Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene.

While thepsychoactive inhalant toluene causes behavioral effects similarto those produced by other drugs of abuse, the persistent behavioral and anatomical abnormalities induced by toluene exposure are not well known. To mimic human "binge-like" inhalant intoxication, adolescent, male Sprague-Dawley rats were exposed to toluene vapor (5700ppm) twice daily for five consecutive days. These rats remained in their home cages until adulthood (P60), when they were trained in operant boxes to respond to a palatable food reward and then challenged with several different cognitive tasks. Rats that experienced chronic exposure to toluene plus abstinence ("CTA") showed enhanced performance in a strategy set-shifting task using a between-session, but not a within-session test design. CTA also blunted operant and classical conditioning without affecting responding during a progressive ratio task. While CTA rats displayed normal latent inhibition, previous exposure to a non-reinforced cue enhanced extinction of classically conditioned approach behavior of these animals compared to air controls. To determine whether CTA alters the structural plasticity of brain areas involved in set-shifting and appetitive behaviors, we quantified basal dendritic spine morphology in DiI-labeled pyramidal neurons in layer 5 of the medial prefrontal cortex (mPFC) and medium spiny neurons in the nucleus accumbens (NAc). There were no changes in dendritic spine density or subtype in the mPFC of CTA rats while NAc spine density was significantly increased due to an enhanced prevalence of long-thin spines. Together, these findings suggest that the persistent effects of CTA on cognition are related to learning and memory consolidation/recall, but not mPFC-dependent behavioral flexibility.

Persistent Alterations of Accumbal Cholinergic Interneurons and Cognitive Dysfunction after Adolescent Intermittent Ethanol Exposure.

Adolescent binge drinking renders young drinkers vulnerable to alcohol use disorders in adulthood; therefore, understanding alcohol-induced brain damage and associated cognitive dysfunctions is of paramount importance. Here we investigated the effects of binge-like adolescent intermittent ethanol (AIE) exposure on nonspatial working memory, behavioral flexibility and cholinergic alterations in the nucleus accumbens (NAc) in male and female rats. On postnatal days P25-57 rats were intubated with water or ethanol (at a dose of 5 g/kg) on a 2-day-on/2-day-off cycle and were then tested in adulthood on social recognition and probabilistic reversal learning tasks. During the social recognition task AIE-treated rats spent similar amounts of time interacting with familiar and novel juveniles, indicating an impaired ability to sustain memory of the familiar juvenile. During probabilistic reversal learning, AIE-treated male and female rats showed behavioral inflexibility as indicated by a higher number of trials needed to complete three reversals within a session, longer response latencies for lever selection, and for males, a higher number of errors as compared to water-treated rats. AIE exposure also reduced the number of cholinergic interneurons in the NAc in males and females. These findings indicate AIE-related pathologies of accumbal cholinergic interneurons and long lasting cognitive-behavioral deficits, which may be associated with cortico-striatal hypofunction.

Opposing roles for the nucleus accumbens core and shell in cue-induced reinstatement of food-seeking behavior.

Reinstatement of previously extinguished instrumental responding for drug-related cues has been used as an animal model for relapse of drug abuse, and is differentially affected by inactivation of the core and shell subregions of the nucleus accumbens (NAc). To compare the roles of these subregions in reinstatement induced by cues associated with natural and drug rewards, the present study assessed the effects of inactivation of the NAc core and shell on cue-induced reinstatement of food-seeking behavior. Rats acquired a lever pressing response for food reward paired with a light/tone conditioned stimulus (CS). They were then subjected to extinction, where both food and the CS were withheld. Reinstatement of responding was measured during response-contingent presentations of the CS. Following saline infusions into the NAc core or shell, rats displayed a significant increase in lever pressing during reinstatement sessions. Inactivation of the core, induced by infusion of GABA agonists muscimol and baclofen, attenuated responding for the CS, but did not affect pavlovian approach toward the food receptacle. In contrast, inactivation of the shell had the opposite effect, potentiating responding relative to vehicle treatments. These data suggest that the NAc core and shell play opposing, yet complementary roles in mediating the influence that food-associated conditioned stimuli exert over behavior. The core enables reward-related stimuli to bias the direction and vigor of instrumental responding. In contrast, the shell facilitates alterations in behavior in response to changes in the incentive value of conditioned stimuli. The fact that the NAc core appears to play a similar role in cue-induced reinstatement induced by both natural and drug rewards suggests that this region of the ventral striatum may be a final common pathway through which both drug- and food-associated stimuli may influence the direction and magnitude of ongoing behavior.

The role of different subregions of the basolateral amygdala in cue-induced reinstatement and extinction of food-seeking behavior.

Reinstatement of previously extinguished instrumental responding for drug-related cues has been used as an animal model for relapse of drug abuse, and is disrupted by inactivation of the basolateral amygdala (BLA). However, the role that the BLA plays in reinstatement induced by cues associated with natural rewards is unclear. The present study assessed the effects of inactivation of different regions of the BLA in cue-induced reinstatement of food-seeking behavior and in the extinction of instrumental responding for food. In experiment 1, rats acquired a lever pressing response for food reward paired with a light/tone conditioned stimulus (CS). They were then subjected to extinction training, where both food and the CS were withheld. Reinstatement of extinguished responding was measured during response-contingent presentations of the CS alone. Following saline infusions into the caudal or rostral BLA, rats displayed a significant increase in lever pressing during reinstatement sessions. Inactivation of these subregions with bupivacaine did not attenuate responding for the CS in the absence of food delivery. In fact, inactivation of the caudal BLA potentiated responding relative to vehicle treatments. Analysis of within-session responding revealed that caudal BLA inactivation retarded extinction of lever pressing in response to the CS. In experiment 2, inactivation of the caudal BLA on the first or second day of extinction training significantly retarded the acquisition of extinction learning on the following day. These data indicate that that the caudal BLA may play a specific role in the extinction of appetitive conditioned responses, by monitoring changes in the reinforcing value of pavlovian conditioned stimuli linked to action-outcome associations once these associations have been formed. Moreover, these findings support a growing body of evidence indicating that separate neural circuits incorporating the BLA may play different roles in mediating reinstatement of reward-seeking behaviors induced by either drug or food related stimuli.

Dopamine D1 and NMDA receptors mediate potentiation of basolateral amygdala-evoked firing of nucleus accumbens neurons.

Interactions between the basolateral amygdala (BLA) and the nucleus accumbens (NAc) mediate reward-related processes that are modulated by mesoaccumbens dopamine (DA) transmission. The present in vivo electrophysiological study assessed: (1) changes in the firing probability of submaximal BLA-evoked single neuronal firing activity in the NAc after tetanic stimulation of the BLA, and (2) the functional roles of DA and NMDA receptors in these processes. Tetanic stimulation of the BLA potentiated BLA-evoked firing activity of NAc neurons for a short duration ( approximately 25 min). This short-term potentiation was associated with an increase in DA oxidation currents that was monitored with chronoamperometry. Systemic or iontophoretic application before BLA tetanus of the D(1) receptor antagonist SCH23390, but not the D(2) receptor antagonist sulpiride, abolished the potentiation of BLA-evoked NAc activity, whereas administration of SCH23390 3 min after tetanus had no effect. However, systemic administration of the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), either before or after BLA tetanus, abolished the potentiation of BLA-evoked firing of NAc neurons. These data suggest that higher-frequency activity in BLA efferents can autoregulate their excitatory influence over neural activity of NAc neurons by facilitating the release of DA and activating both DA D(1) and NMDA receptors. This may represent a cellular mechanism that facilitates approach behaviors directed toward reward-related stimuli that are mediated by BLA-NAc circuitries.

Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: cellular mechanisms of input selection.

Inputs from multiple sites in the telencephalon, including the hippocampus and basolateral amygdala (BLA), converge on neurons in the nucleus accumbens (NAc), and dopamine (DA) is believed to play an essential role in the amplification and gating of these different limbic inputs. The present study used extracellular single-unit recordings of NAc neurons in combination with chronoamperometric sampling of mesoaccumbens DA efflux to assess the importance of DA in the integration of different limbic inputs to the NAc. Tetanic stimulation of the fimbria potentiated hippocampal-evoked firing activity of NAc neurons and increased DA extracellular levels. Systemic administration of the D(1) receptor antagonist SCH23390 or the NMDA receptor antagonist CPP abolished the potentiation of hippocampal-evoked activity and produced a D(2) receptor-mediated suppression of evoked firing. In neurons that received converging input from the hippocampus and BLA, fimbria tetanus potentiated hippocampal-evoked firing activity and suppressed BLA-evoked activity in the same neurons. Both D(1) and NMDA receptors participated in the potentiation of fimbria-evoked activity, whereas the suppression of BLA-evoked activity was blocked by either D(1) receptor antagonism with SCH23390 or the adenosine A(1) antagonist 8-cyclopentyl-1,2-dimethylxanthine. Coincidental tetanus of both the fimbria and BLA resulted in potentiation of both inputs, indicating that DA and adenosine-mediated suppression of BLA-evoked firing was activity-dependent. These data suggest that increases in mesoaccumbens DA efflux by hippocampal afferents to the NAc play a critical role in an input selection mechanism, which can ensure preferential responding to the information conveyed from the hippocampus to the ventral striatum.

Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons.

Several studies have shown that the mesolimbic dopamine (DA) system is strongly influenced by the ventral subiculum (vSub) of the hippocampus. To examine whether this occurs by activation of DA neuron firing, the effects of chemical stimulation of the vSub on ventral tegmental area (VTA) DA neuron activity were examined using extracellular single-unit recordings. Infusions of NMDA into the vSub increased the number of spontaneously firing DA cells recorded per electrode track, while having no effect on firing rate or burst firing. This response was abolished by intranucleus accumbens (NAc) infusions of the glutamate receptor antagonist kynurenic acid. This effect did not involve the prefrontal cortex, because infusions of tetrodotoxin into the prefrontal cortex did not affect the increase in spontaneously active DA cells. Infusions of either kynurenic acid into the NAc or tetrodotoxin into the vSub decreased the firing rate and burst firing of DA neurons without altering the number of spontaneously active DA neurons. These data show that glutamatergic afferents from the vSub to the NAc exert a potent excitatory effect on VTA DA neurons, influencing both DA neuron population activity and the regulation of the firing properties of these neurons. As a result, dysfunctions in hippocampal circuitries may contribute to the hyperexcitable state of the DA system that is present in schizophrenia.

Thalamic-cortical-striatal circuitry subserves working memory during delayed responding on a radial arm maze.

The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the ventral striatum form an interconnected neural circuit that may subserve certain types of working memory. The present series of experiments investigated functional interactions between these brain regions in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. In Experiment 1, transient inactivation of the MDNt by a bilateral injection of lidocaine selectively disrupted performance on a delayed task but not on a nondelayed random foraging version of the radial arm maze task. In Experiment 2, asymmetrical lidocaine injections into the MDNt on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task. Similarly, disconnections between the prefrontal cortex and the nucleus accumbens also disrupted foraging on this task, whereas disconnections between the MDNt and the nucleus accumbens had no effect. These data suggest that serial transmission of information among the MDNt, the prefrontal cortex, and the nucleus accumbens is required when trial-unique, short-term spatial memory is used to guide prospective search behavior. The results are discussed with respect to a distributed neural network linking limbic, thalamic, cortical, and striatal regions, which mediates executive functions of working memory.

Neuronal Gonadotrophin-Releasing Hormone (GnRH) and Astrocytic Gonadotrophin Inhibitory Hormone (GnIH) Immunoreactivity in the Adult Rat Hippocampus.

Gonadotrophin-releasing hormone (GnRH) and gonadotrophin inhibitory hormone (GnIH) are neuropeptides secreted by the hypothalamus that regulate reproduction. GnRH receptors are not only present in the anterior pituitary, but also are abundantly expressed in the hippocampus of rats, suggesting that GnRH regulates hippocampal function. GnIH inhibits pituitary gonadotrophin secretion and is also expressed in the hippocampus of a songbird; its role outside of the reproductive axis is not well established. In the present study, we employed immunohistochemistry to examine three forms of GnRH [mammalian GnRH-I (mGnRH-I), chicken GnRH-II (cGnRH-II) and lamprey GnRH-III (lGnRH-III)] and GnIH in the adult rat hippocampus. No mGnRH-I and cGnRH-II+ cell bodies were present in the hippocampus. Sparse mGnRH-I and cGnRH-II+ fibres were present within the CA1 and CA3 fields of the hippocampus, along the hippocampal fissure, and within the hilus of the dentate gyrus. No lGnRH-III was present in the rodent hippocampus. GnIH-immunoreactivity was present in the hippocampus in cell bodies that resembled astrocytes. Males had more GnIH+ cells in the hilus of the dentate gyrus than females. To confirm the GnIH+ cell body phenotype, we performed double-label immunofluorescence against GnIH, glial fibrillary acidic protein (GFAP) and NeuN. Immunofluorescence revealed that all GnIH+ cell bodies in the hippocampus also contained GFAP, a marker of astrocytes. Taken together, these data suggest that GnRH does not reach GnRH receptors in the rat hippocampus primarily via synaptic release. By contrast, GnIH might be synthesised locally in the rat hippocampus by astrocytes. These data shed light on the sites of action and possible functions of GnRH and GnIH outside of the hypothalamic-pituitary-gonadal axis.

Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex.

Dopamine (DA) in the medial prefrontal cortex (PFC) can modulate the short-term retention of information and other executive functions. The present study examined whether administration of a DA D1 agonist into the PFC could have differential effects on memory retrieval in circumstances in which memory was either excellent or poor. Separate groups of rats were trained on a delayed version of the radial maze task. On the test day, the delay between the phases was either 30 min or 12 hr. Infusions of the D1 receptor agonist SKF 81297 (0.05, 0.10, or 0.20 microg/0.5 microl) into the PFC before the test phase improved memory retrieval after a 12-hr delay but disrupted performance after a 30-min delay. These data suggest that D1 receptor activity can exert differential effects over PFC function, depending on the strength of the memory trace. When memory is decremented by an extended delay, activation of PFC DA D1 receptors by an agonist can improve cognitive function.

Functional differences between the prelimbic and anterior cingulate regions of the rat prefrontal cortex.

The effects of reversible lidocaine-induced lesions of 2 subregions of the rat medial prefrontal cortex (mPFC) were examined on a series of cognitively based foraging behaviors on a radial-arm maze. Lesions of the prelimbic (PL) or anterior cingulate (AC) cortex prior to the retention phase of a delayed-foraging task disrupted performance differentially; rats with PL lesions visited arms in a random manner, whereas rats with AC lesions revisited previously baited arms preferentially. Rats with AC lesions were also impaired on a single-trial foraging task; they made numerous revisits to previously baited arms. PL lesions had no effect on performance of this task in well-trained rats. However, rats trained on the 2-phase task did not adapt to a new foraging strategy after a PL lesions, when they were switched unexpectedly to the single-trial foraging task. These data demonstrate functional heterogeneity within the rat mPFC and suggest that the PL is involved in processes through which recently acquired information is used to organize and modify foraging behavior, whereas the AC may play an important role in response flexibility.

Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats.

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.

Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: role of ionotropic glutamate and dopamine D1 receptors.

RATIONALE AND OBJECTIVES: The role of glutamatergic afferents from the hippocampus in the modulation of dopamine (DA) efflux in the nucleus accumbens (NAcc) and concomitant increases in locomotor activity was examined following brief high-frequency electrical stimulation of the ventral subiculum (vSub). Reverse dialysis of ionotropic glutamate receptor (iGluR) antagonists into the NAcc identified the relative contributions of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the modulation of DA efflux, whereas microinjection of these compounds or selective DA D1 or D2 receptor antagonists were used to analyze the roles of glutamatergic and DA receptors in the stimulation-induced hyperlocomotion. METHODS AND RESULTS: Electrical stimulation of the vSub at 20 Hz (10 s, 300 microA) induced a significant increase in (1) DA levels in the NAcc (approximately 30% from pre-stimulation DA levels) and (2) locomotor activity (approximately 400%). The evoked DA release was completely blocked by reverse dialysis of a selective non-NMDA antagonist DNQX (10 microM and 100 microM), whereas only a high dose of the NMDA antagonist AP-V (100 microM) was effective. The increased motor activity, however, was only slightly attenuated by reverse dialysis of these drugs. Bilateral intra-NAcc injection of DNQX (1 microg/0.5 microl) blocked the increased motor activity induced by vSub stimulation relative to saline treatment. In contrast, bilateral intra-NAcc injection of AP-V (1 microg/0.5 microl) alone caused a significant increase in locomotor activity. The increased motor activity induced by vSub stimulation appears to be mediated through the DA D1 receptor, as systemic administration of the D1 antagonist SCH 23390 (0.25 mg/kg and 1 mg/kg), but not the D2 antagonist sulpiride (2 mg/kg and 10 mg/kg) blocked these effects. CONCLUSIONS: These data indicate an important role for hippocampal glutamatergic afferents in modulating the release of DA through iGluR on DA-receptive neurons in the NAcc and possibly on output neurons to the ventral tegmental area, which subsequently elicits a prolonged increase in locomotor behavior. The role of this circuit in mediating context-dependent behavioral sensitization to repeated administration of psychostimulants is discussed.

Reversible lesions of the rhinal cortex produce delayed non-matching-to-sample deficits in rats.

Rats with cannulae guides implanted in the rhinal cortex were tested on a delayed non-matching-to-sample task, following either lidocaine or sham microinfusions. Bilateral lidocaine microinfusions to the rhinal cortex produced significant delayed non-matching-to-sample deficits. These results are consistent with the putative role of the rhinal cortex in object recognition but because the deficits were not shown to be time dependent, non-mnemonic interpretations cannot be ruled out. These results also illustrate the utility of reversible lidocaine lesions in the study of the neuroanatomical basis of delayed non-matching-to-sample.

A selective role for dopamine in the nucleus accumbens of the rat in random foraging but not delayed spatial win-shift-based foraging.

The role of mesoaccumbens dopamine (DA) in radial-arm maze foraging is assessed by infusing low doses of the DA antagonist haloperidol into the nucleus accumbens (N.Acc.). Infusions of haloperidol (0, 125, 250 or 500 ng/0.5 microliter) into the N.Acc. of well-trained rats dose-dependently increase the number of re-entries to arms (errors) during the random foraging task, in which 4 arms on an 8-arm maze are baited randomly. However, in a separate group of animals, similar infusions produce no impairment when delivered prior to the test phase of the delayed spatial win-shift task, which require the animal to acquire information during a training phase, and to use that information 30 min later, during a test phase. These results suggest that DA neurotransmission in the N.Acc. is crucial for foraging behavior when there is ambiguity about the location of reward in a spatial environment, but is not needed for efficient foraging behavior when an animal has previous information as to the location of rewarding stimuli. The results are discussed with respect to of the underlying physiological interactions between limbic glutamate and mesoaccumbens DA transmission in the N.Acc.

Differential effects of lidocaine infusions into the ventral CA1/subiculum or the nucleus accumbens on the acquisition and retention of spatial information.

Reversible, lidocaine-induced lesions of the CA1/subicular subfield of the ventral hippocampus or the shell region of the nucleus accumbens (N.Acc.) were used to assess the roles of these structure during the acquisition and retention of a spatial response as measured by the Morris water-maze task. Acquisition and retention tests were administered over 2 phases of 6 trials, respectively. Rats receiving reversible lesions of the ventral CA1/subiculum prior to the acquisition phase of this task required significantly longer path lengths to find a hidden platform than animals which received control infusions of artificial cerebrospinal fluid. Rats with similar lesions to the N.Acc. were unimpaired. During the retention phase, 30 min after the acquisition phase, rats with prior ventral CA1/subiculum or N.Acc. lesions had similar path lengths to control animals. Lidocaine infusions into either the ventral CA1/subiculum or N.Acc. prior to the retention phase did not impair performance relative to control animals. These results suggest that the N.Acc. is not involved in either the acquisition or retention of spatial information. In contrast, the ventral CA1/subiculum does appear to be involved in the initial use of novel spatial information necessary for the performance of a spatially mediated escape response, but is not involved in the retention or retrieval of previously acquired spatial information.

High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory.

The present study investigated the effects of high levels of estradiol in female rats on four different radial arm maze tasks: the hippocampus-dependent spatial working-reference memory task; the prefrontal cortex-hippocampus dependent delayed win-shift task; the striatum-dependent cued win-stay task; and the amygdala-dependent conditioned place preference task. Ovariectomized female rats were injected daily with either 10 microg of estradiol benzoate or sesame oil vehicle approximately 4 h prior to testing. In Experiment 1, treatment with estradiol disrupted learning on the spatial working-reference memory task by increasing the number of reference memory errors to reach criterion. In Experiment 2, treatment with estradiol had no significant effect on the delayed win-shift task. In Experiment 3, treatment with estradiol resulted in impaired performance on a striatum-dependent cued win-stay task. In Experiment 4, treatment with estradiol impaired the acquisition of a conditioned place-preference task. Taken together these findings suggest that high levels of estradiol inhibit reference memory, stimulus response learning, and amygdala-dependent appetitive conditioning while having little effect on working memory.

Acute stress impairs set-shifting but not reversal learning.

The ability to update and modify previously learned behavioral responses in a changing environment is essential for successful utilization of promising opportunities and for coping with adverse events. Valid models of cognitive flexibility that contribute to behavioral flexibility include set-shifting and reversal learning. One immediate effect of acute stress is the selective impairment of performance on higher-order cognitive control tasks mediated by the medial prefrontal cortex (mPFC) but not the hippocampus. Previous studies show that the mPFC is required for set-shifting but not for reversal learning, therefore the aim of the present experiment is to assess whether exposure to acute stress (15 min of mild tail-pinch stress) given immediately before testing on either a set-shifting or reversal learning tasks would impair performance selectively on the set-shifting task. An automated operant chamber-based task, confirmed that exposure to acute stress significantly disrupts set-shifting but has no effect on reversal learning. Rats exposed to an acute stressor require significantly more trials to reach criterion and make significantly more perseverative errors. Thus, these data reveal that an immediate effect of acute stress is to impair mPFC-dependent cognition selectively by disrupting the ability to inhibit the use of a previously relevant cognitive strategy.

D1 receptor modulation of hippocampal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat.

Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D1 and D2 receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D1 antagonist SCH-23390 (0.05, 0.5, or 5 microg/µl), but not the D2 antagonist sulpiride (0.05, 0.5, or 5 microg/microl), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D1 receptors in modulating activity in hippocampal-PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 receptor activation in the PFC and D1 receptor modulation of hippocampal inputs to the PFC. These data suggest that D1 receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA modulation of limbic-PFC circuits during behavior.