scholarly journals Pharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats

2021 ◽  
Author(s):  
Yang Li ◽  
Nan Li ◽  
Liang Qu ◽  
Xin Wang ◽  
Ping Wang ◽  
...  
Keyword(s):  
Drug Addiction ◽  
Sch 23390 ◽  
Memory Reconsolidation ◽  
High Dose ◽  
Negative Consequences ◽  
Self Administration ◽  
Pharmacological Interventions ◽  
Drug Seeking ◽  
Motivation System ◽  
Seeking Behavior

Abstract Drug addiction is a disorder related to dysfunction in the neural reward memory circuits, and it is characterized by compulsive drug use despite terrible negative consequences. Memory reconsolidation, during which aroused memory is easy to strengthening, weakening or updating, plays an extremely important role in drug addiction. Effectively interfering with the drug memory reconsolidation process would be key in treating drug addiction, but this intervention currently remains impossible. The dopamine motivation system has been widely recognized as an important system for reward, but whether the dopamine motivation system participates in drug memory reconsolidation is unclear. We aimed to explore the role of the dopamine motivation system during the cue-induced cocaine memory reconsolidation process by examining the effect of different pharmacological interventions on the dopamine motivation system during cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. Using a combined behavioral and biological method, our results showed that high concentrations of SCH 23390 and raclopride, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior in rats. However, low concentrations of SCH 23390 and raclopride could not block this behavior. In summary, only a high dose of dopamine D1 and D2 receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. These findings indicated that pharmacological interventions in the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation. Thus, pharmacological interventions on the dopamine motivation system might have therapeutic potential for drug addiction.

scholarly journals Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

2021 ◽  
Author(s):  
◽  
Caleb Carati
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
High Dose ◽  
Gbr 12909 ◽  
Self Administration ◽  
Drug Seeking ◽  
Skf 81297 ◽  
Pre Treatment

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

scholarly journals Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

2021 ◽  
Author(s):  
◽  
Caleb Carati
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
High Dose ◽  
Gbr 12909 ◽  
Self Administration ◽  
Drug Seeking ◽  
Skf 81297 ◽  
Pre Treatment

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

scholarly journals Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Zhao ◽  
Xinyu Du ◽  
Mingzhu Chen ◽  
Shimin Zhu
Keyword(s):  
Growth Hormone ◽  
Drug Addiction ◽  
Addiction Treatment ◽  
Memory Reconsolidation ◽  
Potential Candidate ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Drug Seeking ◽  
Food And Water Intake ◽  
Drug Addiction Treatment

Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.

2. A role for DA Mechanisms in the ovBNST in Compulsive Responding in Rats

2018 ◽  
Author(s):  
Valerie Bian
Keyword(s):  
Drug Addiction ◽  
Sch 23390 ◽  
Food Group ◽  
Sweet Taste ◽  
Social Consequences ◽  
Control Group ◽  
Negative Consequences ◽  
Bed Nucleus ◽  
Group 12 ◽  
Work Done

Out of the primary characteristics of drug addiction, compulsive drug seeking and intake is perhaps the most insidious, as it results in voluntary substance use despite negative physical and social consequences. For substances that are not considered classically addictive, such as sucrose, animal models of drug addiction may be utilized to explore reward-related synaptic changes underlying compulsive behavior similarly observed in binge eating disorders. Binge eaters, like those who compulsively seek out and consume drugs, continue to consume food despite the negative consequences. Based on previous work done by Maracle (2012), we examined the effects of modulating signalling in the oval bed nucleus of the stria terminalis (ovBNST) with a competitive D1 antagonist and its effects on compulsive intake. Prior to the intermitted access phase, subjects (N=66) underwent intracranial surgeries targeting the ovBNST. We utilized the same intermitted access cycle developed by (Avena, 2010). The subjects were randomly assigned to one of the four groups, 12-hr sucrose (primary experimental group),12-hr saccharine (sweet taste control group), 12-hr food only group, and a 24-hr sucrose/food group. After the 28-day cycle, subjects were then randomly assigned to received infusions of either saline or a selective D1 antagonist (SCH 23390) 10mins prior to testing. Compulsive responding for sucrose was then assessed using a conditioned suppression paradigm. It was hypothesized that infusing a DA antagonist into the ovBNST will decrease compulsive responding in subjects who demonstrate bingeing behaviour during the intermitted access phase, but will not affect animals that do not demonstrate bingeing behavior.

Impulsivity and Drug-Seeking Behavior in Substance Misuse

2020 ◽  
pp. 65-86
Author(s):  
Noelle C. Anastasio ◽  
Dennis J. Sholler ◽  
Brionna D. Davis-Reyes ◽  
Amanda E. Price ◽  
Michelle A. Land ◽  
...  
Keyword(s):  
Substance Use ◽  
Cue Reactivity ◽  
Complex Nature ◽  
Psychoactive Drugs ◽  
Negative Consequences ◽  
Drug Seeking ◽  
Drug Cues ◽  
Seeking Behavior ◽  
The Impact ◽  
Substances Of Abuse

Vulnerability to initiate use of psychoactive drugs as well as relapse to drug-seeking in patients with established substance use disorders are precipitated by behavioral disinhibition or impulsivity (a predisposition toward rapid unplanned reactions to stimuli without regard to negative consequences) and attentional bias toward drug cues (cue reactivity). These behavioral phenotypes are not independent mechanistically nor neurobiologically, and preclinical analyses have demonstrated the complex nature of the interactions between these interlocked phenotypic behaviors, including aspects of their shared neurobiology and circuitry. This chapter focuses on impulsivity and drug-seeking behaviors from a preclinical perspective and summarizes studies exploring the impact of substances of abuse in the context of the neurobiology of impulsivity and drug-seeking behaviors in rodents.

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

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 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.

Sign in / Sign up

Export Citation Format

Share Document