Search

Contextual memory driven by abused drugs such as opiates has a central role in maintenance and relapse of drug-taking behaviors. Although dopamine (DA) signaling favors memory storage and retrieval via regulation of hippocampal-prefrontal connectivity, its role in modulating opiate-associated contextual memory is largely unknown. Here, we report roles of DA signaling within the hippocampal-prefrontal circuit for opiate-related memories. Combining-conditioned place preference (CPP) with molecular analyses, we investigated the DA D1 receptor (D1R) and extracellular signal-regulated kinase (ERK)-cAMP-response element binding protein (CREB) signaling, as well as DA D2 receptor (D2R) and protein kinase B (PKB or Akt)/glycogen synthase kinase 3 (GSK3) signaling in the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC) during the formation of opiate-related associative memories. Morphine-CPP acquisition increased the activity of the D1R-ERK-CREB pathway in both the vHip and mPFC. Morphine-CPP reinstatement was associated with the D2R-mediated hyperactive GSK3 via Akt inhibition in the vHip and PFC. Furthermore, integrated D1R-ERK-CREB and D2R-Akt-GSK3 pathways in the vHip-mPFC circuit are required for the acquisition and retrieval of the morphine contextual memory, respectively. Moreover, blockage of D1R or D2R signaling could alleviate normal Hip-dependent spatial memory. These results suggest that D1R and D2R signaling are differentially involved in the acquisition and retrieval of morphine contextual memory, and DA signaling in the vHip-mPFC connection contributes to morphine-associated and normal memory, largely depending on opiate exposure states.

Tobacco smoking is the most common preventable cause of death in the US. Nicotine is considered the primary constituent responsible for tobacco addiction. Its paradoxically high abuse potential may reflect behavioral control by drug-associated stimuli, which appears to play a larger role for tobacco dependence than for other abused drugs. We tested a potential explanation, hypothesizing that nicotine enhances associative learning, the mechanism underlying the conditioning of drug-associated stimuli. Thirty-two non-smokers were exposed to transdermal nicotine (7 mg/24 h) and placebo in a double-blind cross-over study and tested with behavioral paradigms designed to isolate incidental stimulus-stimulus or stimulus-response learning. The stop signal task required speeded gender judgments of face stimuli. A tone signaled when to withhold the response. Unbeknownst to participants, some faces were always paired with stop trials. Nicotine enhanced the facilitation of stop-responses to these stimuli, and the slowing of go-responses when previously stop-associated stimuli were paired with go trials, indicating stronger associations between paired stimuli and the stop signal/stop response. Another task required feedback-based learning of associations between pairs of shape stimuli. Five pairs were made from either ten different stimuli, or from different combinations of two identical sets of five stimuli with correct associations depending on contextual information. Nicotine increased incorrect choices of stimuli that were associated in a different context, indicating stronger stimulus-stimulus associations at the expense of flexible context-adaptive behavior. The results indicate that nicotine can enhance incidental associative learning, a mechanism that may promote the formation of smoking-associated stimuli and cue-controlled drug-taking.

Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTOR loxP/loxP mice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics, and cocaine-induced synaptic plasticity and rewarding effects. We find that targeted deletion of mTOR in the VTA had no significant effects on soma size and dendritic morphology of VTA neurons but significantly decreased dopamine release and reuptake in the nucleus accumbens (NAc) shell, a major target region. Western blot analysis revealed that mTOR deletion led to decreases in phosphorylated tyrosine hydroxylase (pTH-Ser40) levels in the VTA and dopamine transporter expression in the NAc. mTOR deletion had no significant effects on basal excitatory transmission in VTA dopamine neurons but caused an increase in GABAergic inhibition because of an increase in VTA GABAergic neuron firing. Furthermore, mTOR deletion attenuated conditioned place preference to cocaine and cocaine-induced potentiation of excitation and reduction of GABAergic inhibition in VTA dopamine neurons. Taken together, these results suggest that loss of mTOR in the VTA shifts the balance of excitatory and inhibitory synaptic transmission and decreases dopamine release and reuptake in the NAc. In addition, VTA mTOR signaling regulates cocaine-cue associative learning and cocaine-induced synaptic plasticity in VTA dopamine neurons.

Sustained abstinence from cocaine use is frequently compromised by exposure to environmental stimuli that have previously been strongly associated with drug taking. Such cues trigger memories of the effects of the drug, leading to craving and potential relapse. Our work has demonstrated that manipulating cocaine-cue memories by destabilizing them through interfering with the reconsolidation process is one potential therapeutic tool by which to prolong abstinence. Here, we examine the use of the naturally occurring amnestic agent garcinol to manipulate an established cocaine-cue memory. Rats underwent 12 days of cocaine self-administration training during which time active lever presses resulted in an i.v. infusion of cocaine that was paired with a light/tone cue. Next rats underwent lever extinction for 8 days followed by light/tone reactivation and a test of cue-induced cocaine-seeking behavior. Systemic injection of garcinol 30 min after reactivation significantly impaired the reconsolidation of the cocaine-associated cue memory. Further testing revealed that garcinol had no effect on drug-induced cocaine-seeking, but was capable of blocking the initial conditioned reinforcing properties of the cue and prevents the acquisition of a new response. Additional experiments showed that the effects of garcinol are specific to reactivated memories only, temporally constrained, cue-specific, long-lasting, and persist following extended cocaine access. These data provide strong evidence that the naturally occurring compound, garcinol, may be a potentially useful tool to sustain abstinence from drug abuse.

Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

From infancy we learn to comply with societal norms. However, overt compliance is not necessarily accompanied by a change in internal beliefs. The neuromodulatory processes underlying these different phenomena are not yet understood. Here, we test the role of oxytocin in controlling overt compliance versus internalization of information delivered by a social source. After intranasal oxytocin administration, participants showed enhanced compliance to the erroneous opinion of others. However, this expression was coupled with a decrease in the influence of others on long-term memories. Our data suggest that this dissociation may result from reduced conflict in the face of social pressure, which increases immediate conforming behavior, but reduces processing required for deep encoding. These findings reveal a neurobiological control system that oppositely affects internalization and overt compliance.

The capacity to adapt to new situations is one of the most important features of memory. When retrieved, memories may undergo a labile state that is sensitive to modification. This process, called reconsolidation, can lead to memory updating through the integration of new information into a previously consolidated memory background. Thus reconsolidation provides the opportunity to modify an undesired fear memory by updating its emotional valence to a less aversive level. Here we evaluated whether a fear memory can be reinterpreted by the concomitant presentation of an appetitive stimulus during its reactivation, hindering fear expression. We found that memory reactivation in the presence of appetitive stimuli resulted in the suppression of a fear response. In addition, fear expression was not amenable to reinstatement, spontaneous recovery, or rapid reacquisition. Such effect was prevented by either systemic injection of nimodipine or intra-hippocampal infusion of ifenprodil, indicating that memory updating was mediated by a reconsolidation mechanism relying on hippocampal neuronal plasticity. Taken together, this study shows that reconsolidation allows for a 're-signification' of unwanted fear memories through the incorporation of appetitive information. It brings a new promising cognitive approach to treat fear-related disorders.

Anesthesia in infancy impairs performance in recognition memory tasks in mammalian animals, but it is unknown if this occurs in humans. Successful recognition can be based on stimulus familiarity or recollection of event details. Several brain structures involved in recollection are affected by anesthesia-induced neurodegeneration in animals. Therefore, we hypothesized that anesthesia in infancy impairs recollection later in life in humans and rats. Twenty eight children ages 6-11 who had undergone a procedure requiring general anesthesia before age 1 were compared with 28 age- and gender-matched children who had not undergone anesthesia. Recollection and familiarity were assessed in an object recognition memory test using receiver operator characteristic analysis. In addition, IQ and Child Behavior Checklist scores were assessed. In parallel, thirty three 7-day-old rats were randomized to receive anesthesia or sham anesthesia. Over 10 months, recollection and familiarity were assessed using an odor recognition test. We found that anesthetized children had significantly lower recollection scores and were impaired at recollecting associative information compared with controls. Familiarity, IQ, and Child Behavior Checklist scores were not different between groups. In rats, anesthetized subjects had significantly lower recollection scores than controls while familiarity was unaffected. Rats that had undergone tissue injury during anesthesia had similar recollection indices as rats that had been anesthetized without tissue injury. These findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury.

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.

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

Previous studies from our laboratory found that rats express increased preference for drug-paired stimuli following 2 or 5 weeks of protracted abstinence from chronic drug exposure as compared with naive animals. Here, we show that this increased morphine place preference depends upon experiencing drug-stimulus pairings specifically in the abstinent state, indicating a critical role for incentive learning. Male Sprague Dawley rats were initially conditioned for morphine place preference (8 mg/kg) and then made dependent on morphine (by subcutaneous morphine pellets) and subjected to forced abstinence. Place preference was tested every 1-2 weeks with no additional drug-cue conditioning. In this paradigm, there was no difference between morphine-pelleted (dependent) and placebo-pelleted (non-dependent) rats in place preference at any time during abstinence (up to 6 weeks). However, these same morphine-pelleted rats expressed significantly increased preference when they were subsequently re-conditioned for morphine place preference during protracted abstinence. Placebo-pelleted rats did not show enhanced preference after re-conditioning. These findings reveal that incentive learning has a key role in increased morphine place preference when drug is experienced during protracted abstinence. This indicates that incentive learning is involved not only in instrumental responding (as previously reported), but also in updating Pavlovian-conditioned responses to morphine-associated stimuli. Therefore, enhanced morphine preference is not a direct consequence of the negative affective state of abstinence, but instead reflects increased acquisition of morphine-stimulus associations during abstinence. These results indicate that, during the development of addiction in humans, drug-associated stimuli acquire increasingly stronger incentive properties each time they are re-experienced.

Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors.

Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise.

Methamphetamine (METH) induces neurotoxic changes, including partial striatal dopamine depletions, which are thought to contribute to cognitive dysfunction in rodents and humans. The dorsal striatum is implicated in action-outcome (A-O) and stimulus-response (S-R) associations underlying instrumental learning. Thus, the present study examined the long-term consequences of METH-induced neurotoxicity on A-O and S-R associations underlying appetitive instrumental behavior. Rats were pretreated with saline or a neurotoxic regimen of METH (4 × 7.5-10 mg/kg). Rats trained on random ratio (RR) or random interval (RI) schedules of reinforcement were then subjected to outcome devaluation or contingency degradation, followed by an extinction test. All rats then were killed, and brains removed for determination of striatal dopamine loss. The results show that: (1) METH pretreatment induced a partial 45-50% decrease in striatal dopamine tissue content in dorsomedial and dorsolateral striatum; (2) METH-induced neurotoxicity did not alter acquisition of instrumental behavior on either RR or RI schedules; (3) outcome devaluation and contingency degradation similarly decreased responding in saline- and METH-pretreated rats trained on the RR schedule, suggesting intact A-O associations guiding behavior; (4) outcome devaluation after training on the RI schedule decreased extinction responding only in METH-pretreated rats, suggesting impaired S-R associations. Overall, these data suggest that METH-induced neurotoxicity, possibly due to impairment of the function of dorsolateral striatal circuitry, may decrease cognitive flexibility by impairing the ability to automatize behavioral patterns.

Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers. We therefore conducted a randomized, double-blind, placebo-controlled, cross-over study, using functional magnetic resonance imaging, to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent, MA-dependent, and healthy control participants. Modafinil (200 mg) and placebo were administered orally (one single dose each), in counterbalanced fashion, 2 h before each of two testing sessions. Under placebo conditions, MA-dependent participants showed worse learning performance than control participants. Modafinil boosted learning in MA-dependent participants, bringing them to the same performance level as control subjects; the control group did not show changes in performance with modafinil. After controlling for performance differences, MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants. The findings suggest that modafinil improves learning in MA-dependent participants, possibly by enhancing neural function in regions important for learning and cognitive control. These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence.

Social and financial considerations are often integrated when real life decisions are made, and recent studies have provided evidence that similar brain networks are engaged when either social or financial information is integrated. Other studies, however, have suggested that the neuropeptide oxytocin can specifically affect social behaviors, which would suggest separable mechanisms at the pharmacological level. Thus, we examined the hypothesis that oxytocin would specifically affect social and not financial information in a decision making task, in which participants learned which of the two faces, one smiling and the other angry or sad, was most often being rewarded. We found that oxytocin specifically decreased aversion to angry faces, without affecting integration of positive or negative financial feedback or choices related to happy vs sad faces.

Stress exposure increases the risk of addictive drug use in human and animal models of drug addiction by mechanisms that are not completely understood. Mice subjected to repeated forced swim stress (FSS) before cocaine develop significantly greater conditioned place preference (CPP) for the drug-paired chamber than unstressed mice. Analysis of the dose dependency showed that FSS increased both the maximal CPP response and sensitivity to cocaine. To determine whether FSS potentiated CPP by enhancing associative learning mechanisms, mice were conditioned with cocaine in the absence of stress, then challenged after association was complete with the kappa-opioid receptor (KOR) agonist U50,488 or repeated FSS, before preference testing. Mice challenged with U50,488 60 min before CPP preference testing expressed significantly greater cocaine-CPP than saline-challenged mice. Potentiation by U50,488 was dose and time dependent and blocked by the KOR antagonist norbinaltorphimine (norBNI). Similarly, mice subjected to repeated FSS before the final preference test expressed significantly greater cocaine-CPP than unstressed controls, and FSS-induced potentiation was blocked by norBNI. Novel object recognition (NOR) performance was not affected by U50,488 given 60 min before assay, but was impaired when given 15 min before NOR assay, suggesting that KOR activation did not potentiate CPP by facilitating memory retrieval or expression. The results from this study show that the potentiation of cocaine-CPP by KOR activation does not result from an enhancement of associative learning mechanisms and that stress may instead enhance the rewarding valence of cocaine-associated cues by a dynorphin-dependent mechanism.

Previous in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation (LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A(2A) receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A(2A) receptor antagonist, SCH58261, upon a well-known associative learning paradigm-classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus (US). A single electrical pulse was presented to the Schaffer collateral-commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS-US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.) -injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261-injected mice. In conclusion, the endogenous activation of adenosine A(2A) receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.

Rapid eye movement (REM) sleep has been considered important for the consolidation of memories, particularly of procedural skills. REM sleep, in contrast to slow-wave sleep (SWS), is hallmarked by the high, wake-like activity of the neurotransmitter acetylcholine (ACh), which promotes certain synaptic plastic processes underlying the formation of memories. Here, we show in healthy young men that off-line consolidation of a motor skill during a period of late sleep with high amounts of REM sleep depends essentially on high cholinergic activity. After a 3-h sleep period during the early night to satisfy the need for SWS, subjects learned a procedural finger sequence tapping task and a declarative word-pair learning task. After learning, they received either placebo or a combination of the muscarinic receptor antagonist scopolamine (4 microg/kg bodyweight, intravenously) and the nicotinic receptor antagonist mecamylamine (5 mg, orally), and then slept for another 3 h, ie, the late nocturnal sleep period, which is dominated by REM sleep. Retrieval was tested the following evening. Combined cholinergic receptor blockade significantly impaired motor skill consolidation, whereas word-pair memory remained unaffected. Additional data show that the impairing effect of cholinergic receptor blockade is specific to sleep-dependent consolidation of motor skill and does not occur during a wake-retention interval. Taken together, these results identify high cholinergic activity during late, REM sleep-rich sleep as an essential factor promoting sleep-dependent consolidation of motor skills.

Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudate-putamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.

While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. The current study, therefore, examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. Chronic cannabis users (24 h abstinence before study; positive THC urine drug test) free of DSM-IV Axis-I or -II disorders, were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding which corroborates the recent work in CB1 knockout mice.

Prenatal nicotine exposure (PNE) has been associated with increased prevalence of attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD) and substance abuse in exposed children and adolescents. Whether these syndromes are caused by nicotine exposure, or genetic and psychosocial adversities associated with maternal smoking is not completely clear. Animal models suggest a direct impact of PNE. However, the fact that nicotine is forcefully administrated in these paradigms raises some questions about the specificity of these findings. Pregnant C57BI/6J mice were allowed to choose drinking saccharin/nicotine solutions or pure water. Controls could choose saccharin solutions or pure water. Offspring were tested in spontaneous locomotion, fear-associated learning (trace conditioning), addictive (conditioned place preference), and depression-like (learned helplessness) behaviors. There was no significant difference in weight or pup number between the prenatal treatment groups. A significant effect of PNE was observed on spontaneous locomotion, preference for a cocaine-associated place, and latency to escape in the learned helplessness paradigm. Surprisingly, PNE mice exhibited an increased learning of trace-conditioned fear-associated cues. The hyperlocomotive behavior reported in animal models of PNE is not likely an artifact of forceful nicotine administration. The increased prevalence of ADHD, MDD and substance abuse observed in PNE children and adolescents is probably caused by direct behavioral teratogenic effects of PNE. The role of PNE as a risk factor of syndromes associated to increased learning of fear-associated cues such as post-traumatic stress disorder (PTSD) warrants further evaluation.

Endogenous dopamine plays a central role in salience coding during associative learning. Administration of the dopamine precursor levodopa enhances learning in healthy subjects and stroke patients. Because levodopa increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating dopamine-receptor agonist pergolide (0.1 mg) vs placebo 120 min before training on each training day. The dopamine agonist significantly impaired novel word learning compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group. The extent of 'flattened' affect with pergolide was related to the degree of learning inhibition. These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals. Thus, phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and stroke patients.

Late gestational disruption of neurogenesis in rats has been shown to induce behavioral abnormalities thought to mimic aspects of positive and negative symptoms of schizophrenia. Furthermore, it has been shown that the morphological changes produced by the perturbation are relevant to schizophrenia with reduced thickness of the hippocampus, thalamus, and cortical regions. In addition to the positive and negative symptoms, schizophrenia is associated with deficits in a wide variety of cognitive domains. In the present studies, we assessed whether the cognitive deficits are modeled by disruption of neurogenesis late during gestation (gestational day 17) in the rat. In the battery of tests utilized, we describe that rats in which neurogenesis was disrupted have deficits in a reversal-learning paradigm of the Morris water maze and in object recognition, and that they exhibit perseveration in the Porsolt forced swimming test. Additionally, we found deficient associative learning in an acquisition of an active avoidance paradigm and deficits in latent inhibition. No deficits were observed in the reference memory version of the Morris water maze and in a non-match-to position experiment, showing that the deficits are limited to certain aspects of cognition.

In classical conditioning, pre-exposures to either the to-be-conditioned stimulus (CS) or unconditioned stimulus (US) can retard subsequent conditioning between the CS and US. The present experiment evaluated the expression of these two pre-exposure effects in mice of the C57BL6/J strain, one of the most common background strains for genetically altered mice. We tested whether their expression would be disrupted by amphetamine treatment (2.5 mg/kg, i.p.) in a conditioned taste aversion paradigm with sucrose as the CS and lithium chloride-induced gastric malaise as the US. We found that one pre-exposure (PE) to either the CS or the US reduced aversion to sucrose solution in the controls following conditioning, but no such tendency was evident in the amphetamine-treated mice. The present study represents the first report of amphetamine-induced disruption of the CS-PE effect (ie latent inhibition) in mice, and the first attempt to compare it directly with the US-PE effect in any species. It extended previous reports in rats and humans, suggesting that the sensitivity of latent inhibition to amphetamine is largely comparable across species, thereby lending credence to the use of the latent inhibition effect as a behavioral assay for psychotic-like phenotype in transgenic mice. The parallel observation in the US-PE effect further indicates that its expression, at least in the present conditioned taste aversion paradigm, may also be under similar influence of the dopaminergic system.

Incentive motivation theory ascribes a critical role to reward-associated stimuli in the generation and maintenance of goal-directed behavior. Repeated psychomotor stimulant treatment, in addition to producing sensitization to the psychomotor-activating effects, can enhance the incentive salience of reward-associated cues and increase their ability to influence behavior. In the present study, we sought to investigate this incentive sensitization effect further by developing a model of conditioned reinforcement (CR) in the mouse and investigating the effects of a sensitizing treatment regimen of amphetamine on CR. Furthermore, we assessed the role of contextual stimuli in amphetamine-induced potentiation of CR. We found that mice responded selectively on a lever resulting in the presentation of a cue previously associated with 30% condensed milk solution, indicating that the cue had attained rewarding properties. Prior treatment with amphetamine (4 x 0.5 mg/kg i.p.) resulted in psychomotor sensitization and enhanced subsequent responding for the CR. Furthermore, this enhancement of responding for the cue occurred independent of the drug-paired context, whereas the sensitized locomotor response was only observed when mice were tested in the same environment as that in which they had received previous amphetamine. These results demonstrate that the CR paradigm previously developed in the rat can be successfully adapted for use in the mouse, and suggest that behavioral sensitization to amphetamine increases the rewarding properties (incentive salience) of reward-paired cues, independent of the drug-paired context.

Two monkeys were trained on two-problem visuomotor associations: if the cue was a circle pattern, move a handle to the left ('go-left'), and if it was a triangle pattern, move the handle to the right ('go-right'). These two visuomotor associations were unchanged throughout all the experiments and therefore were very familiar to the monkeys. For learning of new visuomotor associations, each monkey was presented with a new set of four novel patterns in each and every daily session, two of which instructed 'go-left' response and the other two 'go-right' response. Systemically administered guanfacine, a selective alpha(2A)-adrenergic agonist, improved the monkeys' learning ability: trials and errors to the learning criterion of 90% correct decreased significantly. The monkeys showed an enhanced capability of using at least three response strategies: win-stay on 'repeat trial', change-stay and change-shift on 'change trial'. The beneficial effect could be reversed by the coadministered idaxozan, an alpha(2)-adrenergic antagonist, which had no effect when administered alone. Similar treatment with guanfacine had no beneficial effect on visual discriminative learning, a task that involves the inferotemporal cortex. The present results indicate that stimulation by guanfacine of alpha(2A)-adrenoceptors improves visuomotor associative learning, probably through actions at alpha(2A)-adrenoceptors in the prefrontal cortex.

The present study compares the effects of two alpha 2-agonists, clonidine (0.5, 2, and 5 micrograms/kg, p.o.) and guanfacine (7 and 29 micrograms/kg, p.o.) in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests. In the PAL test, clonidine 2 and guanfacine 29 micrograms/kg improved the subjects' performance. In the DMTS test, clonidine at 5 micrograms/kg delay-dependently impaired performance accuracy, and at 2 and 5 micrograms/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 micrograms/kg equally increased subjective feelings of sedation and reduced blood pressure. The results suggest that both clonidine and guanfacine facilitated PAL learning by improving "frontal strategies," but only clonidine disrupted "mneomonic processing" decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha 2A-adrenoceptor subtype may explain the different profile of action of the drugs.