Place DMTS water-escape with direct placement or response information runs.

A two-choice, spatial delayed matching-to-sample (DMTS) water-escape task has proved to be a valuable of assay of trial-dependent memory. The task involves giving rats trials consisting of a forced-choice information run and a free-choice test run that are separated by a 5-m retention interval. Two experiments were conducted to determine the importance of making a complete response (R), partial response (P), or no response (NR; direct placement on escape platform) during the information "run" on acquisition and the subsequent performance of the task. Most of the naive, male, Sprague-Dawley rats were capable of attaining a 90% correct choice criterion when trained with P or NR information runs, but rats trained with R information runs required fewer trials to attain criterion and had shorter escape latencies during the criterion trials. Rats in all three groups showed significant retention at retention intervals as long as 1 h. Rats overtrained on the task with R information runs were subsequently able to perform the task at above chance level, regardless of the type information run given on the trial, but performed more accurately on trials where they made P or R information runs. Thus, rats use and perform better on place DMTS when allocentric environmental and egocentric response-associated cues are both available.

Effects of pregnancy and progesterone on the consumption of ethanol by the high ethanol preferring (HEP) rat.

A significant fraction of women continue to drink heavily during pregnancy, which is associated with the fetal alcohol syndrome, alcohol-related birth defects, alcohol-related neurodevelopmental disorder, and spontaneous abortion. The objective of this study was to determine whether the selectively bred genetic drinking Myers High Ethanol Preferring (HEP) rat would continue to drink through pregnancy. Rats from the F7 generation were screened by a 10-day 3-30% (v/v) ethanol concentration 'step up' procedure in order to determine the concentration which resulted in maximal drinking with an ethanol solution to total fluid ratio closest to 0.5. After baseline drinking of the preferred concentrations was established, female HEP rats were randomly selected for mating and their ethanol bottles were removed. Upon finding a 'sperm plug', male rats were removed and the ethanol was returned. A second group received injections of progesterone in sesame oil beginning with a 1.0 mg/kg/day dose which was increased to 3.0 mg/kg/day on gravid days (GD) 5-20. Vaginal smears confirmed that progesterone rendered the rats anoestrous. Neither pregnancy nor progesterone changed either the amount or proportion of ethanol consumed compared to the baseline period. The rats drank an average of 8.4 g/kg daily throughout pregnancy. A sharp drop in food intake was noted the day after mating. Beginning on GD 13, it was observed that pregnant rats showed a marked increase in the variance for proportion of ethanol consumed and body weight. Subsequently, only one of the eight impregnated rats successfully delivered a litter. The ethanol solution was removed and these rats mated again: seven of the eight rats delivered litters. These two findings suggest that the pregnant females must have begun to lose their litters on or after GD 13. Further, pregnancy does not affect the consumption of ethanol in the HEP rat. In addition, due to the fact that drinking by HEP rats during pregnancy leads to such a high rate of resorption of the fetus, this hybrid strain may also constitute a useful model for the study of alcohol-induced spontaneous abortion.

Working memory deficits induced by single but not repeated exposures to domoic acid.

Single injections of domoic acid, given either intraperitoneally to mice or directly into the hippocampal formation of rats, have been shown to impair learning on the place version of the Morris water maze task and the eight arm radial maze task. The present study was designed to test whether both single and repeated exposures of intraperitoneally administered domoic acid (1.0 or 2.0 mg/kg) impair spatial working memory in mice on a delayed matching-to-sample task. DBA strain mice were given a series of four injections over a 7-day period consisting of either saline or one of two doses of domoic acid. During the 18 days of testing, each subject was given one trial per day consisting of one information run, followed by three test runs. On non-alternation days (days in which the correct response was the same as the preceding day) the saline injected group significantly outperformed the single injection 2.0 mg/kg domoic acid group. This indicates that domoic acid-treated animals were incapable of forming a memory that persisted for 24 h and hence were less able to utilize the prior day's experience. However, the repeated exposure groups did not perform as poorly on non-alternation days than the single exposure groups, indicating that domoic acid may affect multiple mechanisms involved in memory consolidation.

A comparison of visual- and response-generated cues in a spatial DMTS task for rats.

In an attempt to clarify the nature of the memory cues used in a spatial, working memory task, rats were tested in a two-choice water maze. Each trial consisted of an information run, which forced the rat to the correct choice compartment, a retention period, and a test run. A response-associated cue condition, in which the relevant cue was the direction of the turn in the information run, was compared to a visual cue condition in which the animal had to remember whether the escape platform had been in the light or dark compartment. Of the subjects supplied with either visual or response-associated cues, the subjects allowed to employ response-associated cues did better, but the best performance occurred when both cues were available. When rats trained with both cues present were forced to choose between cues, they stopped using either and reverted to making a preferred right or left turn. The results support the idea that rats can form integrated, relational-cue memories which, in some circumstances, prove a hindrance to performance.

Comparison of the alcohol-preferring P rat to the Wistar rat in behavioral tests of impulsivity and anxiety.

To determine whether the selectively bred alcohol preferring P rat displays impulsive and anxiety-related behaviors, as have been noted in Type 2 human alcoholics, P rats were compared with outbred Wistar rats, the strain from which P rats were derived, on a series of behaviors reflecting impulsivity and anxiety. The two groups were also compared on their volitional consumption of ethanol. When compared with the Wistar rats, the P rats preferred a higher concentration of ethanol and imbibed a much greater amount of ethanol when they were offered their preferred concentration. However, the behavioral tasks produced inconsistent results. The P rats completed 100 bar presses for food in less time when tested on a constant reinforcement schedule, which suggests that they are hyperactive compared to Wistar rats. However, the P rats also emitted a higher percentage of reinforced responses on differential reinforcement of low rate responding (DRL)-10s and gnawed less from a cork stopper, which suggests that they are less impulsive and possibly neophobic. The two groups did not differ on emergence into or activity in an open field, their activity in or open-arm duration in the elevated plus maze, or performance on DRL-5s and DRL-15s. Collectively, the behavioral data suggest that P rat does not serve as a model for the anxiety and impulsiveness associated with the Type 2 alcoholic individual.

Glucose minimally attenuates scopolamine-but not morphine-induced deficits on a water maze alternation task.

In a previous study, daily injections of glucose, 100 and 250 mg/kg i.p., in Sprague-Dawley rats failed to either facilitate acquisition or to ameliorate scopolamine- or morphine-induced deficits on a water maze alternation task (Means, et al., 1996). The present study demonstrates that daily injections of 1 g/kg minimally ameliorates a scopolamine-induced deficit on the water maze alternation task in Sprague-Dawley rats. However, daily glucose injections of 1, 2 and 4 g/kg failed to improve performance during acquisition or to diminish morphine-induced deficits on the task. The failure of daily administration of glucose to facilitate acquisition or reverse morphine-induced deficits was not due to the daily injection procedure nor to stress elevated glucose levels resulting from exposure to the task. It is suggested that the effects of glucose on memory are task dependent, with facilitation being more easily demonstrated on tasks for which animals have an innate bias to perform the correct response or the ability to acquire in very few trials.

Repeated independent exposures to domoic acid do not enhance symptomatic toxicity in outbred or seizure-sensitive inbred mice.

Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.

Rats perform better on spatial than brightness delayed matching-to-sample water-escape due to an unlearned bias to use spatial cues.

Rats readily acquire water-escape spatial delayed matching-to-sample (DMTS) tasks and show excellent performance with retention intervals as long as 120 m (17). They also acquire the task more readily with a 5-min retention interval (RI) than with a 1-min RI (16). To determine if these observations are unique to spatial DMTS, or are also true of nonspatial water-escape DMTS, 75-day-old rats were compared on acquisition and subsequent retention of spatial and brightness DMTS. A larger proportion of the rats tested on the spatial problem were able to acquire the task, made fewer acquisition errors, and demonstrated better retention when tested at RIs of 1, 5, 15, 30, 60, and 120 min than did the rats tested on the brightness problem. Acquisition RI did not affect the rate of acquisition on either task. Examination of perserveration errors, the occurrence of intrusions, and position-congruent performance (escape platform in the same physical location on both runs of a trial) revealed that the choices of brightness-trained rats were often more influenced by spatial than brightness cues, suggesting that rats have an unlearned bias to use spatial cues in water-escape DMTS tasks.

Scopolamine- and morphine-induced deficits in water maze alternation: failure to attenuate with glucose.

Glucose has previously been shown to improve performance on memory tasks and to ameliorate performance deficits induced by scopolamine or morphine. To test the generality of these observations, Sprague-Dawley rats were trained to alternate choices to reach an escape platform in a two-choice circular water maze. The rats attained a high level of alternation, alternating on a mean of 9 of 10 daily trials. Daily glucose injections (100 and 250 mg/ kg) failed to facilitate acquisition of the alternation. Single injections of scopolamine (0.5, 1.0, and 2.0 mg/kg), but not methylscopolamine (0.5 mg/kg), and daily injections of scopolamine (0.5 mg/kg) or morphine (5.0 mg/kg) impaired alternation performance. The scopolamine- and morphine-induced deficits in alternation behavior were not ameliorated by pretrial glucose injections at doses which have previously been found to be effective (100 and 250 mg/kg). The mechanism of glucose facilitation of memory is currently unknown. The present results show that glucose given at previously established effective doses does not activate the mechanism or produces too weak an effect to be observed in water maze alternation.

Estrogen affects performance of ovariectomized rats in a two-choice water-escape working memory task.

To determine if estrogen would protect treated rats from deficits in performance on a working memory task across time, 18 female 6-month-old Sprague-Dawley rats were trained to a criterion on a water-escape spatial delayed matching-to-sample problem. Following training, rats were ovariectomized, and nine were maintained on estrogen (polyestradiol-phosphate, 0.5 mg every 3 weeks) and nine on its vehicle for 200 days. After recovery from surgery, the rats were tested for performance every 6 weeks under three conditions: 5 min retention interval (RI); 30 min RI; and 30 min RI with an emotional experience during the RI. Analysis of correct choices revealed that estrogen-treated rats made more correct choices (p < .05) than controls on the 5 min undisturbed interval; estrogen tended to impair performance on the emotionally distracting interval. Estrogen apparently protected working memory on the undisturbed trials and might be pertinent to the maintenance of memory in female mammals.

Memory for parking location in large lots.

The recall of automobile parking location was assessed over five consecutive workdays. Completed data from 36 women and 19 men provided measures of accuracy and a survey of specific strategies. Analysis showed a significant recency effect with memory for the most recent parking locations being superior. Less variation in parking location and shorter distance from parking location to building entrance were associated with better recall. Contrary to prevalent belief, older subjects had more accurate recall. Older subjects parked closer to the entrance and used fewer spaces which were also located closer together. The most frequently reported strategy was "favorite location" which was used more often by older subjects. Whereas laboratory tasks show memory deficits with increasing age, some studies in the natural environment have exhibited less such decline; the current data showed an actual improvement. It may be that older people adopt and practice compensatory strategies in the natural environment while laboratory tasks give little opportunity for establishing or practicing such devices.

Biochemical changes, early brain growth suppression and impaired detour learning in nicotine-treated chicks.

Fetal growth suppression associated with chronic maternal intake of cigarette smoke is frequently observed in humans and studies using animal models suggest that in utero nicotine exposure is an important component of this growth suppression. The developing fetal central nervous system (CNS) is sensitive to the growth inhibitory effect of nicotine and morphological as well as functional CNS deficits may result from fetal nicotine exposure. The studies presented here show that nicotine exposure during early embryonic development ultimately inhibits the ability of 7-11 day old chicks to learn a detour task. The brain growth suppression caused by nicotine is paralleled by a failure of the early embryo brain to express the normal developmental increase in ornithine decarboxylase (ODC) activity. This biochemical change may be germane to the mechanism of nicotine-induced growth inhibition and/or nicotine-induced behavioral changes because the appropriate expression of ODC activity is essential to normal growth and differentiation in the fetal CNS. In the chick embryo, nicotine exposure alters several important signaling pathways that regulate ODC expression. For example, nicotine exposure lowers embryonic brain glucose levels and causes significant decreases in whole brain cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels and in cyclic AMP binding proteins (protein kinase-A regulatory activity). Also, in cultured chick cells, nicotine inhibits the ability of a potent mitogen (insulin) to induce ODC activity, but, paradoxically, in ovo nicotine exposure increased insulin binding and stimulated insulin receptor autophosphorylation in brain membranes.

Prenatal exposure to cocaine: effects on aggression in Sprague-Dawley rats.

Social/aggressive behavior in adult rat offspring (beginning at postnatal Day 180) prenatally exposed to saline, cocaine, or amfonelic acid (AFA) was examined. Pregnant rats received injections of 15 mg/kg of cocaine, or 0.9% saline twice daily, s.c., or on 2 consecutive days at 4-day intervals, or 1.5 mg/kg amfonelic acid daily throughout gestational Days 1-20. Frequency, duration, and latency of 11 social/aggressive behaviors were recorded for two 15-min sessions during which a smaller male intruder replaced an ovariectomized female in the resident's home cage. Subjects received a s.c. saline injection before Session 1 and 2.0 mg/kg of gepirone, a 5HT1a partial agonist, prior to Session 2. Prenatal cocaine treatment resulted in alterations of aggressive behavior. Aggressive behavior was reduced by gepirone in all groups but to a lesser extent in the AFA group.

Mid-life onset of dietary restriction extends life and prolongs cognitive functioning.

Fourteen-month-old C57BL/6 (NIA) mice were placed on a nutritionally complete diet providing 139.4 kcal/week. Over a 2-month period the food ration of experimental mice (AE) was reduced to 85 kcal/week, where it remained for the duration of the study. An aged control group (AC) continued with the higher calorie diet. At age 22 months, AC mice and half of the AE mice (AE22) were given a battery of behavioral tests. The remaining AE mice (AE25) were given the test battery at age 25 months. Also, a middle-aged control group (MC) was tested at age 13 months. Midlife onset caloric restriction (CR) increased longevity and preserved strength, coordination, and spontaneous alternation behavior, and altered responses to enclosed alleys. A spatial discrimination in the Morris water maze and a spatial delayed matching-to-sample water-escape task were insensitive to age and diet. The aged mice were adversely affected by testing.

Individual aged rats are impaired on repeated reversal due to loss of different behavioral patterns.

Aged rodents compared to young rodents are impaired in making repeated reversals and more variable in performance on many tasks. In the present study, a comparison of ten aged (21 months) and 10 young (3 months) Sprague-Dawley rats on a repeated spatial discrimination reversal water escape task revealed that the deficient and variable performance of the aged rats was due to the aged animals developing deficits in different behavioral patterns that were necessary to perform the task. Individual aged rats had deficits in inhibiting an unlearned first choice tendency (perseveration), repeating a first choice that lead to escape on the preceding trial (win-stay deficit) or inhibiting a first choice that lead to confinement and delayed escape on the preceding trial (lose-shift deficit). Because the aged animals were deficient on one or more of the necessary behavioral processes, as a group they were deficient on the repeated reversal task. However, because the aged rats differed on the specific behavioral process(es) on which they were deficient, when evaluated on any one process they were more variable than were the younger rats.

Those cheating rats: male and female rats use odor trails in a water-escape "working memory" task.

Three-month-old Sprague-Dawley rats were trained on a working memory win-stay (spatial delayed matching-to-sample) water-escape task with the escape platform location the same for all subjects on a given trial, a procedure that maximizes the buildup of an odor trail to the escape platform. In subsequent tests during which the location of the escape platform varied randomly between subjects, the rats, especially the females, while continuing to perform above chance level, made increased errors. Varying the platform location between subjects eliminated odor trail as a nonambiguous cue for locating the escape platform. In a second experiment females performed better than males on a reference memory odor trail discrimination task which involved following the path of like-gender "pathmaker" rats to the escape platform. The relatively poor use of odor trails by the males was associated with a high frequency of choosing a preferred choice section or returning to the choice section selected first on the immediately preceding trial (perseveration). Collectively, the two experiments demonstrate that rats can use either working memory or odor trails to locate an escape platform in a water maze, and that they, especially females, will use odor trails in a working memory task if odor trails are available. Clearly, the location of the escape platform should be varied randomly between subjects in tests of working memory.

Prenatal exposure to cocaine. II: Effects on open-field activity and cognitive behavior in Sprague-Dawley rats.

Pregnant rats received subcutaneous injections of 15 mg/kg of cocaine twice daily (Cocaine-D), twice daily for two consecutive days at 5-day intervals (Cocaine-I), 0.9% saline (Saline) twice daily, or 1.5 mg/kg amfonelic acid (AFA) daily from gestational days 1-20. Offspring were tested for: rates of spontaneous alteration at postnatal days (PND) 32, 35, 40, and 45; acquisition and retention performance on a water maze task beginning at PND 30 and 60; entrance into and activity in an open-field apparatus at PND 60 and 180. The Cocaine-D offspring were less likely than Control offspring to enter the open field when tested at PND 60. The Cocaine-I offspring were hyperactive in the open-field apparatus when tested at PND 60. The drug treated offspring did not differ from the Saline control animals on all other measures. The failure of the Cocaine-D animals to enter the open field is consistent with neophobic behavior that we have observed before in rats exposed in utero to cocaine.

Prenatal exposure to cocaine. I: Effects on gestation, development, and activity in Sprague-Dawley rats.

Sperm-positive Sprague-Dawley rats received one of four treatments for 20 days beginning within 24 hours of conception. One group received subcutaneous injections of 15 mg/kg cocaine twice daily (Cocaine-D); a second group received 15 mg/kg cocaine twice daily for two consecutive days at 5-day intervals (Cocaine-I); a third group received normal saline twice daily (Saline); and a fourth group received 1.5 mg/kg amfonelic acid (AFA), a dopamine reuptake inhibitor, once daily. Cocaine-D, Cocaine-I, and AFA dams were fed ad lib. An attempt was made to pair-feed the Saline dams with the Cocaine-D dams; however, the Saline dams did not eat as much as the Cocaine-D dams which resulted in dams in all groups essentially eating ad lib. The Cocaine-D pups showed a slightly delayed righting behavior and neophobia at 30 days of age, as evidenced by hypoactivity during the first 15 min of a 6-h activity test. The Cocaine-I pups were hypoactive during the 3-h dark phase of the 6-h activity test when tested at 30 days of age. These effects did not occur in the offspring exposed to AFA, a potent dopamine uptake inhibitor and CNS stimulant which indicate that one or more other sites for cocaine action may combine for its effects on the developing fetus.