Behavioral and Neural Mechanisms of Latent Extinction: A Historical Review.

The present paper provides a comprehensive review of latent extinction. In maze learning situations, latent extinction involves confining an animal to a previously reinforced goal location without food. When returned to the starting position after latent extinction, the animal typically shows a response decrement. Such findings have suggested that latent extinction is sufficient to invoke extinction learning, despite the animal having been prevented from making the original response. The majority of research on latent extinction was conducted between 19491980 and focused on what is being learned during the latent placements. Stimulus-response (S-R) theorists attempted to explain latent extinction via novel S-R mechanisms, namely, the fractional anticipatory response (rG). However, research did not support the role of rG in latent extinction. Cognitive expectancy theorists provided a simpler, more adequate explanation for latent extinction, more consistent with the data. Specifically, latent extinction might instill a change in expectation (i.e., animals learn to expect absence of reinforcement). Evidence also suggests that latent extinction involves place learning mechanisms and is sensitive to modulation via certain experimental factors. More recent work has uncovered some of the neural mechanisms of latent extinction. The hippocampus is critically involved in latent extinction, whereas other brain regions typically implicated in regular "response extinction" in the maze, such as the dorsolateral striatum, are not required for latent extinction. Similar to other kinds of learning, latent extinction requires NMDA receptor activity, suggesting the involvement of synaptic plasticity. Consistent with a multiple memory systems perspective, research on latent extinction supports the hypothesis that extinction learning is not a unitary process but rather there are different kinds of extinction learning mediated by distinct neural systems.

Differential effects of neural inactivation of the dorsolateral striatum on response and latent extinction.

The present study examined the role of the dorsolateral striatum (DLS) in extinction behavior. Male Long-Evans rats were initially trained on the straight alley maze, in which they were reinforced to traverse a straight runway and retrieve food reward at the opposite end of the maze. After initial acquisition, animals were given extinction training using 1 of 2 distinct protocols: response extinction or latent extinction. For response extinction, the animal was released from the same starting position and had the opportunity to perform the originally reinforced approach response to the goal end of the maze, which no longer contained food. For latent extinction, the animal was confined to the original goal location without food, allowing the animal to form a new cognitive expectation (i.e., that the goal location is no longer reinforced). Immediately before response or latent extinction training, animals received bilateral intra-DLS administration of the sodium channel blocker bupivacaine or control injections of physiological saline. Results indicated that neural inactivation of the DLS with bupivacaine impaired response extinction, but did not influence latent extinction. The dissociation observed indicates that the DLS selectively mediates extinction mechanisms involving suppression of the original response, as opposed to cognitive mechanisms involving a change in expectation. (PsycINFO Database Record

Hippocampus NMDA receptors selectively mediate latent extinction of place learning.

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical "response extinction," animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In "latent extinction," animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)-dependent response learning and hippocampus-dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long-Evans rats were trained in a response learning task in a water plus-maze, in which animals were reinforced to make a consistent body-turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra-hippocampal infusions of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were effective at extinguishing memory in the place learning task. In addition, intra-hippocampal AP5 (7.5 µg) impaired latent extinction, but not response extinction, suggesting that hippocampal NMDA receptors are selectively involved in latent extinction. © 2016 Wiley Periodicals, Inc.

Conflation of cocaine seeking and cocaine taking responses in IV self-administration experiments in rats: methodological and interpretational considerations.

IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.

Dopamine and glutamate release in the dorsolateral caudate putamen following withdrawal from cocaine self-administration in rats.

Evidence suggests that cocaine addiction may involve progressive neuroadaptive changes in the dorsolateral caudate putamen (dlCPu). While cocaine seeking following abstinence from chronic self-administration requires intact dlCPu function, in vivo neurotransmitter release in the dlCPu has not been investigated. The current study measured dlCPu dopamine (DA) and glutamate (GLU) release during drug seeking following limited or extended abstinence, as well as in response to a cocaine priming injection alone. Male, Sprague-Dawley rats self-administered cocaine (0.2mg/50µl infusion, i.v.) for 10days (2h/day). In vivo microdialysis occurred in the self-administration chamber after 1 and 14days of abstinence (Experiment 1). A separate set of animals that completed self-administration as well as drug naïve controls received a cocaine priming injection (20mg/kg) during concurrent microdialysis (Experiment 2). DA release increased during drug seeking in the self-administration context at both 1 and 14days post abstinence. In contrast, GLU release only increased after 1day of abstinence. Furthermore, animals with a cocaine self-administration history showed enhanced DA and GLU release following cocaine challenge as compared to drug naïve controls. These results indicate that chronic cocaine self-administration enhances dlCPu DA and GLU under both drug-paired context and drug-primed conditions.

Lesions and reversible inactivation of the dorsolateral caudate-putamen impair cocaine-primed reinstatement to cocaine-seeking in rats.

Recent evidence suggests that cocaine addiction may involve progressive drug-induced neuroplasticity of the dorsal striatum. Here, we examined the effects of a) dorsolateral caudate putamen (dlCPu) lesions on cocaine self-administration, extinction of responding, and subsequent reinstatement to cocaine-seeking, and b) reversible inactivation of the dlCPu with GABA receptor agonists (baclofen and muscimol) immediately prior to reinstatement testing. Male, Sprague-Dawley rats self-administered cocaine (0.2mg/50µl infusion, i.v.) along an FR1 schedule in daily 2h sessions for 10days, whereby lever presses resulted in cocaine infusions and presentation of a paired light-tone stimulus complex. After 14days of abstinence, animals were returned to the self-administration chamber and lever responding was recorded, but had no programmed consequences (relapse test). Animals then underwent daily extinction, followed by reinstatement tests in the presence of the conditioned cues, after a cocaine priming injection (10mg/kg), or cues+cocaine prime. Lesions of the dlCPu failed to affect responding during self-administration, extinction, relapse, or cued-induced reinstatement. However, lesioned animals showed reduced cocaine-seeking during cocaine-primed reinstatement as compared to sham controls. Furthermore, reversible inactivation of the dlCPu significantly impaired both cocaine-primed and cocaine-primed+cue-induced reinstatement. These results demonstrate the critical involvement of the dlCPu in cocaine-primed reinstatement, perhaps via chronic drug-induced changes in the interoceptive effects of cocaine that impact drug-seeking.

Dorsal striatum mediation of cocaine-seeking after withdrawal from short or long daily access cocaine self-administration in rats.

Accumulating evidence has suggested that prolonged use of cocaine may lead to progressive neuroadaptations proceeding from ventral to more dorsal areas of the corpus striatum. We have previously found that reversible inactivation of the dorsolateral caudate/putamen (dlCPu) significantly attenuated cocaine-seeking in rats following chronic cocaine self-administration and withdrawal. Since the cumulative amount of cocaine intake and the time course of withdrawal emergent patterns have been previously shown to alter subsequent cocaine-seeking, the current study investigated the role of the dlCPu in cocaine-seeking after differing access periods of cocaine self-administration and abstinence time points. Rats were catheterized and implanted with infusion cannulae in the dlCPu, trained on cocaine self-administration (0.2 mg/50 µl/infusion), and then allowed to self-administer cocaine for 1 or 6 h daily sessions. After the final session, animals underwent three separate tests of cocaine-seeking in the self-administration context at days 1, 14, and 60 of abstinence immediately following bilateral infusion of baclofen-muscimol or vehicle into the dlCPu. While inactivation of the dlCPu by baclofen-muscimol resulted in reduced cocaine-seeking in both groups, the degree of inhibited responding varied with access history and withdrawal time point. While these data support a role for dorsal striatal regions in cocaine-seeking, greater previous cocaine intake did not lead to a greater dependence on intact dlCPu function for cocaine-seeking after abstinence.

Reversible inactivation of the basolateral amygdala, but not the dorsolateral caudate putamen, attenuates consolidation of cocaine-cue associative learning in a reinstatement model of drug-seeking.

Previous research has shown that the basolateral amygdala (BLA) mediates stimulus-reward learning, including drug-cue associations, whereas the dorsolateral caudate putamen (dlCPu) primarily mediates stimulus-response (habit) learning. Recent evidence has indicated that the dlCPu may be critical in cocaine-seeking following extended self-administration, but it remains unknown whether the dlCPu plays a role in the early formation of drug-cue associations. The current study used a model of Pavlovian learning to compare the roles of the BLA and dlCPu in the consolidation of cocaine-cue associations that maintain cocaine-seeking during cue-induced reinstatement. Male Sprague-Dawley rats self-administered cocaine (0.2 mg/ 50µL infusion, i.v.) in the absence of cues for 6 days (2 h/day). Immediately following a single 1-h classical conditioning session in which passive cocaine infusions were paired with a light/tone cue, animals received bilateral infusions of the GABA receptor agonists, baclofen/muscimol (1.0/0.1 mm), or vehicle into the BLA or dlCPu. Following additional cocaine self-administration (5 days) and subsequent extinction (no cocaine or cues, 7 days), the ability of the previously cocaine-paired cues to reinstate cocaine-seeking was assessed. Inactivation of the BLA, but not the dlCPu, immediately following the classical conditioning session impaired the consolidation of cocaine-cue associations as seen by decreased cue-induced reinstatement. These results extend previous findings that the BLA mediates the consolidation of learned associations that drive cocaine-seeking during subsequent reinstatement and indicate that the dlCPu does not play a role during initial stimulus-drug associative learning.

P-glycoprotein inhibition potentiates the behavioural and neurochemical actions of risperidone in rats.

Antipsychotic drugs are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the metabolic pathways of antipsychotic drugs have been well defined, the role of drug transporters in the disposition and effects of antipsychotic drugs has not been systematically explored. P-glycoprotein has ubiquitous expression in brain endothelial cells and plays a protective role by effluxing substrates for elimination and by limiting their accumulation in the central nervous system. Risperidone and several other antipsychotic drugs are substrates of P-glycoprotein. Increased antipsychotic drug entry into the brain via blockade of the P-glycoprotein transporter may facilitate the amount of available drug to its targets, particularly dopamine receptors. By increasing available antipsychotic drug concentrations, P-glycoprotein inhibition offers a novel means of enhanced drug delivery. This study evaluated whether selective P-glycoprotein transporter inhibition would increase the effects of risperidone on relevant indices of behaviour (catalepsy and locomotion) and neurochemistry (dopamine release and metabolism as measured by in-vivo microdialysis). We administered the P-glycoprotein inhibitor, PSC 833 (100 mg/kg p.o.), to rats prior to administration of risperidone at varying doses (0.01-4.0 mg/kg s.c.). P-glycoprotein inhibition significantly increased risperidone-induced cataleptic effects, blockade of amphetamine-induced locomotion, and effects on dopamine turnover as seen by increased striatal dopamine metabolite levels. These results provide functional evidence concordant with prior data for increased brain levels of risperidone following PSC 833 treatment.

Cocaine self-administration alters the relative effectiveness of multiple memory systems during extinction.

Rats were trained to run a straight-alley maze for an oral cocaine or sucrose vehicle solution reward, followed by either response or latent extinction training procedures that engage neuroanatomically dissociable "habit" and "cognitive" memory systems, respectively. In the response extinction condition, rats performed a runway approach response to an empty fluid well. In the latent extinction condition, rats were placed at the empty fluid well without performing a runway approach response. Rats trained with the sucrose solution displayed normal extinction behavior in both conditions. In contrast, rats trained with the cocaine solution showed normal response extinction but impaired latent extinction. The selective impairment of latent extinction indicates that oral cocaine self-administration alters the relative effectiveness of multiple memory systems during subsequent extinction training.

D-Cycloserine enhances memory consolidation of hippocampus-dependent latent extinction.

Adult male Long-Evans rats were trained to run in a straight-alley maze for food reward and subsequently received hippocampus-dependent latent extinction training. Immediately following latent extinction, rats received peripheral injections of the NMDA receptor partial agonist D-cycloserine (DCS, 15 mg/kg), or saline. Twenty-four hours later, rats received four extinction "probe" trials. Relative to saline controls, latencies to reach the goal box on probe trials were significantly higher in rats that had received DCS. These findings indicate that memory consolidation underlying hippocampus-dependent latent extinction, a cognitive form of learning in which the previously rewarded response is not made during extinction training, can be enhanced by NMDA-receptor agonism.

Evidence of a role for multiple memory systems in behavioral extinction.

The acquisition of learned behavior involves multiple memory systems, and hippocampal system damage impairs cognitive learning while leaving stimulus-response habit learning intact. In view of evidence that extinction also involves new learning, the present experiments examined whether multiple memory systems theory may be applicable to the neural bases of extinction. Adult Long-Evans rats were trained to run in a straight-alley maze for food reward. Twenty-four hours later, rats matched for runway latencies during acquisition received extinction training. In a response extinction condition conducive to habit learning, rats performed a runway approach response to an empty food cup. In a latent extinction condition conducive to cognitive learning, rats were placed at an empty food cup without performing a runway approach response. Prior to daily extinction training, neural activity of the dorsal hippocampus was reversibly inactivated via infusion of bupivacaine (0.75%, 0.5 microl/side). Control rats receiving saline infusions displayed extinction behavior in both the response and latent training conditions. In contrast, rats receiving bupivacaine extinguished normally in the response condition, but did not display latent extinction. The findings (1) confirm that learning underlying extinction of the same overt behavior can occur with or without explicit performance of the previously acquired response, (2) indicate that extinction learning produced by response and latent training procedures can be neuroanatomically dissociated, and (3) suggest that similarly to initial task acquisition, the hippocampus may critically mediate extinction in situations requiring the use of cognitive learning, such as when performance of a previously acquired response habit is prevented.