Persistent spatial working memory deficits in rats following in utero RNAi of Dyx1c1.

Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague-Dawley rats. This task was chosen based on the evidence of short-term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match-to-place radial water maze task that allows the evaluation of memory for a single brief (∼4-10 seconds) swim to a new goal location each day. A 10-min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi-treated rats. Dyx1c1 RNAi-treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory.

Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior.

Organisms often make effort-related choices based upon assessments of motivational value and work requirements. Nucleus accumbens dopamine is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior. Rats with accumbens dopamine depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead they select a less-effortful type of food-seeking behavior. The ventral pallidum is a brain area that receives substantial GABAergic input from nucleus accumbens. It was hypothesized that stimulation of GABA(A) receptors in the ventral pallidum would result in behavioral effects that resemble those produced by interference with accumbens dopamine transmission. The present studies employed a concurrent choice lever pressing/chow intake procedure; with this task, interference with accumbens dopamine transmission shifts choice behavior such that lever pressing for food is decreased but chow intake is increased. In the present experiments, infusions of the GABA(A) agonist muscimol (5.0-10.0 ng) into the ventral pallidum decreased lever pressing for preferred food, but increased consumption of the less preferred chow. In contrast, ventral pallidal infusions of muscimol (10.0 ng) had no significant effect on preference for the palatable food in free-feeding choice tests. Furthermore, injections of muscimol into a control site dorsal to the ventral pallidum produced no significant effects on lever pressing and chow intake. These data indicate that stimulation of GABA receptors in ventral pallidum produces behavioral effects similar to those produced by accumbens dopamine depletions. Ventral pallidum appears to be a component of the brain circuitry regulating response allocation and effort-related choice behavior, and may act to convey information from nucleus accumbens to other parts of this circuitry. This research may have implications for understanding the brain mechanisms involved in energy-related psychiatric dysfunctions such as psychomotor retardation in depression, anergia, and apathy.

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons.

Brief bursts of fast high-frequency action potentials are a signature characteristic of CA3 and CA1 pyramidal neurons. Understanding the factors determining burst and single spiking is potentially significant for sensory representation, synaptic plasticity and epileptogenesis. A variety of models suggest distinct functional roles for burst discharge, and for specific characteristics of the burst in neural coding. However, little in vivo data demonstrate how often and under what conditions CA3 and CA1 actually exhibit burst and single spike discharges. The present study examined burst discharge and single spiking of CA3 and CA1 neurons across distinct behavioral states (awake-immobility and maze-running) in rats. In both CA3 and CA1 spike bursts accounted for less than 20% of all spike events. CA3 neurons exhibited more spikes per burst, greater spike frequency, larger amplitude spikes and more spike amplitude attenuation than CA1 neurons. A major finding of the present study is that the propensity of CA1 neurons to burst was affected by behavioral state, while the propensity of CA3 to burst was not. CA1 neurons exhibited fewer bursts during maze running compared with awake-immobility. In contrast, there were no differences in burst discharge of CA3 neurons. Neurons in both subregions exhibited smaller spike amplitude, fewer spikes per burst, longer inter-spike intervals and greater spike amplitude attenuation within a burst during awake-immobility compared with maze running. These findings demonstrate that the CA1 network is under greater behavioral state-dependent regulation than CA3. The present findings should inform both theoretic and computational models of CA3 and CA1 function.

Timing of administration mediates the memory effects of intraseptal carbachol infusion.

Medial septal neurons innervate the entire hippocampal formation. This input provides a potent regulation of hippocampal formation physiology (e.g. theta) and memory function. Medial septal neurons are rich in cholinergic receptors and thus are potential targets for the development of cognitive enhancers. Direct intraseptal infusion of cholinomimetics alters hippocampal physiology and can produce either promnestic or amnestic effects. Several variables (e.g. age of animal, integrity of septohippocampal circuits, task difficulty) may influence treatment outcome. We have previously demonstrated that intraseptal carbachol (12.5-125 ng) infusion immediately after the sample session of a delayed-non-match-to-sample radial maze paradigm produces a dose-dependent amnesia. The present study examined whether manipulating the timing of intraseptal carbachol infusion with respect to the sample session would alter the amnestic effect. A within-subjects design was used to examine the effect of intraseptal carbachol (125 ng/0.5 microl) in a delayed-non-match to sample radial maze task. During a sample session, rats retrieved rewards from six of 12 maze arms. At the test session (3 h later), only the alternate set contained reward and entries into the sample set arms constituted errors. Intraseptal carbachol was administered: 1) 30 min prior; 2) immediately prior; 3) immediately after and 4) 90 min after the sample session. Intraseptal carbachol prior to the sample had no effect on any index of accuracy. Infusion immediately after the sample, or delayed 90 min into the retention interval, produced an acute amnesia. These findings demonstrate that the timing of treatment is a critical variable in determining the memory effects of septohippocampal manipulations and that dynamic changes in cholinergic tone are important for memory.

Intraseptal infusion of oxotremorine impairs memory in a delayed-non-match-to-sample radial maze task.

The medial septal nucleus is part of the forebrain circuitry that supports memory. This nucleus is rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive-enhancing drugs. Septal neurons, primarily cholinergic and GABAergic, innervate the entire hippocampal formation and regulate hippocampal formation physiology and emergent function. Direct intraseptal drug infusions can produce amnestic or promnestic effects depending upon the type of drug administered. However, intraseptal infusion of the cholinomimetic oxotremorine has been reported to produce both promnestic and amnestic effects when administered prior to task performance. The present study examined whether post-acquisition intraseptal infusion of oxotremorine would be promnestic or amnestic in a delayed-non-match-to-sample radial maze task. In this task rats must remember information about spatial locations visited during a daily sample session and maintain that information over extended retention intervals (hours) in order to perform accurately on the daily test session. Treatments may then be administered during the retention interval. Alterations in maze performance during the test session an hour or more after treatment evidences effects on memory. In the present study, intraseptal infusion of oxotremorine (1.0-10.0 microg) produced a linear dose-related impairment of memory performance. Importantly, we also observed disrupted performance on the day after treatment. This persistent deficit was related only to memory over the retention interval and did not affect indices of short-term memory (ability to avoid repetitive or proactive errors during both the pre- and post-delay sessions). The persistent deficit contrasts with the acute amnestic effects of other intraseptally administered drugs including the cholinomimetics carbachol and tacrine. Thus, intraseptal oxotremorine produced a preferential disruption of memory consolidation as well as a persistent alteration of medial septal circuits. These findings are discussed with regards to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related decline and Alzheimer's dementia.

Hippocampus retains the periodicity of gamma stimulation in vivo.

Several behavioral state dependent oscillatory rhythms have been identified in the brain. Of these neuronal rhythms, gamma (20-70 Hz) oscillations are prominent in the activated brain and are associated with various behavioral functions ranging from sensory binding to memory. Hippocampal gamma oscillations represent a widely studied band of frequencies co-occurring with information acquisition. However, induction of specific gamma frequencies within the hippocampal neuronal network has not been satisfactorily established. Using both in vivo intracellular and extracellular recordings from anesthetized rats, we show that hippocampal CA1 pyramidal cells can discharge at frequencies determined by the preceding gamma stimulation, provided that the gamma is introduced in theta cycles, as occurs in vivo. The dynamic short-term alterations in the oscillatory discharge described in this paper may serve as a coding mechanism in cortical neuronal networks.

Physiological patterns in the hippocampo-entorhinal cortex system.

The anatomical connectivity and intrinsic properties of entorhinal cortical neurons give rise to ordered patterns of ensemble activity. How entorhinal ensembles form, interact, and accomplish emergent processes such as memory formation is not well-understood. We lack sufficient understanding of how neuronal ensembles in general can function transiently and distinctively from other neuronal ensembles. Ensemble interactions are bound, foremost, by anatomical connectivity and temporal constraints on neuronal discharge. We present an overview of the structure of neuronal interactions within the entorhinal cortex and the rest of the hippocampal formation. We wish to highlight two principle features of entorhinal-hippocampal interactions. First, large numbers of entorhinal neurons are organized into at least two distinct high-frequency population patterns: gamma (40-100 Hz) frequency volleys and ripple (140-200 Hz) frequency volleys. These patterns occur coincident with other well-defined electrophysiological patterns. Gamma frequency volleys are modulated by the theta cycle. Ripple frequency volleys occur on each sharp wave event. Second, these patterns occur dominantly in specific layers of the entorhinal cortex. Theta/gamma frequency volleys are the principle pattern observed in layers I-III, in the neurons that receive cortical inputs and project to the hippocampus. Ripple frequency volleys are the principle population pattern observed in layers V-VI, in the neurons that receive hippocampal output and project primarily to the neocortex. Further, we will highlight how these ensemble patterns organize interactions within distributed forebrain structures and support memory formation.

Operational dynamics in the hippocampal-entorhinal axis.

How do ensembles of neurons distributed across the hippocampal and entorhinal cortices effectively interact? In the awake-behaving rat, specific subpopulations of hippocampal and entorhinal neurons become entrained into two prominent fast-frequency rhythms (gamma [40-100 Hz], and 200 Hz). These fast rhythms are coupled to slower synchronizing potentials (theta and sharp wave, respectively), are correlated to macroscopic behavioral states, and to some extent are anatomically distinct. These population dynamics allow distributed populations of neurons across the hippocampal and entorhinal cortices to discharge together in time on the order of tens of milliseconds, and thus allow interconnected domains of a distributed neural network to become transiently entraining into synchronized, fast-frequency, population ensembles. We believe that these transient population dynamics allow interconnected domains to "effectively communicate" and modify their synaptic connectivity.

Gamma oscillations in the entorhinal cortex of the freely behaving rat.

Gamma frequency field oscillations (40-100 Hz) are nested within theta oscillations in the dentate-hilar and CA1-CA3 regions of the hippocampus during exploratory behaviors. These oscillations reflect synchronized synaptic potentials that entrain the discharge of neuronal populations within the approximately 10-25 msec range. Using multisite recordings in freely behaving rats, we examined gamma oscillations within the superficial layers (I-III) of the entorhinal cortex. These oscillations increased in amplitude and regularity in association with entorhinal theta waves. Gamma waves showed an amplitude minimum and reversed in phase near the perisomatic region of layer II, indicating that they represent synchronized synaptic potentials impinging on layer II-III neurons. Theta and gamma oscillations in the entorhinal cortex were coupled with theta and gamma oscillations in the dentate hilar region. The majority of layer II-III neurons discharged irregularly but were phase-related to the negative peak of the local (layer II-III) gamma field oscillation. These findings demonstrate that layer II-III neurons discharge in temporally defined gamma windows (approximately 10-25 msec) coupled to the theta cycle. This transient temporal framework, which emerges in both the entorhinal cortex and the hippocampus, may allow spatially distributed subpopulations to form temporally defined ensembles. We speculate that the theta-gamma pattern in the discharge of these neurons is essential for effective neuronal communication and synaptic plasticity in the perforant pathway.

High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat.

Population bursts of the CA3 network, which occur during eating, drinking, awake immobility, and slow-wave sleep, produce a large field excitatory postsynaptic potential throughout stratum radiatum of the CA1 field (sharp wave). The CA3 burst sets into motion a short-lived, dynamic interaction between CA1 pyramidal cells and interneurons, the product of which is a 200 Hz oscillatory field potential (ripple) and phase-related discharge of the CA1 network. Although many CA1 pyramidal neurons discharge during the time (50-100 msec) of each sharp wave, each wave of a ripple (approximately 5 msec) reflects the synchronization of more discrete subsets of CA1 neurons. When we used multi-site recordings in freely behaving rats, we observed ripples throughout the longitudinal extent (approximately 4-5 mm) of the dorsal CA1 region that were coherent for multiple cycles of each ripple. High-frequency ripples were also observed throughout the hippocampal-entorhinal output pathway that were concurrent but less coherent on a cycle-by-cycle basis. Single and multiunit neuronal activity was phase-related to local ripples throughout the hippocampal-entorhinal output pathway. Entorhinal ripples occurred 5-30 msec after the CA1 ripples and were related to the occurrence of an entorhinal sharp wave. Thus, during each hippocampal sharp wave, there is powerful synchronization among the neuronal networks that connect the hippocampus to the neocortex. We suggest that this population interaction (1) biologically constrains theoretical models of hippocampal function and dysfunction and (2) has the capacity to support an "off-line" memory consolidation process.

Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks.

Network oscillations are postulated to be instrumental for synchronizing the activity of anatomically distributed populations of neurons. Results from recent studies on the physiology of cortical interneurons suggest that through their interconnectivity, they can maintain large-scale oscillations at various frequencies (4-12 Hz, 40-100 Hz and 200 Hz). We suggest that networks of inhibitory interneurons within the forebrain impose co-ordinated oscillatory 'contexts' for the 'content' carried by networks of principal cells. These oscillating inhibitory networks may provide the precise temporal structure necessary for ensembles of neurons to perform specific functions, including sensory binding and memory formation.

Within-subject decline in delayed-non-match-to-sample radial arm maze performance in aging Sprague-Dawley rats.

A within-subject design was used to examine delayed-non-match-to-sample radial arm maze performance in aging (6-18 months) male Sprague-Dawley rats. A decrease in correct choices and an increase in retroactive errors were observed at all retention intervals at 18 months of age compared with performance at 6 or 12 months. No age by retention interval interaction was observed. Neither age nor increasing retention interval influenced proactive errors during the retention test. The observation of an age- and delay-dependent increase in retroactive errors, but not proactive errors, suggests that the deficit relates to a memory dysfunction as opposed to a generalized performance deficit.

Hippocampal theta activity following selective lesion of the septal cholinergic system.

The characteristic electroencephalographic patterns within the hippocampus are theta and sharp waves. Septal neurons are believed to play an essential role in the rhythm generation of the theta pattern. The present study examined the physiological consequences of complete and selective damage of septohippocampal cholinergic neurons on hippocampal theta activity in rats. A selective immunotoxin against nerve growth factor receptor bearing cholinergic neurons (192 immunoglobulin G-saporin), [Wiley R. G. et al. (1991) Brain Res. 562, 149-153] was infused into the medial septal area (0.11-0.42 microgram). Hippocampal electrical activity was monitored during trained wheel running, drinking and the paradoxical phase of sleep, as well as following cholinomimetic treatment. A moderate dose of toxin (0.21 microgram) eliminated the septohippocampal cholinergic projection, as evidenced by a near total absence of choline acetyltransferase-immunoreactive neurons in the medial septum and the vertical limb of the diagonal band, and by the absence of acetylcholinesterase-positive fibers in the dorsal hippocampus. In the same rats, parvalbumin immunoreactivity, a reliable marker for septohippocampal GABAergic neurons, [Freund T. F. (1989) Brain Res. 478, 375-381], remained unaltered. In addition, retrograde transport of the tracer fluorogold demonstrated that the parvalbumin cell population preserved its axonal projection to the hippocampus. Following toxin treatment, the power of hippocampal theta, but not its frequency, decreased in a dose-dependent manner. Reduction of theta power occurred between three and seven days after the toxin treatment and remained unaltered thereafter up to eight weeks. A dose which eliminated all septohippocampal cholinergic neurons (0.21 microgram) left a small but significant theta peak in the power spectra during wheel running, paradoxical phase of sleep and intraseptal infusion of carbachol (5 micrograms). Peripheral administration of physostigmine (1 mg/kg) induced only slow (1.5-2.0 Hz) rhythmic waves. No changes were observed in the gamma (50-100 Hz) band. These findings indicate that the integrity of the septohippocampal GABAergic projection is sufficient to maintain some hippocampal theta activity. We hypothesize that cholinergic neurons serve to increase the population phase-locking of septal cells and thereby regulate the magnitude of hippocampal theta.

Selective activation of deep layer (V-VI) retrohippocampal cortical neurons during hippocampal sharp waves in the behaving rat.

The coordinated activity of hippocampal neurons is reflected by macroscopic patterns, theta and sharp waves (SPW), evident in extracellular field recordings. The importance of these patterns is underscored by the ordered relation of specific neuronal populations to each pattern as well as the relation of each pattern to distinct behavioral states. During awake immobility, consummatory behavior, and slow wave sleep, CA3 and CA1 neurons participate in organized population bursts during SPW. In contrast, during theta-associated exploratory activity, the majority of principle cells are silent. Considerably less is known about the discharge properties of retrohippocampal neurons during theta, and particularly during SPW. These retrohippocampal neurons (entorhinal cortical, parasubicular, presubicular, and subicular) process and transmit information between the neocortex and the hippocampus. The present study examined the activity of these neurons in freely behaving rats during SPW (awake immobility) as well as theta (locomotion and REM sleep). A qualitative distinction between the activity of deep (V-VI) and superficial (II-III) layer retrohippocampal neurons was observed in relation to SPW as compared to theta. Deep layer retrohippocampal neurons exhibited a concurrent increase in activity during hippocampal SPW. In contrast, deep layer neurons were not modulated by the prominent theta oscillations observed throughout the hippocampus and entorhinal cortex. On the other hand, superficial layer retrohippocampal neurons were often phase-related to theta oscillations, but were surprisingly indifferent to the SPW-associated population bursting occurring within the deep layers. These findings indicate a concerted discharge of the hippocampal and retrohippocampal cortices during SPW that includes neurons within CA3, CA1, and subiculum as well as neurons in layers V-VI of the presubiculum, parasubiculum, and entorhinal cortex. Further, they suggest a temporal discontinuity in the input/output relations between the hippocampus and retrohippocampal structures. We suggest that SPW-associated population bursts in hippocampal and retrohippocampal cortices exert a powerful depolarizing effect on their postsynaptic neocortical targets and may represent a physiological mechanism for memory trace transfer from the hippocampus to the neocortex.

Opioid and GABA modulation of accumbens-evoked ventral pallidal activity.

The principle output of the nucleus accumbens innervates the ventral pallidum and rostral substantia innominata. GABA and opioid peptides are among the neurotransmitter candidates for this projection. The goal of the present experiments was to delineate further the physiology and pharmacology of the accumbens projection to the ventral pallidum. The trans-synaptic responsiveness of ventral pallidal and rostral substantia innominata neurons to electrical stimulation of the nucleus accumbens was examined concurrently with the ability of microiontophoretically applied morphine (an opioid agonist), naloxone (an opioid antagonist) and bicuculline (a GABA antagonist) to modulate evoked responses. Accumbens stimulation altered the firing rate in 60% of the 132 neurons tested. Fifty-two percent of responding neurons exhibited simple excitations or inhibitions in response to accumbens stimulation, while 48% exhibited complex response sequences with two or more evoked components. Predominant responses consisted of a short latency (< 10 ms) and short duration (10 ms) excitation (51% of responding neurons) and an inhibition with a variable, onset latency and, duration (52% of responding neurons). Evoked responses often occurred within limited areas within the ventral pallidum suggesting that activation of descending afferents can influence discrete targets within the region. A large majority (> 80%) of neurons evoked by accumbens stimulation also exhibited a current-dependent and naloxone-sensitive increase in spontaneous firing to microiontophoretically applied morphine. Morphine shortened the duration of the accumbens-evoked, short latency excitation and attenuated the magnitude of the long-latency inhibition. Evoked responses in the presence of morphine were opposite to those observed with naloxone, but similar to bicuculline. Thus, opioid receptor activation may be functionally antagonistic to GABAergic neurotransmission in the ventral pallidum. The prominence of accumbens-evoked and morphine-sensitive neurons within the ventral pallidum corroborates the density of accumbens and opioid input to this brain region, and demonstrates that opioids serve as an important influence on neuronal activity and information processing in the ventral-striatopallidal pathway.

Systemic and microiontophoretic administration of morphine differentially effect ventral pallidum/substantia innominata neuronal activity.

In vivo electrophysiological recording techniques were employed to examine responses of ventral pallidum/substantia innominata (VP/SI) neurons to systemic and local administration of morphine. Using a cumulative dosing protocol, intravenous administration (0.1-30 mg/kg i.v.) produced a suppression of firing in 82% of neurons tested. The suppression was dose-related and blocked by the opioid antagonist, naloxone. In contrast, microiontophoretic applications of morphine resulted in current-related suppression (32% of neurons tested) or excitation (26%). Concurrent application of naloxone attenuated or blocked both effects of local morphine application. It was demonstrated that acute tolerance did not develop with repeated morphine exposures following either systemic or local administration. The present findings establish the sensitivity of VP/SI neurons to morphine and provide functional relevance at the level of a single neuron for opioid peptides and their receptors in this region. As reported for most other opioid-receptive brain areas, neuronal rate suppression was the predominate response observed, and it is proposed that excitations to iontophoresed morphine reflect a disinhibitory phenomenon. The differential morphine-induced rate changes, and number of responding neurons, observed with systemic vs. iontophoretic morphine administration suggest that extra-VP/SI regions that also are opioid sensitive can subsequently direct neuronal responsiveness to opioids within the VP/SI.

Evaluations of ventral pallidal dopamine receptor activation in behaving rats.

Recent evidence justifies the inclusion of the ventral pallidum/substantia innominata (VP) into the category of dopaminoceptive brain regions. Since the VP is known to mediate both cognitive and motoric processes, the present study employed intracerebral microinjections of dopamine directly into the VP of rats to determine if the catecholamine influences these processes. Dopamine concentrations of up to 10 micrograms were ineffectual in altering performance parameters in a working memory task. However, concentrations as low as 0.01 micrograms increased locomotion in an open field. The magnitude of this response was related to the dopamine dose injected and the effect was attenuated by systemic pretreatment with the dopaminergic antagonist, flupentixol. These studies suggest that dopamine neurotransmission at the level of the VP may be important in the locomotor functions attributed to ascending dopamine systems.

Antagonism of GABAergic transmission within the septum disrupts working/episodic memory in the rat.

Male Sprague-Dawley rats, trained to perform a standard or delayed-non-match-to-sample radial arm maze task, were implanted with a single cannula aimed at the medial septal nucleus. A within-subjects design was utilized to examine the effects of intraseptal administration of the GABAergic antagonist bicuculline on performance of these tasks. Bicuculline (0-0.5 microgram/0.5 microliter) infusion produced dose-dependent impairments when administered prior to performance of a standard radial arm maze task. Post-training infusion of bicuculline (0.-0.25 microgram/0.5 microliter) also induced dose-dependent impairments in the delayed version (4 h) of the task. Further testing indicated that post-training administration of a low dose of bicuculline (0.05 microgram) in the delayed version of the task induced a deficit at a 4-h, but not a 1-h, retention interval. The latter indicates that the impairment varied as a function of bicuculline dose and increasing task difficulty (longer retention intervals). Previous observations indicated that post-training administration of the GABAergic agonist muscimol and the antagonist bicuculline could induce deficits in the performance of the delayed task. The present findings demonstrate that intraseptal bicuculline treatment can disrupt ongoing radial maze performance, as well as the maintenance and/or retrieval of memories necessary for performance of the delayed version of the task. These findings suggest that either activation or blockade of intraseptal GABA receptors is sufficient to disrupt working/episodic memory processes. The role of septum and septohippocampal pathway in working/episodic memory is discussed.

Delayed-non-match-to-sample performance in the radial arm maze: effects of dopaminergic and gabaergic agents.

Central dopaminergic transmission has been implicated in memory processes. The present experiments examined the effects of several direct acting dopaminergic agents on performance of a delayed-non-match-to-sample radial arm maze task. Preadministration of apomorphine (D1-D2 agonist; 0.25, 0.5, and 1.0 mg/kg), quinpirole (D2 agonist; 0.1 mg/kg), or SKF38393 (D1 agonist; 3 mg/kg) increased the latency of choices but did not affect any index of accuracy with a 1 h retention interval. Post-training administration of quinpirole (0.1, 0.2, 1.0, and 2.0 mg/kg), SKF38393 (0.3, 3.0, and 6.0 mg/kg), sulpiride (D2 antagonist; 3, 10, and 30 mg/kg), or SCH23390 (D1 antagonist; 0.01, 0.1, and 1.0 mg/kg) also did not affect accuracy, although quinpirole produced a dose-dependent increase in the latency of choices, assessed 10 h post-treatment. For comparison, pretraining and post-training administration of the benzodiazepine chlordiazepoxide (1, 3, 5 mg/kg) was also tested and produced dose-dependent impairments in mnemonic performance at either a 1 or 4 h retention interval. The effects of chlordiazepoxide are consistent with evidence indicating that GABAergic agents can influence memory processes. In contrast, the present findings indicate that (peripheral administration of dopaminergic agents IS) not sufficient to alter the mnemonic processes required for accurate performance of this DNMTS-RAM task.