Beyond reconsolidation: The need for a broad theoretical approach in clinical translations of research on retrieval-induced plasticity.

Experimental findings showing that retrieved memories are labile and vulnerable to disruption have led to important theoretical ideas at a basic science level that have been applied to the clinic at a translational level. At a theoretical level, these findings suggest that retrieved memories can be modulated by behavioral or pharmacological treatments as they are reconsolidated and returned to storage. At a clinical level, these findings suggest that treatments that target reconsolidation may help dampen or even erase especially problematic memories, such as those associated with trauma. However, there are many caveats to these effects and issues that need to be considered when thinking broadly about retrieval-induced plasticity and extensions into the clinic. First, performance during a memory test often does not reflect the entirety of the animal's knowledge about a situation; asking questions in different ways may reveal the presence of a memory that was thought to be eliminated. Second, although reconsolidation and extinction are often treated as competing processes, there is abundant evidence that extinction can progress through associative and nonassociative changes in the original memory that are often described in terms of reconsolidation effects. Third, targeting a reconsolidation process as a therapeutic may not be helpful in disorders like posttraumatic stress disorder, in which traumatic experiences induce a cascade of symptoms that are self-perpetuating and may ultimately maintain themselves long after trauma. Underlying all of these challenges is the need for a rich theoretical framework focused on retrieval-induced plasticity that is informed by developments in associative learning theory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Sex-dependent effects of acute stress in adolescence or adulthood on appetitive motivation.

RATIONALE: Intensely stressful experiences can lead to long-lasting changes in appetitive and aversive behaviors. In humans, post-traumatic stress disorder increases the risk of comorbid appetitive disorders including addiction and obesity. We have previously shown that an acute stressful experience in adult male rats suppresses motivation for natural reward. OBJECTIVES: We examine the impact of sex and age on the effects of intense stress on action-based (instrumental) and stimulus-based (Pavlovian) motivation for natural reward (food). METHODS: Rats received 15 unsignaled footshocks (stress) in a single session followed by appetitive training and testing in a distinct context. In Experiment 1, stress occurred in either adolescence (PN28) or adulthood (PN70) with appetitive training and testing beginning on PN71 for all rats. In Experiment 2, stress and appetitive training/testing occurred in adolescence. RESULTS: Acute stress in adolescent females suppressed instrumental motivation assessed with progressive ratio testing when testing occurred in late adolescence or in adulthood, whereas in males stress in adolescence did not suppress instrumental motivation. Acute stress in adulthood did not alter instrumental motivation. In contrast, Pavlovian motivation assessed with single-outcome Pavlovian-to-instrumental transfer (SO-PIT) was consistently enhanced in females following adolescent or adult stress. In males, however, stress in adolescence had no effect, whereas stress in adulthood attenuated SO-PIT. CONCLUSIONS: Acute stress in adolescence or adulthood altered instrumental motivation and stimulus-triggered Pavlovian motivation in a sex and developmentally specific manner. These findings suggest that the persistent effects of acute stress on Pavlovian and instrumental motivational processes differ in females and males, and that males may be less vulnerable to the deleterious effects of intense stress during adolescence on appetitive motivation.

Habituation: It's not what you think it is.

In this review, we take a critical look at the methods used to document habituation and the theoretical assumptions that have been made about it. We point out problems associated with measuring habituation merely as a change over the course of repeated presentations of a stimulus. We argue that a common test procedure is essential to assess the relative magnitudes of habituation learning especially when different training procedures are examined. We further suggest that this would be required in order to draw meaningful conclusions about the conditions for optimizing habituation. We also challenge the view that habituation is nonassociative and consider the implications of various associative learning perspectives not only for context-specific habituation but for encoding a representation of the stimulus. We conclude with our recommendations for future research on habituation and we highlight the need to integrate behavioral and neurobiological studies.

Persistent effects of acute trauma on Pavlovian-to-instrumental transfer.

In humans, an acutely traumatic experience can lead to post-traumatic stress disorder (PTSD), which is often characterized by changes in anxiety and motivation months after trauma. There are few demonstrations of the persistent motivational effects of an acute stressor in rodent approaches to PTSD. In two experiments, we evaluated the persistent effects of a battery of footshocks in one context on appetitive Pavlovian conditioning, instrumental learning, and Pavlovian-to-instrumental transfer (PIT) in a different context. In Experiment 1, a battery of footshocks before appetitive training caused deficits in single-outcome PIT (SO-PIT) in male Long Evans rats. The same battery of footshocks after appetitive training, but before testing had little effect on SO-PIT overall, but there were some deficits in within-stimulus expression of SO-PIT. In Experiment 2, the battery of footshocks had no effect on sensory-specific PIT in male or female rats, but two sex differences emerged: males showed more generalized fear from the aversive to the appetitive context compared to females, and females showed less evidence for sensory-specific PIT compared to males. Males showed robust sensory-specific PIT, with clear extinction and spontaneous recovery of the sensory-specific PIT effect across test sessions. These findings show that (a) an acute trauma can have persistent effects on general motivational processes and (b) in sensory-specific PIT, females may show transfer through generalized motivational processes, whereas males may rely on specific features of the cues and outcomes to augment instrumental responding selectively. We discuss implications for current approaches to stress and motivation in preclinical approaches to PTSD.

Developments in associative theory: A tribute to the contributions of Robert A. Rescorla.

The field of associative learning theory was forever changed by the contributions of Robert A. Rescorla. He created an organizational structure that gave us a framework for thinking about the key questions surrounding learning theory: what are the conditions that produce learning?, what is the content of that learning?, and how is that learning expressed in performance? He gave us beautifully sophisticated experimental designs that tackled deep theoretical problems in experimentally clever and elegant ways. And he left us with a collection of work that fundamentally altered the way we as a field think about basic learning processes. Few scientists have impacted their field in the way that Rescorla impacted animal learning theory. In this paper, we introduce this special issue (Developments in Associative Theory: A Tribute to Robert A. Rescorla) by considering some of the many ways in which Rescorla's empirical and theoretical contributions impacted learning theory over his almost 50-year career. We conclude by identifying multiple fundamental issues we think he would have found especially fruitful to pursue as we continue to move forward. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effects of a cue associated with cocaine or food reinforcers on extinction and postextinction return of behavior.

Studies of instrumental responding often include the delivery of a cue that is coincident with the delivery of the reinforcer. One purpose of this is for the cue to be removed during extinction and then presented later to assess whether responding returns (cue-induced reinstatement). In two experiments, we examined the effects of having a cue associated with reinforcement present or absent during extinction. In Experiment 1, the cue was associated with fixed ratio responding for intravenous cocaine or food pellets in one context (Context A), followed by extinction in another context (Context B), where responding produced the cue in one group but did not produce the cue in the other group. Afterward, contextual renewal was assessed with and without the cue in Context A. During extinction, a cue previously associated with cocaine reinforcement caused an increase in responding initially (an extinction burst) and throughout 16 2-hr extinction sessions, as well as weakened contextual renewal when animals were tested with the cue in Context A. In contrast, there were few detectable effects of the cue on extinction and contextual renewal when food pellets were the reinforcer. In Experiment 2, effects of a cue during extinction of progressive ratio responding were revealed with food pellets when animals showed weakened responding on the initial trials of postextinction reacquisition sessions. These experiments demonstrate that the presence of a cue associated with reinforcement during extinction may prolong responding in the short term while creating a more persistent form of extinction that resists relapse. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C-C motif) ligand 2 levels in rats.

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking-potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.

Involvement of the bed nucleus of the stria terminalis in initial conditioning and rapid reconditioning following extinction of contextual fear.

Although a great deal is known about neurobiological mechanisms of initial conditioning and extinction, relatively little is known about mechanisms involved in the return of behavior following extinction. In this article, we examine the effects of temporarily inactivating the bed nucleus of the stria terminalis (BNST) on initial conditioning and postextinction reconditioning. We investigate effects in unsignaled contextual fear conditioning, in which animals initially receive strong contextual conditioning, followed by three sessions of nonreinforced context exposure (extinction), and then receive a single context-shock reconditioning trial. In 2 experiments with male Long Evans rats, we evaluated the effects of delivery of a muscimol/baclofen cocktail to the BNST prior to initial conditioning or reconditioning. In Experiment 1, we found that a single context-shock pairing results in more freezing following extinction than when it is the initial conditioning trial. This rapid reconditioning effect was impaired by BNST inactivation. In Experiment 2, we found that BNST inactivation also causes a deficit in freezing after strong initial conditioning. These findings suggest that the BNST is involved in both initial conditioning and postextinction reconditioning. We discuss implications of these findings for current thinking about BNST function in learning and memory processes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Behavioral and immunohistochemical characterization of rapid reconditioning following extinction of contextual fear.

A fundamental property of extinction is that the behavior that is suppressed during extinction can be unmasked through a number of postextinction procedures. Of the commonly studied unmasking procedures (spontaneous recovery, reinstatement, contextual renewal, and rapid reacquisition), rapid reacquisition is the only approach that allows a direct comparison between the impact of a conditioning trial before or after extinction. Thus, it provides an opportunity to evaluate the ways in which extinction changes a subsequent learning experience. In five experiments, we investigate the behavioral and neurobiological mechanisms of postextinction reconditioning. We show that rapid reconditioning of unsignaled contextual fear after extinction in male Long-Evans rats is associative and not affected by the number or duration of extinction sessions that we examined. We then evaluate c-Fos expression and histone acetylation (H4K8) in the hippocampus, amygdala, prefrontal cortex, and bed nucleus of the stria terminalis. We find that in general, initial conditioning has a stronger impact on c-Fos expression and acetylation than does reconditioning after extinction. We discuss implications of these results for theories of extinction and the neurobiology of conditioning and extinction.

Context-Dependent and Context-Independent Effects of D1 Receptor Antagonism in the Basolateral and Central Amygdala during Cocaine Self-Administration.

One way that drugs of abuse perturb the dopamine system is by triggering large amounts of extracellular dopamine to efflux into limbic regions. The basolateral (BLA) and central (CeA) nuclei of the amygdala have been shown to play distinct roles in value representation of primary and conditioned reward. However, the precise role of dopaminergic receptors in the BLA and the CeA during reward-related behaviors remains to be determined. Here we investigate the effects of dopamine D1 receptor blockade in the BLA and the CeA during asymptotic performance of cocaine self-administration and in a novel application of contextual renewal under continued access conditions. After more than three weeks of chained seek-take self-administration of cocaine, male Long Evans rats were given a bilateral intra-BLA or intra-CeA infusion of the D1 antagonist SCH-23390 (2 µg/0.3 µl) for multiple days. Intra-BLA D1 receptor blockade before, but not after the self-administration session, gradually suppressed drug seeking and taking responses and persisted with a change in context with continued D1 blockade. In contrast, intra-CeA D1 receptor blockade caused a rapid reduction in self-administration that showed renewal with a change in context with continued D1 blockade. Further, conditioned place aversion developed with intra-BLA but not intra-CeA infusions. Collectively, these results demonstrate that dopamine D1 receptors in the BLA and CeA both contribute to drug seeking and taking, but may do so through distinct mechanisms.

Rapid reacquisition of contextual fear following extinction in mice: effects of amount of extinction, acute ethanol withdrawal, and ethanol intoxication.

RATIONALE: Many studies have found that ethanol intoxication and withdrawal impair initial acquisition or extinction of learned behaviors. Rapid reconditioning following extinction is a form of post-extinction re-emergence of conditioned behavior that has not been studied for its interaction with ethanol intoxication or withdrawal. OBJECTIVES: The goals of this paper were to define the parameters that allow rapid post-extinction reacquisition of fear in mice and investigate the effect of acute ethanol withdrawal and intoxication on acquisition, extinction, and post-extinction reconditioning. METHODS: We examined acquisition, extinction, and post-extinction reconditioning of contextual fear in male C57BL/6 mice. Acute ethanol withdrawal occurred 6 h following a 4 g/kg injection of 20% ethanol and acute ethanol intoxication occurred 5 min following a 1.5 g/kg injection of 20% ethanol. RESULTS: A weak context-shock pairing caused rapid reacquisition of conditioned freezing following moderate, but not extensive extinction. Acute ethanol intoxication impaired initial conditioning and acute ethanol withdrawal impaired rapid reacquisition after extinction, but not reconditioning or extinction itself. CONCLUSIONS: These findings show that rapid reconditioning occurs following moderate but not extensive extinction in C57BL/6J mice. Additionally, acute ethanol withdrawal and intoxication may differentially affect different phases of conditioning. Results are discussed in terms of current ideas about post-extinction behavior and ethanol's effects on memory.

Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats.

RATIONALE: A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior. OBJECTIVES: We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug seeking after intravenous cocaine self-administration. METHODS: Male Long-Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement. RESULTS: RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions. CONCLUSIONS: These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug seeking provides further potential for treatment by epigenetic modulation.

CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity.

Epigenetic mechanisms result in persistent changes at the cellular level that can lead to long-lasting behavioral adaptations. Nucleosome remodeling is a major epigenetic mechanism that has not been well explored with regards to drug-seeking behaviors. Nucleosome remodeling is performed by multi-subunit complexes that interact with DNA or chromatin structure and possess an ATP-dependent enzyme to disrupt nucleosome-DNA contacts and ultimately regulate gene expression. Calcium responsive transactivator (CREST) is a transcriptional activator that interacts with enzymes involved in both histone acetylation and nucleosome remodeling. Here, we examined the effects of knocking down CREST in the nucleus accumbens (NAc) core on drug-seeking behavior and synaptic plasticity in male mice as well as drug-seeking in male rats. Knocking down CREST in the NAc core results in impaired cocaine-induced conditioned place preference (CPP) as well as theta-induced long-term potentiation in the NAc core. Further, similar to the CPP findings, using a self-administration procedure, we found that CREST knockdown in the NAc core of male rats had no effect on instrumental responding for cocaine itself on a first-order schedule, but did significantly attenuate responding on a second-order chain schedule, in which responding has a weaker association with cocaine. Together, these results suggest that CREST in the NAc core is required for cocaine-induced CPP, synaptic plasticity, as well as cocaine-seeking behavior.SIGNIFICANCE STATEMENT This study demonstrates a key role for the role of Calcium responsive transactivator (CREST), a transcriptional activator, in the nucleus accumbens (NAc) core with regard to cocaine-induced conditioned place preference (CPP), self-administration (SA), and synaptic plasticity. CREST is a unique transcriptional regulator that can recruit enzymes from two different major epigenetic mechanisms: histone acetylation and nucleosome remodeling. In this study we also found that the level of potentiation in the NAc core correlated with whether or not animals formed a CPP. Together the results indicate that CREST is a key downstream regulator of cocaine action in the NAc.

Involvement of the dorsal hippocampus in expression and extinction of cocaine-induced conditioned place preference.

A key aspect of substance abuse is that drug taking often occurs in a specific context. As a consequence, exposure to drug-associated contexts can trigger cravings and relapse, even after long periods of abstinence. Although many studies have demonstrated that the hippocampus is critical for developing and retrieving contextual and spatial memories, comparatively little is known about the role of the hippocampus in acquiring and inhibiting memories involving contexts and drugs of abuse. We examined the effects of hippocampal inactivation on expression of cocaine-induced conditioned place preference (CPP) after initial acquisition or extinction of CPP in C57BL/6 mice. During acquisition of CPP, distinct tactile cues were paired with cocaine (20 mg kg-1 , intraperitoneal, CS+) and different tactile cues were paired with saline (CS-) on alternate days. Groups differed in whether the CS+ and CS- cues were presented in the same large space (one-compartment procedure) or distinct small spaces (two-compartment procedure), as previous findings demonstrate that a two-compartment configuration facilitates acquisition and attenuates extinction of a cocaine-induced CPP. Microinjection of the GABAA agonist, muscimol, into the dorsal hippocampus impaired (1) retrieval of a place preference after acquisition, (2) extinction of a place preference, and (3) retrieval of extinction. These effects differed depending on the spatial configuration during acquisition or extinction, suggesting that the dorsal hippocampus may differentially modulate drug seeking during retrieval and extinction of CPP.

Persistent effects of acute stress on fear and drug-seeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction.

Even following long periods of abstinence, individuals with anxiety disorders have high rates of relapse to drugs of abuse. Although many current models of relapse demonstrate effects of acute stress on drug-seeking, most of these studies examine stressful experiences that occur in close temporal and physical proximity to the reinstatement test. Here, we assess the effects of a stressful experience in one context on fear and drug-seeking in a different context. We adapt the stress-enhanced fear learning procedure to examine impacts on drug-seeking long after the stressful experience occurred. We find massive footshock in a distinct environment produced an acute increase in corticosterone, long-term hyper-responsivity to a single shock in different contexts with extensive histories of drug-seeking behaviors, enhancements in cocaine-induced conditioned place preference in mice, and persistent enhancements in cue-induced reinstatement of methamphetamine-seeking behavior in rats. Together, these experiments demonstrate that an acute trauma causes persistent changes in responsivity to mild stressors and drug-seeking behavior in other contexts, which mirrors aspects of the comorbidity between post-traumatic stress disorder and substance use disorders. These behavioral approaches provide novel procedures for investigating basic mechanisms underlying this comorbidity and they provide powerful tools for testing preclinical pharmacological and behavioral interventions.

Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom.

Epigenetic mechanisms have the potential to give rise to lasting changes in cell function that ultimately can affect behavior persistently. This concept is especially interesting with respect to fear reconsolidation and fear memory extinction. These two behavioral approaches are used in the laboratory to investigate how fear memory can be attenuated, which becomes important when searching for therapeutic intervention to treat anxiety disorders and post-traumatic stress disorder. Here we review the role of several key epigenetic mechanisms in reconsolidation and extinction of learned fear and their potential to persistently alter behavioral responses to conditioned cues. We also briefly discuss how epigenetic mechanisms may establish persistent behaviors that challenge our definitions of extinction and reconsolidation.

Effects of D1 receptor knockout on fear and reward learning.

Dopamine signaling is involved in a variety of neurobiological processes that contribute to learning and memory. D1-like dopamine receptors (including D1 and D5 receptors) are thought to be involved in memory and reward processes, but pharmacological approaches have been limited in their ability to distinguish between D1 and D5 receptors. Here, we examine the effects of a specific knockout of D1 receptors in associative learning tasks involving aversive (shock) or appetitive (cocaine) unconditioned stimuli. We find that D1 knockout mice show similar levels of cued and contextual fear conditioning to WT controls following conditioning protocols involving one, two, or four shocks. D1 knockout mice show increased generalization of fear conditioning and extinction across contexts, revealed as increased freezing to a novel context following conditioning and decreased freezing to an extinguished cue during a contextual renewal test. Further, D1 knockout mice show mild enhancements in extinction following an injection of SKF81297, a D1/D5 receptor agonist, suggesting a role for D5 receptors in extinction enhancements induced by nonspecific pharmacological agonists. Finally, although D1 knockout mice show decreased locomotion induced by cocaine, they are able to form a cocaine-induced conditioned place preference. We discuss these findings in terms of the role of dopamine D1 receptors in general learning and memory processes.

Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking.

The comorbidity of substance- and alcohol-use disorders (AUD) with other psychiatric conditions, especially those related to stress such as post-traumatic stress disorder (PTSD), is well-established. Binge-like intoxication is thought to be a crucial stage in the development of the chronic relapsing nature of the addictions, and self-medication through binge-like drinking is commonly seen in PTSD patients. We have selectively bred two separate High Drinking in the Dark (HDID-1 and HDID-2) mouse lines to reach high blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol starting shortly after the onset of circadian dark. As an initial step toward the eventual goal of employing binge-prone HDID mice to study PTSD-like behavior including alcohol binge drinking, we sought first to determine their ability to acquire conditioned fear. We asked whether these mice acquired, generalized, or extinguished conditioned freezing to a greater or lesser extent than unselected control HS/Npt mice. In two experiments, we trained groups of 16 adult male mice in a standard conditioned fear protocol. Mice were tested for context-elicited freezing, and then, in a novel context, for cue-induced freezing. After extinction tests, renewal of conditioned fear was tested in the original context. Mice of all three genotypes showed typical fear responding. Context paired with shock elicited freezing behavior in a control experiment, but cue unpaired with shock did not. These studies indicate that fear learning per se does not appear to be influenced by genes causing predisposition to binge drinking, suggesting distinct neural mechanisms. However, HDID mice are shown to be a suitable model for studying the role of conditioned fear specifically in binge-like drinking.

G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward.

BACKGROUND: G protein-gated inwardly rectifying potassium (GIRK) channels contribute to the effects of a number of drugs of abuse, including ethanol. However, the roles of individual subunits in the rewarding effects of ethanol are poorly understood. METHODS: We compare conditioned place preference (CPP) in GIRK3 subunit knock-out (GIRK3(-/-)), heterozygote (GIRK3(+/-)), and wild-type (WT) mice. In addition, the development of locomotor tolerance/sensitization and the effects of EtOH intoxication on associative learning (fear conditioning) are also assessed. RESULTS: Our data show significant EtOH CPP in GIRK3(-/-) and GIRK3(+/-) mice, but not in the WT littermates. In addition, we demonstrate that these effects are not due to differences in EtOH metabolism, the development of EtOH tolerance/sensitivity, or associative learning abilities. While there were no consistent genotype differences in the fear conditioning assay, our data do show a selective sensitization of the impairing effects of EtOH intoxication on contextual learning, but no effect on cued learning. CONCLUSIONS: These findings suggest that GIRK3 plays a role in EtOH reward. Furthermore, the selectivity of this effect suggests that GIRK channels could be an effective therapeutic target for the prevention and/or treatment of alcoholism.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.