoreSectionsPDF (797 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRelapse to opioid seeking in rat models: behavior, pharmacology and circuits6 October 2018 | Neuropsychopharmacology, Vol. 44, No. 3Context-induced relapse after extinction versus punishment: similarities and differences24 May 2018 | Psychopharmacology, Vol. 236, No. 1Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking24 October 2018 | The Journal of Neuroscience, Vol. 38, No. 50Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats7 September 2015 | Psychopharmacology, Vol. 233, No. 10Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence16 March 2016 | The Journal of Neuroscience, Vol. 36, No. 11Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress15 May 2015 | Neuropsychopharmacology, Vol. 41, No. 1Role of corticostriatal circuits in context-induced reinstatement of drug seekingBrain Research, Vol. 1628Metabolic hormones, dopamine circuits, and feedingFrontiers in Neuroendocrinology, Vol. 31, No. 1Ibotenic acid lesion of the lateral hypothalamus increases preference and aversion thresholds for saccharin and alters the morphine modulation of tastePharmacology Biochemistry and Behavior, Vol. 36, No. 3Effects of lateral hypothalamic lesions on thermoregulation in the ratPhysiology & Behavior, Vol. 38, No. 2Amine accumulation in behavioural pathologyBrain Research Reviews, Vol. 9, No. 2The physiological control of appetite in fishComparative Biochemistry and Physiology Part A: Physiology, Vol. 78, No. 4The behavioural effects of intrahypothalamic multistage versus single injections of 6-hydroxydopamineBrain Research, Vol. 245, No. 2Depletion of dopamine in the striatum as an experimental model of parkinsonism: direct effects and adaptive mechanismsProgress in Neurobiology, Vol. 18, No. 2-3Accelerated recovery from eating behavior deficits after sequential lesions of cortex and hypothalamus: Is dopamine involved?Experimental Neurology, Vol. 70, No. 2Serial lateral hypothalamic destruction with various interlesion intervalsExperimental Neurology, Vol. 67, No. 3Effects of serial lateral hypothalamic destruction on feeding behavior, body weight, and neocortical and hippocampal EEG activityExperimental Neurology, Vol. 66, No. 2A role for the dopaminergic nigrostriatal bundle in the pathogenesis of altered brain glucose consumption after lateral hypothalamic lesions. Evidence using the14C-labeled deoxyglucose techniqueBrain Research, Vol. 158, No. 1Body weight and regulatory deficits following unilateral nigrostriatal lesionsBrain Research, Vol. 132, No. 3Serial lateral hypothalamic destruction: Infancy and adulthoodExperimental Neurology, Vol. 53, No. 3Gustatory neural coding in the ponsBrain Research, Vol. 110, No. 2The Influence of Experience on Recovery Following Brain Damage in Rodents: Hypotheses Based on Development ResearchRecovery of function after serial or one-stage lesions of the lateral hypothalamic area in ratsBehavioral Biology, Vol. 14, No. 3The pontine taste area in the ratBrain Research, Vol. 91, No. 1Gustatory afferents to ventral forebrainBrain Research, Vol. 81, No. 2Effect of coagulation of the dorsal hippocampus and mesencephalic reticular formation of the food responseBulletin of Experimental Biology and Medicine, Vol. 78, No. 4Autonomic and behavioral temperature regulationPfl�gers Archiv European Journal of Physiology, Vol. 352, No. 2Increased food intake elicited by adrenergic stimulation of the diencephalon in rhesus monkeysBrain Research, Vol. 65, No. 3Hyperphagia produced by knife cuts between the medial and lateral hypothalamus in the ratPhysiology & Behavior, Vol. 4, No. 4THE INTERRELATIONSHIP OF FOREBRAIN AND MIDBRAIN STRUCTURES INVOLVED IN FEEDING BEHAVIORActa Neurologica Scandinavica, Vol. 44, No. 5Effects of unilateral hypothalamic lesions on drinking and self-stimulation in the rat4 November 2013 | Psychonomic Science, Vol. 10, No. 9Aphagia and adipsia following unilateral and bilaterally asymmetrical lesions in ratsPhysiology & Behavior, Vol. 2, No. 2 More from this issue > Volume 211Issue 5November 1966Pages 1274-1276 Copyright & PermissionsCopyright © 1966 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1966.211.5.1274PubMed5924054History Published online 1 November 1966 Published in print 1 November 1966 Metrics