Involvement of the sigma receptor in passive-avoidance learning in the day-old chick during the second wave of neuronal activity

The specific sigma-receptor agonist (+)-SKF 10047 and antagonist BD 1047 were used to investigate whether this receptor was involved in passive-avoidance training in the day-old chick. We found 300 microM (+)-SKF 10047 to be amnesic when injected into the lobus parolfactorius 5 h after training (p < .01). Higher or lower concentrations of (+)-SKF 10047 did not disrupt memory formation. The amnesia produced by the efficacious dose of (+)-SKF 10047 was reversed by the specific antagonist, BD 1047. It is suggested that the sigma-receptor may exert its effect on passive-avoidance memory consolidation during the later stages of long-term memory formation by modulation of memory-related neurotransmission.     

Involvement of the σ Receptor inPassive-Avoidance Learning in the Day-Old Chick during the Second Wave of Neuronal Activity

The specific σ-receptor agonist (+)-SKF 10047 and antagonist BD 1047 were used to investigate whether this receptor was involved in passive-avoidance training in the day-old chick. We found 300 μM (+)-SKF 10047 to be amnesic when injected into the lobus parolfactorius 5 h after training (p < .01). Higher or lower concentrations of (+)-SKF 10047 did not disrupt memory formation. The amnesia produced by the efficacious dose of (+)-SKF 10047 was reversed by the specific antagonist, BD 1047. It is suggested that the σ-receptor may exert its effect on passive-avoidance memory consolidation during the later stages of long-term memory formation by modulation of memory-related neurotransmission.     

Inhibition of passive-avoidance memory formation in the day-old chick by the opioid cytochrophin-4

Cytochrophin-4 (cyt-4), a tetrapeptide with opioid-like activity, caused amnesia when injected into chick forebrain 5 hr after passive-avoidance training. Bilateral injections of cyt-4 directly into the lobus parolfactorius (LPO) resulted in the chicks being amnesic for the training task 24 hr later, whereas unilateral injections of cyt-4 were effective only when injected into the right LPO. Cyt-4-induced amnesia was reversed by the general opioid antagonist, naloxone, indicating that cyt-4 was acting via an opioid receptor. The mu- and delta-opioid receptors (but not kappa-opioid or ORL(1)-receptors) have been shown to be involved in memory formation 5 hr after training (). Because an antagonist of the mu-opioid receptor inhibited memory, we attempted to reverse the effect of cyt-4 using mu-opioid receptor agonists. Met[enk] was unable to reverse the inhibition of memory formation by cyt-4 suggesting that the mu-opioid receptor is not involved in this effect. However endomorphin-2 (endo-2) reversed the effect of cyt-4. We further investigated the action of endo-2 using an irreversible antagonist of the mu-receptor, beta-funaltrexamine (beta-FAN), and found that endo-2 reversed beta-FAN-induced amnesia indicating that endo-2 was not acting on the mu-opioid receptor in the chick. Because unilateral injections of beta-FAN were not amnesic (bilateral injections were amnesic) this provided further evidence that the effect of cyt-4 was not mediated via the mu-opioid receptor. Coinjection of the delta-receptor agonist, (D-Pen(2), L-Pen(5))enkephalin (DPLPE), reversed the disruptive effect of cyt-4 on memory. However, memory modulation via the delta-opioid receptor was not lateralized to the right hemisphere suggesting that cyt-4 does not act via this receptor either. It was shown that an antagonist of the epsilon-opioid receptor inhibited memory at the 5 hr time point. We conclude that the epsilon-opioid receptor or an unidentified opioid receptor subtype could be involved in the action of cyt-4.     

Inhibition of Intermediate-Term Memory Following Passive Avoidance Training in Neonate Chicks by a Presynaptic Cholinergic Blocker

The effects of a specific presynaptic cholinergic antagonist, toosendanin, on memory formation following a passive avoidance training experience in day-old chicks was investigated. Bilateral injection of toosendanin into the neostriatal/hyperstriatal region of the chick forebrain produced memory impairment in a dose-dependent manner. Retention deficits were apparent from 20 min following training in chicks treated with toosendanin, regardless of the injection time relative to training. Chicks that received injections of the drug at corresponding times prior to retention tests showed normal retention levels, suggesting that toosendanin has no effect on performance and memory retrieval. These results indicate an involvement of cholinergic transmission during an early stage of memory formation.     

Passive avoidance training results in lasting changes in deoxyglucose metabolism in left hemisphere regions of chick brain

Day-old chicks peck when offered a bright bead; if the bead is coated with the bitter-tasting methylanthranilate (M) they avoid it thereafter. 2-[14C] Deoxyglucose injected 1 min prior to training shows increased uptake into the hyperstriatum ventrale (HV) and lobus parolfactorius (LPO) 30 min later compared with control birds which have pecked a water-coated bead (W). To distinguish effects of training from those of consolidation, and to study lateralization of the increased uptake, 2-[14C]deoxyglucose (4 muCi) was injected ip either 5 min before, or 10 or 30 min after training. Thirty minutes after injection, bilateral samples of medial hyperstriatum ventrale (MHV), LPO and palaeostriatum augmentatum (PA)-enriched regions were dissected. Specific radioactivity (dmp/mg X prot) in left and right MHV and left and right LPO was standardized on the mean PA-specific radioactivity for each bird. When 2-DG was injected 5 min prior to training, standardized radioactivity in the left LPO was 26% greater, and in the left MHV 13% greater in M than W birds. There were no differences in the right hemisphere. With injection 10 min after training, there was an increase of 22% in the left LPO of M birds over W, of 29% in the left MHV and 22% in the right MHV. If injection was delayed to 30 min after training, there was no increase in the LPO, but a 13% increase persisted in the left MHV. Enhanced 2DG metabolism following passive avoidance training is thus persistent, lateralized, and, in the MHV at least may represent an aspect of cellular reorganization consequent on experience but independent of the immediate concomitants of training--perhaps part of the process of memory consolidation.     

Inhibition of monoADP-ribosylation prevents long-term memory consolidation of a single-trial passive avoidance task in the day-old chick

The cytosolic posttranslational protein-modifying mechanism of monoADP-ribosylation has been implicated in long-term potentiation, a synaptic model of memory formation. The current study investigated the effect of inhibiting mono(ADP-ribosyl) transferase on memory for the passive avoidance task in day-old chicks (white Leghorn-black Australorp). Various doses of novobiocin or menadione sodium bisulfite were administered intracranially at different times before or after training. Control chicks were administered saline at matched times. Novobiocin (650 microM) or menadione sodium bisulfite (250 microM) administered between 5.0 min pretraining and 2.5 min posttraining was found to cause a persistent loss of retention from 120 min posttraining. These data provide the first demonstration that monoADP-ribosylation is required for the maintenance of long-term memory. Furthermore, the temporal characteristics of the memory loss caused by monoADP-ribosylation inhibition appears to exclude this mechanism as a downstream effect of the well-established nitric oxide activity previously shown to occur within 40 min of passive avoidance training.     

Memantine ameliorates scopolamine-induced amnesia in chicks trained on taste-avoidance learning

In day-old chicks trained on the one-trial taste-avoidance task, activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. In addition, acetylcholine receptor activation has been shown to be a necessary component of memory formation for this task because injection of scopolamine produces amnesia. Memantine, a non-competitive NMDA receptor antagonist, improves memory formation under certain impairing circumstances, despite inhibiting the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can ameliorate scopolamine-induced amnesia in day-old chicks (Gallus gallus domesticus) trained on the one-trial taste-avoidance task. Three experiments assessed the effects of scopolamine, memantine, and glutamate in this task. The results of Experiment 1 demonstrated that 50.0 mM scopolamine produces significant amnesia. In Experiment 2, 1.0 mM memantine reversed the scopolamine-induced amnesia, while other doses were ineffective. In Experiment 3, injection of 50.0 mM glutamate in combination with scopolamine reversed the memantine amelioration. These results indicate a relationship between glutamate and acetylcholine in memory formation in the day-old chick.     

Passive avoidance learning produces focal elevation of bursting activity in the chick brain: amnesia abolishes the increase

Presentation of a bright bead to day-old chicks (Gallus domesticus: Ross 1 Chunky Chicks) elicits spontaneous pecking. If the bead is coated with an aversive substance (e.g., methylanthranilate), they will avoid similar beads subsequently; if it is coated with water, they peck avidly on re-presentation. Formation of a memory for this one-trial passive avoidance task is unaffected by subconvulsive transcranial electroshock when applied 10 min after training in 60% of birds, whereas "immediate" post-training electroshock renders 63% of chicks amnesic. Memory formation and retention is associated with a large bilateral enhancement in trained over control chicks (320 and 350% in left and right hemispheres, respectively; p less than 0.001) of a particular spontaneous multi-unit activity firing pattern, that is, short-duration (15-40 ms) bursts of large-amplitude (greater than or equal to 200 microV, 450 microV max p-p), high-frequency (400-450 Hz) spiking in anesthetized chicks. This effect is observed in data lumped from 1-13 h after training and is restricted to the intermediate medial hyperstriatum ventrale. When chicks are rendered amnesic by electroshock immediately following training, there is a complete abolition of this increase in burst firing; in those chicks where this treatment fails to elicit amnesia, the increase in bursting is still observed. In birds in which the shock is delayed and memory formation occurs, the increase in bursting activity is maintained; however, if the delayed shock produces apparent amnesia, then the increase is once again abolished. The electroshock had no effect on bursting per se in untrained chicks. There was no significant difference in tonic spiking between the chicks. A marked increase in the occurrence of bursting epochs in the IMHV of anesthetized chicks following passive avoidance training is therefore closely associated with memory formation, but not with the nonspecific concomitants of the training procedure.     

Expression of Fos and Jun Proteins Following Passive Avoidance Training in the Day-Old Chick

It has been shown previously that the immediate-early genes, c-fos and c-jun mRNA are induced in the 1-day-old chick forebrain after one-trial passive avoidance training in which chicks learn to avoid pecking at a bitter-tasting bead. Here, we have studied the expression of their proteins using antibodies to Fos and Jun. Western blotting disclosed two immunoreactive bands for the anti-Fos antibody (47 and 54 kD) and two immunoreactive bands for the anti-Jun antibody (39 and 54 kD). Two hours post-training there was an increase in the number of Fos-positive stained nuclei in right intermediate medial hyperstriatum ventrale (IMHV) (P<0.01), left IMHV (P<0.05), right lobus parolfactorius (LPO) (P<0.025) and left LPO (P<0.05) of birds trained on the bitter bead compared with controls that had pecked a water-coated bead. Staining for Jun protein was significantly greater in the right LPO of trained chicks (P<0.01). Other forebrain regions showed no increase over quiet control levels. The findings are discussed in the context of the cascade of events involved in passive avoidance memory consolidation in the day-old chick.     

Memantine facilitates memory consolidation and reconsolidation in the day-old chick

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been approved for the treatment of the cognitive deficits noted in Alzheimer's disease. While there is a body of research that supports memantine's facilitative action upon memory compromise, this series of studies aimed to investigate the effects of this drug in healthy animals with intact memory functioning. A 0.1 mM dose of memantine injected immediately after a weakly aversive training event (i.e. 20% v/v methyl anthranilate) was found to enhance passive avoidance learning for this event in day-old chicks up to 24 h following training. The same dose of memantine was also observed to enhance memory for the training event when it was administered in conjunction with a reminder trial. These results suggest that memantine is capable of facilitating both memory consolidation as well as memory reconsolidation. It was concluded that memantine's mechanism may involve the short-term or intermediate memory phases of the Gibbs and Ng model of memory, and that the current findings represent enhancement of intact memory, rather than amelioration of memory compromise.     

The effects of the dopamine D1 receptor antagonist SCH23390 on memory reconsolidation following reminder-activated retrieval in day-old chicks

This series of experiments examined the involvement of the dopamine D1 receptor antagonist, SCH23390, on memory reconsolidation following reminder-activated retrieval. Day-old male New HampshirexWhite Leghorn chicks were trained on a single trial passive avoidance task. A dose of 0.5 mg/kg of SCH23390 was administered subcutaneously 5 min before reminder trials, which were presented at 30, 60, and 90 min following training. Memory deficits were observed when reminder trials were presented at 30 and 60 min following training, but not when a reminder was presented at 90 min. No effect on memory retention was observed when reminder trials were not presented, suggesting that reconsolidation mechanisms were both contingent on the presentation of the reminder and independent of the consolidation process. Following a reminder presented at 60 min post-training, deficits in memory retention emerged between 45 and 60 min. The deficit was prolonged, lasting for up until 48 h after reminder presentation. The results indicate an important role for the D1 receptor in reconsolidation processes.     

Glucocorticoid-induced impairment of long-term memory retrieval in rats: an interaction with dopamine D2 receptors

This study investigated glucocorticoid-dopaminergic interactions in modulating retrieval of long-term memory in an inhibitory avoidance task. Young adult male rats were trained in one trial inhibitory avoidance task (0.5 mA, 3 s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment of the apparatus was recorded. Systemically administered corticosterone (1 or 3 mg/kg) given to rats 30 min before retention testing impaired their memory retrieval, but the lower dose was more effective than the higher one. Administration of the dopamine (DA) D2 receptor antagonist sulpiride (6 or 20 mg/kg) 30 min before corticosterone attenuated the impairing effects of corticosterone (1 mg/kg) on memory retrieval. Administration of the DA D1 receptor antagonist SCH23390 (25 or 50 microg/kg) had no effect on corticosterone-induced impairment of memory retrieval. Further, applied doses of sulpiride or SCH23390 alone were ineffective in modulating memory retrieval. These findings provide evidence for the existence of an interaction between glucocorticoids and DA D2 receptor on memory retrieval process.     

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.     

Amino acid release from the intermediate medial hyperstriatum ventrale (IMHV) of day-old chicks following a one-trial passive avoidance task

Indirect evidence has implicated glutamate and gamma-amino butyric acid in memory formation for one-trial passive avoidance learning. We have further examined this by following the time course of glutamate and gamma-amino butyric acid release from slices prepared from the intermediate medial hyperstriatum ventrale of day-old chicks (Ross 1 Chunky) trained to avoid a bead covered in the aversant methylanthranilate. At various times after training, slices of left and right intermediate medial hyperstriatum ventrale were incubated in medium containing 50 mM potassium chloride and amino acid release was determined. Thirty minutes after training there was a bilateral increase in calcium-dependent glutamate release in slices from methylanthranilate-trained chicks compared to those trained to peck water. This increase was sustained until 1 h in the left hyperstriatum when an increase in calcium-dependent gamma-amino butyric acid release was also apparent. Glutamate uptake was also enhanced in left hyperstriatum (30 and 60 min) and in the right at 30 min. In the right intermediate medial hyperstriatum ventrale of methylanthranilate birds glutamate release was increased from 3 to 6.5 h and gamma-amino butyric acid at 6.5 h: a time that corresponded to the mobilization of a late process required if long-term memory was to be formed. These results confirm that the amino acids glutamate and gamma-amino butyric acid are released from the intermediate hyperstriatum ventrale in a calcium-dependent, neurotransmitter-like manner. Furthermore, changes in the release of these two amino acids accompany memory formation for a one-trial learning task in the day-old chick.     

Amnesia induced by 2-deoxygalactose in the day-old chick: lateralization of effects in two different one-trial learning tasks

2-Deoxy-D-galactose, an inhibitor of brain glycoprotein fucosylation, was injected intracranially (10 mumole dose in 10 microliters) into either the left or the right forebrain hemisphere of day-old chicks (Gallus domesticus). Bilateral injection of this dose of 2-deoxy-D-galactose is known to induce amnesia for several learning tasks including one-trial passive avoidance and sickness-induced learning. When a tritiated form of the drug was injected into one forebrain hemisphere only, a significantly large proportion of the dose remained in that hemisphere. Chicks were trained in two different one-trial learning tasks. The first was a passive avoidance task in which the chicks were allowed to peck at a green training stimulus (a small light-emitting diode, LED) coated in the bitter liquid, methylanthranilate, giving rise to a strong disgust response and consequent avoidance of the green stimulus. In the second paradigm the chicks were allowed to peck at a similarly colored dry stimulus but, 30 min later, were injected intraperitoneally with lithium chloride (0.1 ml of 1 M solution), causing a sickness-induced aversion for the green LED. 2-Deoxy-D-galactose caused amnesia for the passive avoidance task when injected before training into the right hemisphere but not the left. However, unilateral injection of the drug before training on the sickness-induced learning task did not cause amnesia. The results indicate that fucosylation of brain glycoproteins is required in the right hemisphere for learning the passive avoidance task but that memory for sickness-induced learning can be retained by either hemisphere.     

The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning

The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((−)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.     

Sequence-Specific Impairment of Memory Formation by NCAM Antisense Oligonucleotides

The functional role of NCAM gene expression in memory formation was studied in the one-trial passive avoidance task in day-old chicks by pretraining injections of one of three different 18-mer end-protected oligonucleotides corresponding to positions 190-, 207-, and 332- of the NCAM Ig1 domain. Twenty-four-hour-old chicks were trained by pecking at a bitter-tasting bead and tested for avoidance 30 min, 3, 8, or 24 hr later. Memory retention was significantly reduced only in the group of animals injected with the NCAM antisense corresponding to position 207- (AS-ODN-207), and only if given twice, both immediately after hatching and 12 hr before training. This antisense was without effect on the general behavior of the chicks, training or acquisition, and did not produce observable neurotoxic damage. Under such conditions amnesia was evident by 3 hr after training and lasted until at least 24 hr after training. The two other tested oligonucleotides were without behavioral effect. To control for nonsequence-specific effects of AS-ODN-207, brains from injected and trained animals were processed for Western blotting and probed using anti-NCAM, anti-L1, and anti-actin antibodies. NCAM antisense corresponding to position 207- significantly reduced the level of NCAM, whereas the level of L1 and actin remained unchanged. These results confirm our earlier conclusion that NCAM is necessary for longer term memory retention.     

Involvement of Glutamate Receptors, Protein Kinases, and Protein Synthesis in Memory for Visual Discrimination in the Young Chick

Two-day-old chicks were trained to discriminate between edible chick crumbs and arrays of colored beads glued to the floor of their cage. Normal chicks learned this task within a few minutes and retained it for at least 24 h. The role of several biochemical systems known to be required for other forms of early learning in the chick was explored in this task. Antagonists and inhibitors of these systems were used in the doses known to produce amnesia in a related passive avoidance learning model. Drugs were injected intracerebrally just before training, and retention was tested at various times subsequently. The protein synthesis inhibitor anisomycin (240 nmol/chick) was without effect on retention at 30 min posttraining, but chicks were amnestic at 3 and 24 h. The protein kinases inhibitors melittin (1.2 nmol/chick) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine hydrochloride (100 nmol/chick) were without effect on retention at 30 min posttraining but were amnestic by 3 h. While these effects are similar to those found for one-trial passive avoidance training, neither theN-methyl-D-aspartate receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine maleate (up to 15 nmol/chick) orDL-2-amino-5-phosphonovalerate (1.3 nmol/chick), both of which are amnestic for passive avoidance, nor the non-NMDA-glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3,-dione (4 nmol/chick) were amnestic for the visual discrimination task. By contrast, the metabotropic glutamate receptor blocker (RS)-α-methyl-4-carboxyphenylglycine (300 nmol/chick) injected 5 min pretraining resulted in amnesia at 3 h posttraining. The implications of these findings for the putative “memory consolidation cascade” are discussed.     

Microinjections of the dopamine D2 receptor antagonist sulpiride into the medial prefrontal cortex attenuate glucocorticoid-induced impairment of long-term memory retrieval in rats

We recently reported that blockade of dopamine (DA) D2 receptors attenuated deficits in long-term memory retrieval induced by a systemic injection of corticosterone, but the anatomical sites of such interaction were not known. In this study, we investigated whether the DA D2 receptors located in the medial prefrontal cortex (mPFC) may play a role in the impairing effects of glucocorticoids on the memory retrieval process. Young adult male rats were trained in a one trial inhibitory avoidance task (0.5 mA, 3s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment and the time spent in light compartment of the apparatus were recorded. Systemically administered corticosterone (1mg/kg) given to rats 30 min before retention testing impaired their memory retrieval. Bilateral microinjections of the DA D2 receptor antagonist sulpiride (10 or 100 ng/0.5 microl per side) into the mPFC 30 min before corticosterone administration attenuated the glucocorticoid-induced impairment of memory retrieval. Furthermore, applied doses of sulpiride alone were ineffective in modulating memory retrieval. These findings indicate that D2 receptors located in the mPFC play an important role in mediating the impairing effects of glucocorticoids on memory retrieval.     

Scopolamine interactions with D1 and D2 antagonists on radial-arm maze performance in rats

Recent evidence indicates that acetylcholine and dopamine play complementary roles in cognitive as well as motor functions. In our previous study, the dopamine receptor blocker, haloperidol, was found to attenuate the radial-arm maze choice accuracy deficit caused by the muscarinic acetylcholine receptor blocker, scopolamine. Haloperidol has activity in blocking both D1 and D2 dopamine receptor subtypes. The current study was conducted to determine whether this dopamine-acetylcholine interaction specifically involved D1 or D2 dopamine receptors. The D1 antagonist, SCH 23390, and the D2 antagonist, raclopride, were administered with a dose of scopolamine which caused choice accuracy deficits in the radial-arm maze. The scopolamine-induced deficit was reversed by SCH 23390, the D1 antagonist, indicating that D1 blockade alone is sufficient to reverse the amnestic effects of muscarinic blockade. There was no indication in this study that the D2 blocker, raclopride, had a similar effect. However, this does not mean that such an effect may not be present at other doses of raclopride or with other D2 antagonists. The present finding that D1 blockade counteracts scopolamine-induced cognitive dysfunction not only furthers the understanding of dopamine-acetylcholine relationships in cognitive function, it also suggests a promising direction for the development of treatments for cognitive dysfunction due to cholinergic loss.