Role of Conditioning Factors in the Development of Drug Dependence

Drug addiction is characterized by compulsive drug-seeking and drug-taking behavior and by a high rate of relapse even after long periods of abstinence. Although the mesocorticolimbic dopamine (DA) pathway is thought to play a critical role in drug craving and relapse, recent evidence also implicates glutamate, an amino acid known to activate DA neurons in the ventral tegmental area (VTA) via ionotropic receptors. To assess whether increased glutamate transmission in the VTA is involved in cocaine-primed drug-seeking behavior, we tested rats in a between-session reinstatement model. They were trained to press a lever for cocaine infusions (0.25 mg/ infusion) accompanied by compound stimuli (light and tone) under a modified fixed-ratio 5 reinforcement schedule. Cocaine-primed reinstatement was conducted after lever pressing was extinguished in the absence of the conditioned stimuli. Blockade of ionotropic glutamate receptors in the VTA by local application of kynurenate (0.0, 1.0, 3.2, and 5.6 mg/side) dose-dependently decreased cocaineprimed reinstatement, whereas sucrose-primed reinstatement of sucrose-seeking behavior was unaffected. In addition, the minimum effective dose for decreasing cocaine-primed reinstatement was ineffective in the substantia nigra. Together, these data indicate that glutamatergic activation of the VTA is critical for cocaine-primed reinstatement. Because such activation can increase impulse flow in DA neurons and thus DA release in mesocorticolimbic targets, this glutamate-DA interaction in the VTA may underlie cocaine-primed relapse to cocaine-seeking behavior.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

Sun

Akins

Mattingly

et al. 2005

“…Drug-associated cues elicit craving and relapse in addicts (Childress et al, 1986;Foltin and Haney, 2000), and disruption of drug-cue associations would therefore limit relapse susceptibility. Recent evidence reveals that memory retrieval is susceptible to disruption that is persistent.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement

Otis

Fitzgerald

Mueller

2013

Retrieval of drug-associated memories is critical for maintaining addictive behaviors, as presentation of drug-associated cues can elicit drug seeking and relapse. Recently, we and others have demonstrated that b-adrenergic receptor (b-AR) activation is necessary for retrieval using both rat and human memory models. Importantly, blocking retrieval with b-AR antagonists persistently impairs retrieval and provides protection against subsequent reinstatement. However, the neural locus at which b-ARs are required for maintaining retrieval and subsequent reinstatement is unclear. Here, we investigated the necessity of dorsal hippocampus (dHipp) b-ARs for drugassociated memory retrieval. Using a cocaine conditioned place preference (CPP) model, we demonstrate that local dHipp b-AR blockade before a CPP test prevents CPP expression shortly and long after treatment, indicating that dHipp b-AR blockade induces a memory retrieval disruption. Furthermore, this retrieval disruption provides long-lasting protection against cocaine-induced reinstatement. The effects of b-AR blockade were dependent on memory reactivation and were not attributable to reconsolidation disruption as blockade of b-ARs immediately after a CPP test had little effect on subsequent CPP expression. Thus, cocaine-associated memory retrieval is mediated by b-AR activity within the dHipp, and disruption of this activity could prevent cue-induced drug seeking and relapse long after treatment.

“…Presentation of these cues can elicit craving in humans (Childress et al, 1986;Ehrman et al, 1992;Foltin and Haney, 2000;O'Brien et al, 1977) and stimulate active drug seeking in rodents (Banna et al, 2010;Chauvet et al, 2009;Fuchs et al, 2004;Mueller and Stewart, 2000). The associations between these cues and the drug reinforcer are acquired, consolidated, and readily retrieved in the presence of the cues.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

Otis

Mueller

2011

Drug-seeking behavior is maintained by encounters with drug-associated cues. Preventing retrieval of drug-associated memories that these cues provoke would therefore limit relapse susceptibility; however, little is known regarding the mechanisms of retrieval. Here, we show that b-adrenergic receptor activation is necessary for the retrieval of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. When administered before a CPP trial, propranolol, but not saline, prevented retrieval of a cocaine-associated CPP. In subsequent drug-free trials, rats previously treated with propranolol continued to show a retrieval deficit, as no CPP was evident. This retrieval deficit was long lasting and robust, as the CPP did not re-emerge during a test for spontaneous recovery 14 days later or reinstate following a priming injection of cocaine. Moreover, the peripheral b-adrenergic receptor antagonist sotalol did not affect retrieval. Thus, retrieval of cocaine-associated memories is mediated by norepinephrine acting at central b-adrenergic receptors. Our findings support the use of propranolol, a commonly prescribed b-blocker, as an adjunct to exposure therapy for the treatment of addiction by preventing retrieval of drugassociated memories during and long after treatment, and by providing protection against relapse.