scholarly journals Social Interaction With Relapsed Partner Facilitates Cocaine Relapse in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiqiu Meng ◽  
Wei Yan ◽  
Xiaoxing Liu ◽  
Yimiao Gong ◽  
Shanshan Tian ◽  
...  
Keyword(s):  
Social Interaction ◽  
Social Factors ◽  
Sprague Dawley ◽  
Self Administration ◽  
Facilitation Effect ◽  
Drug Seeking ◽  
Cocaine Seeking ◽  
Social Partners ◽  
Seeking Behavior ◽  
Drug Relapse

Social factors strongly contribute to drug use and relapse, and epidemiological studies have found that members of peer groups influence each other to use drugs. However, previous animal models mostly failed to incorporate social factors and demonstrate the effects of social partners on drug addiction and relapse. In the present study, we investigated the transfer of relapse to cocaine seeking between drug-addicted partners in rats. Male Sprague–Dawley rats were pair-housed and subjected to training and extinction of cocaine self-administration and conditioned place preference (CPP). 24 h after extinction test, the targeted rats interacted with a cocaine-primed (relapsed) partner or stranger, or saline-injected (unrelapsed) partner for 30 min, after which the targeted rats were tested for drug seeking behavior. We found that social interaction with a relapsed partner increased drug seeking behavior in cocaine self-administration and CPP models in rats, while social interaction with an unrelapsed partner or relapsed stranger had no effect on cocaine seeking. Moreover, the effect of social interaction on cocaine seeking could last for at least 1 day. Our findings demonstrate a facilitation effect of relapsed social partners on drug relapse in rats and provide a novel animal model for social transfer of drug relapse.

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 The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Hadas Ahdoot-Levi ◽  
Ofri Croitoru ◽  
Tzofnat Bareli ◽  
Einav Sudai ◽  
Hilla Peér-Nissan ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Brain Cell ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Drug Seeking ◽  
Tissue Organization ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Dhea Treatment

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

scholarly journals Activation of lateral hypothalamic group III mGluRs suppresses drug-seeking following abstinence and cocaine-associated increases in excitatory drive to orexin/hypocretin cells

2018 ◽  
Author(s):  
Jiann W. Yeoh ◽  
Morgan H. James ◽  
Cameron D. Adams ◽  
Jaideep S. Bains ◽  
Takeshi Sakurai ◽  
...  
Keyword(s):  
Glutamate Release ◽  
Cell Activity ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Drug Seeking ◽  
Group Iii ◽  
Lateral Hypothalamic ◽  
Cocaine Seeking ◽  
Presynaptic Plasticity ◽  
Seeking Behavior

AbstractThe perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced, both acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, and tested whether activating these receptors could normalize orexin cell activity following cocaine and reduce cocaine-seeking elicited by drug-associated stimuli during abstinence. First, we verified that group III mGluRs regulate orexin cell activity in vivo by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces Fos expression in orexin cells following 24h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. L-AP4 had no effect on general motor activity of sucrose self-administration. Finally, using whole-cell patch clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show that enhanced presynaptic drive to orexin cells persists for up to 14d into withdrawal and that this plasticity is normalized by L-AP4. L-AP4 had no effect on measures of postsynaptic plasticity in cocaine-exposed animals. Together, these data indicate that agonism of LHA group III mGluRs reduces orexin cell activity in-vivo and is an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure.

scholarly journals Restoration of Kv7 channel mediated inhibition reduces cued-reinstatement of cocaine seeking

2018 ◽  
Author(s):  
Jeffrey Parrilla-Carrero ◽  
William C. Buchta ◽  
Priyodarshan Goswamee ◽  
Oliver Culver ◽  
Greer McKendrick ◽  
...  
Keyword(s):  
Rat Model ◽  
Prelimbic Cortex ◽  
Spike Frequency Adaptation ◽  
Self Administration ◽  
Cellular Mechanisms ◽  
Drug Seeking ◽  
Kv7 Channels ◽  
Channel Function ◽  
Cocaine Seeking ◽  
Seeking Behavior

AbstractCocaine addicts display increased sensitivity to drug-associated cues, due in part to pathological changes in the prelimbic cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a male rat model of relapse to cocaine-seeking, we sampled over 600 neurons to examine spike frequency adaptation (SFA) and after-hyperpolarizations (AHPs), two systems that attenuate low frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a sub-population of PL-PFC neurons, but only with cocaine did the resulting hyper-excitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 minutes prior to reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Lastly, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Taken together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This sub-population of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.Significance StatementLong after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced after-hyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC prior to reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.

scholarly journals Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking

2018 ◽  
Vol 33 (1) ◽  
pp. 132-144
Author(s):  
Tracey A Larson ◽  
Casey E O’Neill ◽  
Michaela P Palumbo ◽  
Ryan K Bachtell
Keyword(s):  
Dose Response ◽  
Extinction Training ◽  
Schedules Of Reinforcement ◽  
Sprague Dawley ◽  
Self Administration ◽  
Caffeine Consumption ◽  
Adult Rats ◽  
Sprague Dawley Rats ◽  
Cocaine Seeking ◽  
Administration Procedure

Background: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. Aim: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Methods: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62–82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Results: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. Conclusions: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.

scholarly journals Maternal Diet Influences the Reinstatement of Cocaine-Seeking Behavior and the Expression of Melanocortin-4 Receptors in Female Offspring of Rats

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1462
Author(s):  
Dawid Gawliński ◽  
Kinga Gawlińska ◽  
Małgorzata Frankowska ◽  
Małgorzata Filip
Keyword(s):  
Maternal Diet ◽  
Dorsal Striatum ◽  
Brain Structures ◽  
Female Offspring ◽  
Self Administration ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Pregnancy And Lactation ◽  
The Impact ◽  
Cocaine Reward

Recent studies have emphasized the role of the maternal diet in the development of mental disorders in offspring. Substance use disorder is a major global health and economic burden. Therefore, the search for predisposing factors for the development of this disease can contribute to reducing the health and social damage associated with addiction. In this study, we focused on the impact of the maternal diet on changes in melanocortin-4 (MC-4) receptors as well as on behavioral changes related to cocaine addiction. Rat dams consumed a high-fat diet (HFD), high-sugar diet (HSD, rich in sucrose), or mixed diet (MD) during pregnancy and lactation. Using an intravenous cocaine self-administration model, the susceptibility of female offspring to cocaine reward and cocaine-seeking propensities was evaluated. In addition, the level of MC-4 receptors in the rat brain structures related to cocaine reward and relapse was assessed. Modified maternal diets did not affect cocaine self-administration in offspring. However, the maternal HSD enhanced cocaine-seeking behavior in female offspring. In addition, we observed that the maternal HSD and MD led to increased expression of MC-4 receptors in the nucleus accumbens, while increased MC-4 receptor levels in the dorsal striatum were observed after exposure to the maternal HSD and HFD. Taken together, it can be concluded that a maternal HSD is an important factor that triggers cocaine-seeking behavior in female offspring and the expression of MC-4 receptors.

scholarly journals Fos Protein Expression and Cocaine-Seeking Behavior in Rats after Exposure to a Cocaine Self-Administration Environment

2000 ◽  
Vol 20 (2) ◽  
pp. 798-805 ◽  
Author(s):  
Janet L. Neisewander ◽  
David A. Baker ◽  
Rita A. Fuchs ◽  
Ly T. L. Tran-Nguyen ◽  
Art Palmer ◽  
...  
Keyword(s):  
Protein Expression ◽  
Self Administration ◽  
Fos Protein ◽  
Cocaine Seeking ◽  
Seeking Behavior

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 Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior

2021 ◽  
Vol 12 ◽  
Author(s):  
Fushen Zhang ◽  
Shihao Huang ◽  
Haiyan Bu ◽  
Yu Zhou ◽  
Lixiang Chen ◽  
...  
Keyword(s):  
Spontaneous Recovery ◽  
Time Window ◽  
Mammalian Target Of Rapamycin ◽  
Self Administration ◽  
Mtor Inhibition ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Previously Treated ◽  
Cocaine Infusion ◽  
Paired Tone

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.

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