Time-dependent deficits in delay conditioning produced by trimethyltin

Trimethylin (TMT) produces behavioral and cognitive deficits resulting, in part, from limbic system toxicity. To determine whether these effects result from learning deficits or accelerated memory loss, the present experiment examined two delay conditioning paradigms in rats previously treated with either saline or TMT. Saline-treated Long-Evans rats receiving injections of lithium after consuming saccharin-flavored water later avoided saccharin ingestion: the degree of avoidance varied inversely with the time (0.5, 3 or 6 h) separating initial saccharin availability and lithium injection. Rats treated with TMT (8 mg/kg IV, 30 days prior) showed impaired conditioning at the long but not the short or intermediate delay conditions, suggesting that the deficits were mnemonic and not associative. Similar delay-dependent deficits in rats treated with TMT were observed in a passive avoidance task that arranged one of two delays between response emission and shock delivery during training. The effects of TMT on delay conditioning were accompanied by reduced bodyweight and hippocampal pathology. In summary, TMT appears to alter the temporally dependent association of events (entering darkened compartment versus saccharin consumption) and consequences (foot shock versus lithium administration) during acquisition. Furthermore, the observed deficits in delay conditioning produced by TMT did not appear to be task specific, with similar effects determined with tests of both somatosensory and gustatory avoidance learning designed to distinguish between functional alterations due to deficits in memorial processes from those due to altered sensory, motor, or associative processes.Although the research described in this article has been supported by the United States Environmental Protection Agency (through contract 68-02-4450 to NSI — Environmental Sciences), it has not been subjected to Agency review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. A preliminary report of these data was given at the 1987 annual meeting of the Society of Toxicology, Washington, DC     

Cocaine and vigilance task performance of rats: effects of delay of reinforcement

In two experiments rats were food-reinforced for pressing one of two levers in an operant chamber, with the correct lever being indicated by the position of a briefly illuminated light. In Experiment 1 the levers were always in the chamber, whereas in Experiment 2 the levers were inserted into the chamber immediately after cue light termination and withdrawn immediately after a choice response. The rats were tested under four conditions: after an injection (SC) of saline or 2.5 mg/kg cocaine and with delay of reinforcement (DOR) of either 0 or 8 s. In both experiments, cocaine enhanced accuracy under the 0-s DOR condition. However, in neither experiment was there evidence of facilitation with cocaine under 8-s DOR, which by itself increased choice latencies and decreased accuracy when choice latencies exceeded 0.5 s. These results indicate that cocaine may only enhance performance in vigilance tasks under constrained conditions, e.g., those that require minimal levels of information processing.     

Modelling working and reference memory in rats: effects of scopolamine on delayed matching-to-position(1,2)

A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent components of spatial matching (for working memory) and nonspatial discrimination (for reference memory). On each trial in the matching component, rats received food for pressing one of two retractable levers after a delay if that lever had been presented in the prior sample phase of the trial. On each trial in the discrimination component, food was delivered if the rat pressed a lever illuminated by a cue light after the delay interval. The model was tested with scopolamine (0.10 to 0.56 mg/kg, ip), which reduced matching accuracy in a dose-related manner. Linear slope and intercept estimates of retention gradients showed that intercepts declined and slopes remained unchanged with increasing scopolamine dose. In contrast, scopolamine had no significant effect on nonspatial discrimination accuracy, indicating a relative insensitivity of reference memory to cholinergic blockade. Because the matching component involved spatial cues and the discrimination component did not, a second group of rats was trained to discriminate between the spatial locations of two levers, to compare the effects of scopolamine on spatial and nonspatial discriminations. Scopolamine at the same doses caused a small, consistent decrease in spatial discrimination accuracy, suggesting that spatial discrimination was more sensitive to disruption by scopolamine than was nonspatial discrimination. The combined delayed matching-to-position/nonspatial discrimination procedure appears to provide a useful technique for characterizing mnemonic effects of drugs and toxicants in rats.     

Neuropeptide-Y both improves and impairs delayed matching-to-sample performance in rats.

Neuropeptide-Y (NPY) was administered intracerebroventricularly to rats performing on delayed matching-to-sample (DMTS) to determine if NPY modulates short-term (working) memory. Rats administered saline demonstrated a characteristic DMTS delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 2 to 8 to 16 seconds. At 8- and 16-second delays, low doses of NPY (0.25 and 0.5 nmol/kg) increased matching accuracy. As doses increased from 1 to 16 nmol/kg, accuracy decreased in a dose- and delay-dependent manner. NPY effects were specific to working memory, since NPY did not affect accuracy of responses to the sample stimulus (reference memory). At higher doses, a greater decline in accuracy occurred when the correct stimulus was on the opposite side from the response on the previous trial compared to accuracy when the previous response was on the same side. These data show NPY may both improve and impair accuracy on DMTS and that some portion of impairment is due to proactive interference resulting from previous trials.     

Assessment of drug effects on memory by delayed discrimination responses in rats

Delayed discrimination experiments were conducted to examine drug effects on memory in rats. Three kinds of experimental situations: a Y-maze, an operant chamber with two retractable levers, and an operant chamber with two fixed levers were used. A discriminative stimulus light either on the left or the right side of a stimulus panel was presented for a brief period in each situation. After a certain delay time following extinguishment of the light, a choice response to the previously lighted side was termed as a correct choice. Scopolamine at 0.015-0.06 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0 sec in the Y-maze situation and in trials with longer delay times in the operant chamber situations. Nicotine at 0.06-1 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0-4 sec in the Y-maze situation, a delay time of 4 sec in the retractable-lever operant chamber situation, and a delay time of 0.1 sec in the fixed-lever operant chamber situation. Using this delayed discrimination procedure, drug effects on the relationship between delay time and correct choice ratio were observed. From these results, the present procedure was found to be useful for the evaluation of drug effects on memory in rats.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on temporal memory: quantitative analysis with a delayed interval bisection task

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a ‘correct’ response, reinforcer delivery. When > 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. Received: 30 April 1996 / Final version: 20 August 1996     

Cocaine and level of arousal: effects on vigilance task performance of rats

Rats were food-reinforced for pressing one of two levers in an operant chamber, with the correct lever being indicated by the position of a briefly illuminated light. After stable accuracy levels were achieved, the rats were tested after an injection of either saline or cocaine (2.5 mg/kg) under two conditions. In the "low arousal" condition, animals were tested during the light phase of a 12-hr light-dark cycle and were fed approximately 5 hr prior to testing. In the "high arousal" condition, animals were tested during the dark phase after approximately 28-hr food deprivation. As expected, accuracy was higher and median choice and food retrieval latencies were shorter under the high arousal condition. Contrary to predictions, cocaine enhanced accuracy under both conditions. These results indicate that cocaine-enhanced performance in some tasks is not necessarily dependent on the animal performing at suboptimal arousal levels.     

Rectal and brain temperatures in ethanol intoxicated mice

The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other non-specific behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.     

Effects of selection delays on radial maze performance: acquisition and effects of scopolamine

The effects of post-selection confinement (delays) on both the acquisition of performance and the response to the muscarinic blocker, scopolamine, were examined in an automated version of the eight arm radial maze. Long-Evans rats, exposed to post-selection delays of 0.5 sec (n = 4) or 100 sec (n = 4) during daily training trials did not differ in either the number of trials to acquire an accurate baseline of performance or in the amount of time required to obtain all eight food pellets. However, the pattern (delta-arm scores) of within-session arm selections demonstrated by the two groups of rats differed. Rats exposed to the 0.5-sec delay typically selected arms adjacent to arms from which they exited while rats exposed to the 100-sec delay were more likely to enter arms 2-removed from the exit arm. When scopolamine (0.03 to 1.0 mg/kg) was administered prior to testing, rats in the 100-sec delay group showed a greater reduction of accuracy and a larger increase in selection latency than rats in the 0.5-sec delay group. The differential effect of delay value on delta-arm scores was also eliminated in a dosage dependent manner with scopolamine. Scopolamine methylbromide (0.3 mg/kg) was found to have little effect on performance. In summary, the results indicate that the post-selection delay procedure is a sensitive and selective test for chemical-induced dysfunctioning of spatial memory in rats.     

The NMDA antagonist EAA 494 does not impair working memory in an operant DNMTP task in rats

There is contrasting evidence for an impairment of spatial working memory in operant delayed matching/or nonmatching to position (DMTP/DNMTP) tasks, as both delay-dependent and -independent disruption of choice accuracy has been found following N-methyl-D-aspartate (NMDA) receptor blockade. Using a within-subjects experimental design, the effect of the competitive NMDA receptor antagonist, EAA 494 (D-CPP-ene) (1, 1.5, 2 mg/kg IP 30 min prior), on working memory was investigated in male Lister Hooded rats pretrained to the DNMTP task (0-16-s delay in intervals). Metal barriers were inserted between the food magazine and levers to inhibit the use of mediating strategies, such as orientation towards the correct lever during the delay interval, because this behavior may contribute to the delay-dependent disruption noted in previous studies. It was found that EAA 494 did not modify working memory either in the presence or absence of barriers. However, a dose-dependent impairment of task performance was recorded, notably in the presence of barriers. These results indicate that competitive blockade of NMDA receptors with EAA 494 does not result in impaired working memory in rats and parallel the lack of effect of the compound upon working memory in humans. Activation of NMDA receptors does not appear to be essential for the performance of spatial tasks requiring working memory.     

Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats

The present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory-impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non-matching to position paradigm in a T-maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T-maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley-Liss, Inc.     

Effects of nicotine, oxotremorine and 9-amino 1,2,3,4- tetrahydroacridine (tacrine) on matching and non matching to position in rats: no evidence for mnemonic enhancement

Groups of rats were trained on one of two variants of an operant memory task which allows strength of memory (accuracy), bias and response rates to be measured directly. In matching to position (MTP), one of two retractable response levers appeared at random as the sample. A response caused the lever to retract and this was followed by a delay (0-64 s) interval, during which the rat had to approach, and respond at, the magazine tray. Both levers were then presented and the rat had to respond to the lever which had most recently appeared as the sample, for food reward. A second group of rats learned non-matching to position (NMTP). In this task, rats had to respond to the lever which had not appeared as the sample.The subjects were then divided into subgroups and injected, peripherally and prior to test, with one of three cholinergic drugs. These were nicotine (NIC: 0-0.3 mg/kg), oxotremorine (OXO: 0-0.3 mg/kg) and 9-amino 1,2,3,4-tetrahydroacridine (tacrine, THA: 0-3.0 mg/kg). NIC had a delay-independent disruptive effect on accuracy, but only in the non-matching version, and it did not affect rate of responding. OXO and THA had no effect on accuracy, but adversely affected response latencies and rates.The results suggest that these drugs do not affect memory mechanisms; instead, and at the doses used, certain types of bias may be induced (NIC) and general responsiveness altered (OXO and THA).     

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly forgetting curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.     

2,4-Dithiobiuret in rats: cognitive facilitation after acute injection precedes motor impairment after repeated daily injections

2,4-Dithiobiuret (DTB) is a sulfonated derivative of urea that is used as a reducing agent in chemical manufacture. Its low acute toxicity to rodents belies a peripherally mediated, delayed-onset muscle weakness which develops during repeated daily exposure. In experiment 1, a standard dose regimen of DTB (0.5 mg/kg per day IP for 5 days) was used to induce motor dysfunction as a way to dissociate peripheral and central influences on a test of cognitive and motor function in rats. Sixteen male rats were trained to perform a Delayed Matching-to-Position/Visual Discrimination (DMTP/VD) task which permits quantification of working memory (matching accuracy), reference memory (discrimination accuracy), and motor function (choice response latency and nosepoke inter-response time, IRT). The first dose of DTB significantly increased matching accuracy; during the following week, DTB reduced matching accuracy, increased choice response latency and nosepoke IRT, and reduced trial completion. Discrimination accuracy remained unaffected. Experiment 2 explored the effects of single administrations of DTB on DMTP/VD. Sixteen other trained rats were divided into two groups with equal matching accuracy. One group received DTB (0.5,1.0, and 2.0 mg/kg, IP) in separate injections at least 1 week apart; the other group received vehicle at the same times. Matching accuracy increased significantly in the treated rats and not in the controls following each dose of DTB. The magnitude of this increase was dose-dependent, and lasted from 1 to 8 weeks after each injection. Discrimination accuracy, response latency, nosepoke IRT and trial completion remained unaffected throughout the study. After DTB, matching accuracy was less easily disrupted by scopolamine (0.1–0.3 mg/kg, IP). However, DTB did not alter the rats' response to reducing the distance between the response levers, to reversal of the matching rule to a nonmatching rule, or to challenge with MK-801 (0.05–0.10 mg/kg, IP). These data indicate that acute DTB causes a long-lasting facilitation of working memory in rats in the absence of any of the indications of motor impairment which follow repeated, daily injections of the chemical.A portion of these data was presented at the annual meeting of the Society of Toxicology, Dallas, Texas, March 14 1994. The research described in this article has been reviewed by the Health Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.     

Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats

Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16 mg/kg) and the nicotinic blocker mecamylamine (10 mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.     

Dopaminergic modulation of hippocampus-dependent learning: blockade of hippocampal D1-class receptors during learning impairs 1-trial place memory at a 30-min retention delay

Consistent with the requirement of D1-class dopamine receptors for the induction of late (>3 h) hippocampal long-term potentiation (LTP), hippocampus-dependent 1-trial memory at long retention delays (>6 h) requires hippocampal D1-class receptors during learning. Hippocampal D1-class receptors also modulate the induction and magnitude of early LTP (<1-3 h). However, a corresponding modulation of the formation of hippocampus-dependent early (<1 h) memory remains to be revealed. We addressed this conceptually important issue, using a novel modification of the watermaze delayed-matching-to-place (DMP) test with an improved measure of hippocampus-dependent 1-trial place memory. On the DMP test, rats learn the novel location of a hidden escape platform on trial 1 of every day, so that 1-trial place memory can be measured on trial 2. Our new task modification includes the measurement of search preference for the correct location on trial 2 - a very sensitive index of hippocampus-dependent place memory. We examined the effects of hippocampal D1-class receptor blockade or stimulation during learning on memory at a 30-min retention delay. Bilateral hippocampal infusion of the D1-class receptor antagonist SCH23390 (1 or 5 μg/1 μl/side) before trial 1 dose-dependently impaired such early memory: rats infused with the higher dose showed reduced search preference for the correct location and took longer paths to reach this location. Infusion of the D1-class partial agonist SKF38393 (1 or 5 μg/1 μl/side) did not affect measures of 1-trial place memory. Our data reveal a behavioural correlate of the dopaminergic modulation of early LTP, thereby supporting the close correspondence between hippocampal LTP and hippocampus-dependent learning.     

Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys

ABT-594 and A-582941 are high affinity neuronal nicotinic acetylcholine receptor agonists with differential selectivity for the alpha4beta2 and the alpha7 subtypes, respectively. This study was designed to determine whether either compound, like nicotine also possesses cognitive-enhancing ability. The compounds were administered by intramuscular injection to young adult Rhesus monkeys trained to perform two versions of a computer-assisted delayed matching-to-sample (DMTS) task. ABT-594 (0.115-3.7 microg/kg) significantly improved DMTS accuracies, shifting the retention curve (accuracy-delay relationship) to the right in a parallel fashion. DMTS accuracy also was maintained during the sessions initiated 24h after compound administration. Because task accuracy was improved during short delay trials, a separate study was performed in which non-predictable distractors were inserted within the DMTS format to impair accuracy. The 0.115 microg/kg dose of ABT-594 almost completely reversed distractor-impaired performance associated with short delay trials. The alpha7 nAChR agonist, A-582941 (1.14-38 microg/kg) also significantly improved DMTS accuracies. The compound produced a significant improvement during long delay trials. The effect was twice as robust for long delay as compared with short delay trials and A-582941 was not as effective as ABT-594 in improving short delay trial accuracy. A-582941 also failed to sustain task improvement during sessions run 24h after dosing. These data are consistent with the ability of subtype-preferring nicotinic receptor agonists to enhance specific components of working memory and cognitive function, and they suggest that differential subtype selectivity could result in varied pharmacological response profiles.     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

Memory and perseveration on a win-stay, lose-shift task in rats exposed neonatally to alcohol

OBJECTIVE: It is important to understand the relationship between perseverative responding resulting from perinatal exposure to alcohol and potential underlying causes, including attention, memory, or response-inhibition problems. The present study was designed to examine the relationship between perseveration and memory. METHOD: Rats exposed neonatally to 6 g/kg/day alcohol from postnatal day (PD) 4 through PD 9 using an artificial rearing technique (n = 8) were compared with an artificially reared gastrostomy control group (n = 8) and a suckle control group (n = 8). Activity levels were assessed from PD 18-21. Beginning on PD 45, subjects were deprived of food and responded for food on a two-lever win-stay, lose-shift task in which reinforcement probability was a function of reinforcement delivery on the previous trial. If reinforcement was delivered, only a response on the same lever (stay) was reinforced. If reinforcement was not delivered, only a response on the opposite lever (shift) was reinforced. Effective responding depended on subjects remembering whether a reinforcer was delivered on the preceding trial. The intertrial interval varied across conditions (5 seconds or 60 seconds). RESULTS: Alcohol-exposed rats showed increased activity during activity testing but did not differ from controls on win-stay, lose-shift accuracy. All groups showed a performance decrease at longer intertrial intervals. Alcohol-exposed rats showed increased lever pressing during the intertrial interval compared with suckle control rats but not with gastrostomy control rats. CONCLUSIONS: Choice behavior was comparable for all groups on the win-stay, lose-shift task, indicating that memory, as assessed by this task, was not differentially affected by alcohol exposure. Alcohol-exposed rats responded more during the intertrial interval compared with suckle controls, suggesting increased activity without increased response inhibition. The win-stay, lose-shift procedure is a potentially useful tool for separating simple activity level effects, memory-related effects, and response-inhibition effects. This study also highlights the need for additional research describing the relationship between perseverative responding and underlying mechanisms.     

Impulsivity (delay discounting) for food and cocaine in male and female rats selectively bred for high and low saccharin intake

Previous research in rats indicates that delay discounting for food, a model of impulsivity, predicted the rate of acquisition of cocaine self-administration. In other studies, rats bred for high saccharin intake (HiS) acquired cocaine self-administration at higher rates than those with low saccharin intake (LoS), and female (F) rats acquired cocaine self-administration more rapidly than males (M). The purpose of this study was to examine a possible connection between impulsivity, saccharin intake, and sex by comparing M and F rats from the HiS and LoS selectively bred lines on measures of impulsivity; i.e., their rate of delay discounting for food or i.v. cocaine infusions. The adjusting delay procedure allowed rats access to 2 response levers, and a pellet dispenser or an i.v. drug infusion pump. In 4 groups (HiS M, HiS F, LoS M, LoS F) responses under a fixed-ratio (FR) 1 schedule on one lever resulted in one 45 mg pellet immediately, and responses on the other lever resulted in 3 or 6 pellets after a delay. Four additional groups received either a small cocaine (0.2, 0.4, or 0.8 mg/kg) infusion immediately or a delayed larger infusion (3x the amount of the small infusions). The delay to the larger reinforcer began at 6 s and increased or decreased by 1 s following responses on the delay or immediate levers, respectively. A mean adjusted delay (MAD) was calculated over 30 choice trials during each daily 3-hour session, and it was used as a quantitative measure of impulsivity. In groups maintained by food, HiS rats were more impulsive (lower MADs) than LoS rats, and LoS females were more impulsive than LoS males. There were no phenotype or sex differences in delay discounting for cocaine. Understanding the relationship between impulsivity and other predictors of drug abuse (e.g., sex, saccharin intake) is important in developing prevention and treatment strategies.