An extended history of drug self-administration results in multiple sources of control over drug seeking behavior

2018 ◽  
Vol 87 ◽  
pp. 48-55 ◽  
Author(s):  
Kelly J. Clemens ◽  
Nathan M. Holmes
Keyword(s):  
Multiple Sources ◽  
Self Administration ◽  
Drug Seeking ◽  
Seeking Behavior ◽  
History Of

scholarly journals S-Equol mitigates motivational deficits and dysregulation associated with HIV-1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristen A. McLaurin ◽  
Sarah J. Bertrand ◽  
Jessica M. Illenberger ◽  
Steven B. Harrod ◽  
Charles F. Mactutus ◽  
...  
Keyword(s):  
Therapeutic Effects ◽  
Self Administration ◽  
Drug Seeking ◽  
Motivated Behavior ◽  
Seeking Behavior ◽  
Underlying Basis ◽  
History Of ◽  
Potential Clinical Utility ◽  
And Control ◽  
Hiv 1

AbstractMotivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

scholarly journals HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol

2021 ◽  
Author(s):  
Kristen A. McLaurin ◽  
Sarah J. Bertrand ◽  
Jessica M. Illenberger ◽  
Steven B. Harrod ◽  
Charles F. Mactutus ◽  
...  
Keyword(s):  
Self Administration ◽  
Drug Seeking ◽  
Motivated Behavior ◽  
Dendritic Branching ◽  
Seeking Behavior ◽  
History Of ◽  
Potential Clinical Utility ◽  
And Control ◽  
Goal Directed Behavior ◽  
Hiv 1

ABSTRACTThe persistence of motivational alterations, including apathy, in older HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

The effects of GSK-3β blockade on ketamine self-administration and relapse to drug-seeking behavior in rats

2015 ◽  
Vol 147 ◽  
pp. 257-265 ◽  
Author(s):  
Xianni Huang ◽  
Kunyu Huang ◽  
Wenhui Zheng ◽  
Thomas J.R. Beveridge ◽  
Shujun Yang ◽  
...  
Keyword(s):  
Self Administration ◽  
Drug Seeking ◽  
Seeking Behavior ◽  
Gsk 3Β

scholarly journals Administration of orexin A in the posterior paraventricular nucleus of the thalamus promotes cocaine-seeking behavior and is associated with hypothalamic activation

2017 ◽  
Author(s):  
Alessandra Matzeu ◽  
Rémi Martin-Fardon
Keyword(s):  
Paraventricular Nucleus ◽  
Priming Effect ◽  
Cocaine Dependence ◽  
Activation Pattern ◽  
Neuronal Activation ◽  
Drug Seeking ◽  
Protracted Abstinence ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
History Of

ABSTRACTHypothalamic orexin (Orx) neurons that project to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. When injected in the posterior PVT (pPVT), OrxA reinstated extinguished cocaine-seeking behavior in rats that had long access (LgA) to cocaine for 6 h/day after an intermediate period of abstinence (I-Abst, 2-3 weeks). Considering the long-lasting nature of drug-seeking behavior and that the PVT sends projections to the hypothalamus, the present study examined whether (i) OrxA’s priming effect is preserved after a period of protracted abstinence (P-Abst, 4-5 weeks) in LgA rats and (ii) the neural activation pattern (i.e., Fos+ and Fos+/Orx+ cells) in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) following intra-pPVT OrxA administration that may explain OrxA-induced reinstatement in LgA animals. As reported previously, OrxA administration in the pPVT triggered cocaine-seeking behavior after I-Abst. With P-Abst, the priming effect of OrxA was absent. An intra-pPVT injection of OrxA produced a strong increase in neuronal activation (i.e., Fos expression) in the LH/DMH/PFA at I-Abst but not at P-Abst. The analysis of the activation (Fos+) of Orx neurons (Orx+) revealed an increase in Fos+/Orx+ expression in the LH/DMH/PFA at I-Abst only, thus paralleling the behavioral data. These data indicate that shortly after abstinence, PVT↔LH/DMH/PFA connections are strongly recruited in animals with a history of cocaine dependence. The lack of effect at P-Abst suggests that the function of Orx receptors and connectivity of the PVT↔LH/DMH/PFA circuit undergo significant neuroadaptations following P-Abst.SIGNIFICANCE STATEMENTA better understanding of the pathophysiological changes associated with cocaine addiction is needed to develop efficient pharmacotherapies. The paraventricular nucleus of the thalamus (PVT) and orexin (Orx) transmission within the PVT have been implicated in maladaptive (compulsive) behavior that is characteristic of drug addiction. The present study shows OrxA injections in the posterior PVT reinstates cocaine-seeking behavior in animals with a history of cocaine dependence, and this effect disappears after protracted abstinence, paralleled by the neuronal activation pattern in the hypothalamus. In subjects with a history of cocaine dependence, the function of Orx receptors and connectivity of the PVT↔ LH/DMH/PFA circuit undergo significant neuroadaptations.

Accumbal Neural Responses During the Initiation and Maintenance of Intravenous Cocaine Self-Administration

2004 ◽  
Vol 91 (1) ◽  
pp. 314-323 ◽  
Author(s):  
Laura L. Peoples ◽  
Kevin G. Lynch ◽  
Jamie Lesnock ◽  
Nidhi Gangadhar
Keyword(s):  
Drug Effects ◽  
Extracellular Recording ◽  
Neural Responses ◽  
Self Administration ◽  
Drug Seeking ◽  
Recording Session ◽  
Seeking Behavior ◽  
Excitatory Responses ◽  
Drug Free ◽  
Intravenous Cocaine

During a chronic extracellular recording session, animals with a history of cocaine self-administration were allowed to initiate drug seeking under drug-free conditions. Later, in the same recording session, animals engaged in intravenous cocaine self-administration. During the drug-free period, 31% of 70 accumbal neurons showed a significant increase in average firing rate in association with either or both the exposure to cues that signaled the onset of cocaine availability and the subsequent onset of drug-seeking behavior. The neurons that showed an average excitatory response during the drug-free period were the only group of neurons that showed an average excitatory phasic response to cocaine-reinforced lever presses during the drug self-administration session. A majority of the neurons that were activated during the drug-free period, like the majority of other neurons, showed decreases in average firing in response to self-administered cocaine. However, the neurons that were activated during the drug-free period maintained a higher rate of firing throughout the self-administration session than did other accumbal neurons. The data of the present study are consistent with the conclusion that accumbal neurons contribute to, or otherwise process, initiation of drug seeking under drug-free conditions and that they do so via primarily excitatory responses. Furthermore, there is continuity between the drug-free and -exposed conditions in neural responses associated with drug seeking. Finally, the data have potential implications for understanding mechanisms that transduce accumbal-mediated drug effects that contribute to drug addiction.

scholarly journals Context-induced relapse to drug seeking: a review

2008 ◽  
Vol 363 (1507) ◽  
pp. 3233-3243 ◽  
Author(s):  
Hans S Crombag ◽  
Jennifer M Bossert ◽  
Eisuke Koya ◽  
Yavin Shaham
Keyword(s):  
Basolateral Amygdala ◽  
Dorsal Hippocampus ◽  
Dorsal Striatum ◽  
Self Administration ◽  
Occasion Setting ◽  
Drug Seeking ◽  
Psychological Mechanisms ◽  
History Of ◽  
Study Context

In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced ‘renewal’ of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin–cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.

scholarly journals Drug-associated cues and drug dosage contribute to increased opioid seeking after abstinence

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mary Tresa Zanda ◽  
Gabriele Floris ◽  
Stephanie E. Sillivan
Keyword(s):  
Drug Dosage ◽  
Opioid Use Disorder ◽  
Drug Intake ◽  
Opioid Use ◽  
Self Administration ◽  
Drug Seeking ◽  
Drug Cues ◽  
Rehabilitation Programs ◽  
Key Factor ◽  
Seeking Behavior

AbstractPatients with opioid use disorder experience high rates of relapse during recovery, despite successful completion of rehabilitation programs. A key factor contributing to this problem is the long-lasting nature of drug-seeking behavior associated with opioid use. We modeled this behavior in a rat drug self-administration paradigm in which drug-seeking is higher after extended abstinence than during the acute abstinence phase. The goal of this study was to determine the contribution of discrete or discriminative drug cues and drug dosage to time-dependent increases in drug-seeking. We examined heroin-seeking after 2 or 21 days of abstinence from two different self-administration cue-context environments using high or low doses of heroin and matched animals for their drug intake history. When lower dosages of heroin are used in discriminative or discrete cue protocols, drug intake history contributed to drug-seeking after abstinence, regardless of abstinence length. Incubation of opioid craving at higher dosages paired with discrete drug cues was not dependent on drug intake. Thus, interactions between drug cues and drug dosage uniquely determined conditions permissible for incubation of heroin craving. Understanding factors that contribute to long-lasting opioid-seeking can provide essential insight into environmental stimuli and drug-taking patterns that promote relapse after periods of successful abstinence.

scholarly journals Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

2019 ◽  
Author(s):  
William C. Buchta ◽  
Aubin Moutal ◽  
Bethany Hines ◽  
Constanza Garcia-Keller ◽  
Alexander C.W. Smith ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Treatment Options ◽  
Health Concern ◽  
Self Administration ◽  
Drug Seeking ◽  
Binding Partner ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Medial Pfc

AbstractCocaine addiction is a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug-seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to Yoked saline controls. By contrast, cued-reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.

scholarly journals Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking

2021 ◽  
Vol 12 ◽  
Author(s):  
Liangpei Chen ◽  
Shihao Huang ◽  
Chang Yang ◽  
Feilong Wu ◽  
Qiuyao Zheng ◽  
...  
Keyword(s):  
Relapse Prevention ◽  
Adrenergic Receptors ◽  
Time Windows ◽  
Stimulus Exposure ◽  
Self Administration ◽  
Pharmacological Interventions ◽  
Drug Seeking ◽  
History Of ◽  
Propranolol Treatment ◽  
Β Adrenergic Receptors

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention.

scholarly journals The Molecular-Container Calabadion-2 Prevents Methamphetamine-Induced Reinstatement in Rats: A Potential Approach to Relapse Prevention?

2020 ◽  
Vol 23 (6) ◽  
pp. 401-405 ◽  
Author(s):  
Michael Z Leonard ◽  
Paul Rostin ◽  
Kevin P Hill ◽  
Stephanie D Grabitz ◽  
Matthias Eikermann ◽  
...  
Keyword(s):  
Relapse Prevention ◽  
Preclinical Model ◽  
Priming Dose ◽  
Self Administration ◽  
Drug Seeking ◽  
Molecular Container ◽  
Seeking Behavior ◽  
Multi Phase ◽  
Pharmacokinetic Approach

Abstract Background Reexposure to methamphetamine with a single “priming dose” can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril “molecular container” calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats. Methods Male Long-Evans rats were trained to self-administer i.v. methamphetamine (0.06 mg/kg/infusion). Following 10 days of stable self-administration, rats underwent extinction training and were subsequently tested on a multi-phase reinstatement procedure. Drug-primed reinstatement sessions (0.3 mg/kg methamphetamine, i.v.) were preceded by either saline or calabadion-2 (130 mg/kg). Additional reinstatement tests were conducted after administration of yohimbine (1.0 mg/kg, i.v.) to define the pharmacological specificity of calabadion-2. Results Pretreatment with calabadion-2 significantly attenuated methamphetamine-induced reinstatement of responding. Cal2 did not affect drug-seeking behavior stimulated by the pharmacological stressor yohimbine, indicating a mechanism of action specific to methamphetamine. Conclusions These results demonstrate the effectiveness of calabadion-2 in a preclinical model relapse-like behavior. With further structural optimization, molecular containers may provide a novel and efficacious pharmacokinetic approach to relapse prevention for methamphetamine-dependent individuals.

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