NMDA receptor blockade in the dorsolateral striatum impairs consolidation but not retrieval of habit memory.

The present study investigated whether N-methyl-d-aspartate (NMDA) receptors in the dorsolateral striatum (DLS) mediate consolidation and retrieval of habit memory. Adult male Long-Evans rats were trained in a response learning version of a water plus-maze task in which rats were reinforced to make a habitual and consistent body-turn response at the maze choice point in order to mount a hidden escape platform. Prior research indicates that acquisition, consolidation, and retrieval in this task requires DLS function. The present study consisted of two experiments. In Experiment 1, rats received intra-DLS post-training injections of the NMDA receptor antagonist 2-amino-5- phosphonopentanoic acid (AP5; 2 µg/side) to examine the role of NMDA receptors in consolidation of habit memory. In Experiment 2, different groups of rats received a single pre-retrieval injection of AP5 in the DLS (AP5; 2 µg/side) during the last day of maze training to examine the potential role of NMDA receptors in retrieval of habit memory. Results indicated that post-training intra-DLS AP5 injections impaired memory consolidation. However, administration of AP5 at the same dose that impaired consolidation had no effect on memory retrieval. The findings are consistent with previous research indicating a role for NMDA receptors in the DLS in memory consolidation, and suggest that NMDA-dependent synaptic activity in the DLS may not be a critical component of habit memory retrieval.

Oxytocin and Addiction: Potential Glutamatergic Mechanisms.

Recently, oxytocin (OXT) has been investigated for its potential therapeutic role in addiction. OXT has been found to diminish various drug-seeking and drug-induced behaviors. Although its behavioral effects are well-established, there is not much consensus on how this neuropeptide exerts its effects. Previous research has given thought to how dopamine (DA) may be involved in oxytocinergic mechanisms, but there has not been as strong of a focus on the role that glutamate (Glu) has. The glutamatergic system is critical for the processing of rewards and the disruption of glutamatergic projections produces the behaviors seen in drug addicts. We introduce the idea that OXT has direct effects on Glu transmission within the reward processing pathway. Thus, OXT may reduce addictive behaviors by restoring abnormal drug-induced changes in the glutamatergic system and in its interactions with other neurotransmitters. This review offers insight into the mechanisms through which a potentially viable therapeutic target, OXT, could be used to reduce addiction-related behaviors.

Regionally Specific Effects of Oxytocin on Reinstatement of Cocaine Seeking in Male and Female Rats.

Background: Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement. Methods: To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking. Results: We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin's ability to attenuate cued reinstatement. Conclusions: While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking.

Oxytocin Reduces Cocaine Cued Fos Activation in a Regionally Specific Manner.

Background: Oxytocin may be a possible treatment for multiple neuropsychiatric disorders, including cocaine addiction. Little is known about the site-specific effects of oxytocin on various drug addiction-related brain regions. Furthermore, sexually dimorphic effects of oxytocin on neural function in the addiction circuit have not been established. Here, we studied Fos expression following cocaine-cued reinstatement in both male and female rats. Methods: Male and female rats underwent self-administration, extinction, and reinstatement tests. On test days, rats were given oxytocin or vehicle, and lever pressing was measured in response to conditioned cocaine cues. Rats were perfused and Fos staining measured in the central amygdala, medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Fos/oxytocin double labeling occurred in the paraventricular nucleus of the hypothalamus. Results: Rats reinstated to cocaine cues relative to extinction responding and oxytocin reduced cocaine seeking. Oxytocin combined with contingent cue presentations increased Fos+ oxytocin cell bodies within the paraventricular nucleus of the hypothalamus relative to vehicle. Fos expression robustly increased in the central amygdala following oxytocin administration. Oxytocin reversed cue-induced Fos expression in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Central oxytocin infusion also attenuated reinstated cocaine seeking. Conclusions: Oxytocin decreased reinstated cocaine seeking, increased Fos activation in the paraventricular nucleus of the hypothalamus and central amygdala, but normalized cue-induced Fos activation in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus, thereby demonstrating regionally specific activation patterns. No sex differences were seen for the effects of oxytocin on cocaine seeking and Fos activation, indicating that oxytocin acts on similar central neural circuits critical to reinstated cocaine seeking in both males and females.

Exposure to predator odor influences the relative use of multiple memory systems: role of basolateral amygdala.

In a dual-solution plus-maze task in which both hippocampus-dependent place learning and dorsolateral striatal-dependent response learning provide an adequate solution, the relative use of multiple memory systems can be influenced by emotional state. Specifically, pre-training peripheral or intra-basolateral (BLA) administration of anxiogenic drugs result in the predominant use of response learning. The present experiments were designed to extend these findings by examining whether exposure to a putatively ethologically valid stressor would also produce a predominant use of response learning. In experiment 1, adult male Long-Evans rats were exposed to either a predator odor (trimethylthiazoline [TMT], a component of fox feces) or distilled water prior to training in a dual-solution water plus maze task. On a probe trial 24h following task acquisition, rats previously exposed to TMT predominantly displayed response learning relative to control animals. In experiment 2, rats trained on a single-solution plus maze task that required the use of response learning displayed enhanced acquisition following pre-training TMT exposure. In experiment 3, rats exposed to TMT or distilled water were trained in the dual-solution task and received post-training intra-BLA injections of the sodium channel blocker bupivacaine (1.0% solution, 0.5 µl) or saline. Relative to control animals, rats exposed to TMT predominantly displayed response learning on the probe trial, and this effect was blocked by neural inactivation of the BLA. The findings indicate that (1) the use of dorsal striatal-dependent habit memory produced by emotional arousal generalizes from anxiogenic drug administration to a putatively ecologically valid stressor (i.e. predator odor), and (2) the BLA mediates the modulatory effect of exposure to predator odor on the relative use of multiple memory systems.

Oxytocin attenuates cocaine-associated place preference via the dorsal hippocampus in male and female rats.

Cocaine addiction is the third largest cause of overdose-related deaths in the United States. Research investigating therapeutic targets for cocaine reward processes is key to combating this issue. The neuropeptide oxytocin (OXT) has been shown to reduce cocaine reward processes, though specific mechanisms are not understood. This study examines the effect of intra-dorsal hippocampal (DH) OXT on the expression of cocaine context associations using a conditioned place preference (CPP) paradigm. In this paradigm, one of two visually distinct chambers is paired with a drug. With repeated pairings, control animals display preference for the drug-associated context by spending more time in that context at test. In the present study, four conditioning days took place where male and female rats were injected with either cocaine or saline and placed into the corresponding chamber. On test day, rats received infusions of OXT or saline (VEH) into the DH and were allowed access to both chambers. The results show that while VEH-infused rats displayed cocaine CPP, OXT-infused rats did not prefer the cocaine-paired chamber. These findings implicate the DH as necessary in the mechanism by which OXT acts to block the expression of cocaine-context associations, providing insight into how OXT may exert its therapeutic effect in cocaine reward processes.

Oxytocin Attenuates Yohimbine-Induced Reinstatement of Alcohol-Seeking in Female Rats via the Central Amygdala.

Alcohol use disorder is a significant public health concern, further exacerbated by an increased risk of relapse due to stress. In addition, factors such as biological sex may contribute to the progression of addiction, as females are especially susceptible to stress-induced relapse. While there have been many studies surrounding potential pharmacological interventions for male stress-induced ethanol reinstatement, research regarding females is scarce. Recently, the neuropeptide oxytocin has gained interest as a possible pharmacological intervention for relapse. The present study examines how oxytocin affects yohimbine-induced reinstatement of ethanol-seeking in female rats using a self-administration paradigm. Adult female rats were trained to press a lever to access ethanol in daily self-administration sessions. Rats then underwent extinction training before a yohimbine-induced reinstatement test. Rats administered with yohimbine demonstrated significantly higher lever response indicating a reinstatement of ethanol-seeking behavior. Oxytocin administration, both systemically and directly into the central amygdala, attenuated the effect of yohimbine-induced reinstatement of ethanol-seeking behavior. The findings from this study establish that oxytocin is effective at attenuating alcohol-relapse behavior mediated by the pharmacological stressor yohimbine and that this effect is modulated by the central amygdala in females. This provides valuable insight regarding oxytocin's potential therapeutic effect in female stress-induced alcohol relapse.

Emotional modulation of multiple memory systems: implications for the neurobiology of post-traumatic stress disorder.

In lower animals and humans, stress/anxiety can enhance dorsal striatal-dependent habit memory,at the expense of hippocampal-dependent cognitive memory. The present review considers the potential for this 'stress/anxiety-induced habit bias' to explain some aspects of post-traumatic stress disorder (PTSD). In rats,anxiety induced by peripheral or intra-amygdala infusions of anxiogenic drugs can enhance habit memory and impair cognitive memory. In tasks in which both habit and cognitive memory processes may provide a learned solution, stress and drug-induced anxiety favors the use of habit memory. The effect of stress and anxiety on the use of multiple memory systems in rats depends on the functional integrity of the basolateral amygdala. Thus,under robust emotional arousal, amygdala activation can modulate the relative use of memory systems in a manner that favors habit memory. We propose a similar mechanism may underlie the development and persistence of some PTSD symptoms. The traumatic memories of PTSD patients can be deficient in hippocampus-dependent contextual or autobiographical aspects, and enhanced in responding to trauma-related cues, which we suggest may reflect increased involvement of the dorsal striatum.We briefly consider the potential role of a stress/anxiety induced habit bias with regard to other psychopathologies,including obsessive-compulsive disorder and drug addiction.

Paired Housing or a Socially-Paired Context Decreases Ethanol Conditioned Place Preference in Male Rats.

Alcohol abuse dramatically affects individuals' lives nationwide. The 2020 National Survey on Drug Use and Health (NSDUH) estimated that 10.2% of Americans suffer from alcohol use disorder. Although social support has been shown to aid in general addiction prevention and rehabilitation, the benefits of social support are not entirely understood. The present study sought to compare the benefits of social interaction on the conditioned ethanol approach behavior in rats through a conditioned place preference (CPP) paradigm in which a drug is paired with one of two distinct contexts. In experiment 1A, rats were single-housed and received conditioning trials in which ethanol was paired with the less preferred context. In experiment 1B, rats underwent procedures identical to experiment 1A, but were pair-housed throughout the paradigm. In experiment 1C, rats were single-housed, but concurrently conditioned to a socially-paired context and an ethanol-paired context. By comparing the time spent between the ethanol-paired environment and the saline-paired or socially-paired environment, we extrapolated the extent of ethanol approach behavior in the pair-housed, single-housed, and concurrently conditioned rats. Our results revealed that social interaction, both in pair-housed animals or concurrently socially-conditioned animals, diminished the ethanol approach behavior, which highlights the importance of social support in addiction prevention, treatment, and recovery programs.

Oxytocin Attenuates the Stress-Induced Reinstatement of Alcohol-Seeking in Male Rats: Role of the Central Amygdala.

Factors such as stress and anxiety often contribute to alcohol-dependent behavior and can trigger a relapse of alcohol addiction and use. Therefore, it is important to investigate potential pharmacological interventions that may alleviate the influence of stress on addiction-related behaviors. Previous studies have demonstrated that the neuropeptide oxytocin has promising anxiolytic potential in mammals and may offer a pharmacological target to diminish the emotional impact on reinstatement of alcohol-seeking. The purpose of the present study was to investigate the effect of oxytocin on stress-induced alcohol relapse and identify a neural structure mediating this effect through the use of an ethanol self-administration and yohimbine-induced reinstatement paradigm. While yohimbine administration resulted in the reinstatement of ethanol-seeking behavior, the concurrent administration of yohimbine and oxytocin attenuated this effect, suggesting that oxytocin may disrupt stress-induced ethanol-seeking behavior. The central amygdala (CeA) is a structure that drives emotional responses and robustly expresses oxytocin receptors. Intra-CeA oxytocin similarly attenuated the yohimbine-induced reinstatement of ethanol-seeking behavior. These results demonstrate that oxytocin has the potential to attenuate stress-induced relapse into ethanol-seeking behavior, and that this mechanism occurs specifically within the central amygdala.

Oxytocin Attenuates Expression, but Not Acquisition, of Sucrose Conditioned Place Preference in Rats.

Maladaptation of reward processing for natural rewards, such as sucrose or sugar, may play a role in the development of diseases such as obesity and diabetes. Furthermore, uncovering mechanisms to disrupt or reverse maladaptation of reward-seeking behaviors for natural reinforcers can provide insight into treatment of such diseases, as well as disorders such as addiction. As such, studying the effects of potential pharmacotherapeutics on maladaptive sugar-seeking behavior offers valuable clinical significance. Sucrose conditioned place preference (CPP) paradigms can offer insight into aspects of reward processes as it provides a way to assess acquisition and expression of context-reward associations. The present study examined the effect of peripheral oxytocin injections on sucrose CPP in rats. Oxytocin, when administered prior to CPP test, attenuated expression of sucrose CPP. However, oxytocin, when administered during sucrose conditioning, did not affect subsequent place preference. These findings suggest oxytocin sufficiently attenuates expression of sucrose-associated place preference.

Oxytocin and Rodent Models of Addiction.

Interest for the use of oxytocin as a treatment for addiction began over 40years ago. Better known for its roles in parturition, lactation and pair bonding, oxytocin also has anxiolytic properties, reduces immune and inflammatory responses, and has a role in learning and memory. In this chapter, oxytocin effects on addiction processes are described by highlighting research findings that have used oxytocin within current preclinical animal models of addiction, relapse, or craving. First, we provide a brief background of the endogenous oxytocin system followed by descriptions of the behavioral models used to study addiction, including models of drug taking and seeking. Then we review recent preclinical studies that have used oxytocin as a therapeutic intervention throughout multiple stages of the addiction cycle from a behavioral and neurobiological perspective. These models encompass the entire range of the addiction cycle including acquisition and maintenance of drug taking, withdrawal and craving during periods of drug abstinence, and ultimately relapse. We then posit several theories about how oxytocin interacts with both drug and social reward, as well as presenting a mechanistic account of how specific oxytocin receptor localization may contribute to oxytocin's efficacy as an addiction therapeutic.

Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats.

Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin's effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin's effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues.

Methamphetamine self-administration modulates glutamate neurophysiology.

World-wide methamphetamine (meth) use is increasing at a rapid rate; therefore, it has become increasingly important to understand the synaptic changes and neural mechanisms affected by drug exposure. In rodents, 6-h access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. There is a dearth of knowledge regarding the underlying physiological changes within this circuit following meth self-administration. We assessed pre- and postsynaptic changes in glutamate transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following daily 6-h meth self-administration. In the mPFC, meth caused postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the NAc, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. These changes in mPFC synapses and NAc activity begin to characterize the impact of meth on the corticostriatal circuitry.

Extended cocaine-seeking produces a shift from goal-directed to habitual responding in rats.

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goal-directed responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaine-associated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold.

Enhancement of striatum-dependent memory by conditioned fear is mediated by beta-adrenergic receptors in the basolateral amygdala.

Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs) enhance dorsolateral striatum (DLS)-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA). Recent work indicates that, like unconditioned emotional stimuli, exposure to an aversive conditioned stimulus (CS) (i.e., a tone previously paired with shock) can also enhance consolidation of DLS-dependent habit memory. The present experiments examined whether noradrenergic activity, particularly within the BLA, is required for a fear CS to enhance habit memory consolidation. First, rats underwent a fear conditioning procedure in which a tone CS was paired with an aversive unconditioned stimulus. Over the course of the next five days, rats received training in a DLS-dependent water plus-maze task, in which rats were reinforced to make a consistent body-turn response to reach a hidden escape platform. Immediately after training on days 1-3, rats received post-training systemic (Experiment 1) or intra-BLA (Experiment 2) administration of the ß-adrenoreceptor antagonist, propranolol. Immediately after drug administration, half of the rats were re-exposed to the tone CS in the conditioning context (without shock). Post-training CS exposure enhanced consolidation of habit memory in vehicle-treated rats, and this effect was blocked by peripheral (Experiment 1) or intra-BLA (Experiment 2) propranolol administration. The present findings reveal that noradrenergic activity within the BLA is critical for the enhancement of DLS-dependent habit memory as a result of exposure to conditioned emotional stimuli.

Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females.

Post-training re-exposure to fear conditioned stimuli enhances memory consolidation and biases rats toward the use of dorsolateral striatum-dependent response learning.

In a dual-solution task that can be acquired using either hippocampus-dependent "place" or dorsolateral striatum-dependent "response" learning, emotional arousal induced by unconditioned stimuli (e.g. anxiogenic drug injections or predator odor exposure) biases rats toward response learning. In the present experiments emotionally-arousing conditioned stimuli were used to modulate the relative use of multiple memory systems. In Experiment 1, adult male Long-Evans rats initially received three standard fear-conditioning trials in which a tone (2 kHz, 75 dB) was paired with a brief electrical shock (1 mA, 2s). On day 2, the rats were trained in a dual-solution plus-maze task to swim from the same start arm (South) to a hidden escape platform always located in the same goal arm (East). Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli (i.e. tone and context) without shock. On day 3, the relative use of place or response learning was assessed on a probe trial in which rats were started from the opposite start arm (North). Post-training re-exposure to fear-conditioned stimuli produced preferential use of a response strategy. In Experiment 2, different rats received fear conditioning and were then trained in a single-solution task that required the use of response learning. Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli without shock. Re-exposure to fear-conditioned stimuli enhanced memory consolidation in the response learning task. Thus, re-exposure to fear-conditioned stimuli biases rats toward the use of dorsolateral striatum-dependent response learning and enhances memory consolidation of response learning.

Differential effects of massed and spaced training on place and response learning: A memory systems perspective.

Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and dorsolateral striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the dorsolateral striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a dorsolateral striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus-dependent and dorsolateral striatum-dependent learning may have differential temporal characteristics.

Failure to Recognize Novelty after Extended Methamphetamine Self-Administration Results from Loss of Long-Term Depression in the Perirhinal Cortex.

Exposure to methamphetamine (meth) can produce lasting memory impairments in humans and rodents. We recently demonstrated that extended access meth self-administration results in novel object recognition (NOR) memory deficits in rats. Recognition of novelty depends upon intact perirhinal (pRh) cortex function, which is compromised by meth-induced downregulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors. NMDA receptors containing this subunit have a critical role in pRh long-term depression (LTD), one of the primary physiological processes thought to underlie object recognition memory. We hypothesized that meth-induced downregulation of GluN2B receptors would compromise pRh LTD, leading to loss of NOR memory. We found that meth self-administration resulted in an inability to induce pRh LTD following 1 Hz stimulation, an effect that was reversed with bath application of the NMDA receptor partial agonist D-cycloserine (DCS). In addition, pRh microinfusion of DCS restored meth-induced memory deficits. Furthermore, blockade of GluN2B-containing NMDA receptors with Ro 25-6981 prevented DCS restoration of pRh LTD in meth subjects. Thus, targeting pRh LTD may be a promising strategy to treat meth-induced cognitive impairment.