Eric L. Hargreaves

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism : Nonspatial pretraining eliminates spatial learning deficits

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performances and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.

Detailed behavioral analysis of water maze acquisition under APV or CNQX: Contribution of sensorimotor disturbances to drug-induced acquisition deficits.

N-methyl-D-aspartate (NMDA) receptor antagonists disrupt acquisition of the water maze and cause sensorimotor disturbances. In a detailed behavioral analysis in male rats, it was found that the NMDA antagonist DL-2-aminophosphonovaleric acid (APV) caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under APV. The results are consistent with the known role of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA may contribute to but does not appear to be essential for spatial learning in the water maze.

Sexually dimorphic spatial learning varies seasonally in two populations of deer mice

Spatial learning in photoperiodically induced breeding (reproductive) and non-breeding (non-reproductive) adult male and female deer mice (Peromyscus maniculatus) was examined in a Morris water-maze task. Sexually mature, adult male and female deer mice that were derived from either a mainland population (P. m. artemisiae) or an island population (P. m. angustus) were required to learn the spatial position of a hidden, submerged platform in a water maze. Deer mice were tested either during the breeding season (summer; long day photoperiod) or during the non-breeding season (winter; short day photoperiod) with a total of six blocks of four trials conducted in a single day. Retention was tested with two probe trials which occurred one and three days after acquisition. During the breeding season male spatial task acquisition was superior to female spatial task acquisition for both populations. In contrast, during the non-breeding season there were no significant sex differences in spatial acquisition for either population. This change in sexually dimorphic spatial learning was due to female spatial-performance decreasing from non-breeding season to the breeding season and male spatial-performance increasing over the same period. Both populations displayed similar seasonal variations in sexually dimorphic water-maze task performance. There were, however, overall population differences in water-maze task performance that were related to the ecology of the mice, with the insular mice displaying shorter latencies to reach the hidden platform than did the mainland deer mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801

Three doses of MK801 (0.05 mg/kg, 0.3 mg/kg and 1.0 mg/kg) were given systemically to adult male rats, which were then tested on a battery of previously learned, reactive and spontaneous behaviors. Hyperactivity, hyper-reactivity, reductions in rearing behavior and deficits in tongue extension were found at the 0.05 mg/kg dose. Similar, but more severe results were found at the 0.3 mg/kg dose, with the addition of difficulties in climbing, balancing on a beam, and abnormalities in orienting to tactile stimuli. A number of tasks could not be performed at the 1.0 mg/kg dose including tongue extension, orienting, balancing on a beam, and climbing. Additionally, abnormal postures, gaits, and swimming behaviors were observed at this dose. These results characterize the behavioral effects of MK801 as a syndrome of hyperactivity, hyper-reactivity, and sensorimotor deficits. Evidence of this syndrome was present at all three doses, including the 0.05 mg/kg dose, which previously has been claimed to induce deficits similar to hippocampal lesions. Learning literature employing MK801 is discussed in the context of the behavioral deficits found in this study.

Reaching to ipsilateral or contralateral targets: within-hemisphere visuomotor processing cannot explain hemispatial differences in motor control

Aiming movements made to visual targets on the same side of the body as the reaching hand typically show advantages as compared to aiming movements made to targets on the opposite side of the body midline in the contralateral visual field. These advantages for ipsilateral reaches include shorter reaction time, higher peak velocity, shorter duration and greater endpoint accuracy. It is commonly hypothesized that such advantages are related to the efficiency of intrahemispheric processing, since, for example, a left-sided target would be initially processed in the visual cortex of the right hemisphere and that same hemisphere controls the motor output to the left hand. We tested this hypothesis by examining the kinematics of aiming movements made by 26 right-handed subjects to visual targets briefly presented in either the left or the right visual field. In one block of trials, the subjects aimed their finger directly towards the target; in the other block, subjects were required to aim their movement to the mirror symmetrical position on the opposite side of the fixation light from the target. For the three kinematic measures in which hemispatial differences were obtained (peak velocity, duration and percentage of movement time spent in deceleration), the advantages were related to the side to which the motor response was directed and not to the side where the target was presented. In addition, these effects tended to be larger in the right hand than in the left, particularly for the percentage of the movement time spent in deceleration. The results are interpreted in terms of models of biomechanical constraints on contralateral movements, which are independent of the hemispace of target presentation.

Spatial learning in an enclosed eight-arm radial maze in rats with sodium arsanilate-induced labyrinthectomies

Bilateral vestibular dysfunction was induced in Long-Evans male rats (n = 7) by intratympanic injections of sodium arsanilate (30 mg/side). Control rats (n = 6) received isotonic saline. Animals were tested for labyrinthine integrity by measuring air-righting and contact-righting reflexes. Rats were reduced to 85% of free-feeding body weight and tested in an enclosed 8-arm radial maze (1 trial/day over 10 days). Labyrinthectomized animals made significantly more errors (p < .001) and, unlike the controls, showed no significant improvement on this measure over acquisition training. These rats also made significantly more (p = 0.018) sequential same arm reentries and fewer sequential adjacent arm entries (p < .01). These findings demonstrate that information obtained from the vestibular system is very important in spatial learning in the rat.

p-Chlorophenylalanine-induced serotonin depletion : reduction in exploratory locomotion but no obvious sensory-motor deficits

Para-chlorophenylalanine (PCPA) depletes central serotonin (5-hydroxytryptamine, 5-HT) by inhibiting tryptophan hydroxylase, an enzyme necessary for the synthesis of 5-HT. The effects of a wide range of PCPA doses (150-1000 mg/kg) on spontaneous exploratory locomotor activity in a novel environment, activity in running wheels and a number of sensory-motor capacities were examined. Administration of 1000 mg/kg PCPA reduced whole brain levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid to 9.4 and 8.2% of control levels, respectively. Treatment with PCPA produced a dose-dependent decrease in exploratory locomotion in an unfamiliar automated open field relative to vehicle-treated animals. Further, all measures of general, horizontal and vertical activity were suppressed by PCPA treatment. In contrast to previous work, hyperactivity of rats chronically housed in cages with running wheel access was not observed. In their home cages, some PCPA-treated rats exhibited hyper-reactivity to cutaneous stimulation. No other sensory-motor deficits were apparent. Previous theories of 5-HT function state that its action may be to inhibit motor activity or promote sleep. The present results challenge this view and suggest that 5-HT, at least in certain environments, may stimulate locomotor activity without directly controlling various sensory-motor capacities in rats.

Sodium arsanilate-induced vestibular dysfunction in rats : effects on open-field behavior and spontaneous activity in the automated digiscan monitoring system

Vestibular dysfunction was chemically induced in Long-Evans rats by intratympanic injections (30 mg per side) of sodium arsanilate (atoxyl). Following a one-week recovery period the rats were behaviorally assayed for integrity of the labyrinthine systems. All subjects were tested for presence of the air-righting reflex, the contact-righting reflex (by lightly holding a sheet of Plexiglas against the soles of the rats feet), and body rotation-induced nystagmus. All animals were then tested for their ability to remain on a small (15 x 15 cm) platform. Next, the subjects were given two 10-min open-field tests during which ambulation, rearing, grooming, and defecation responses were recorded. Four to five weeks later all rats were tested twice (60 min per session) in the automated Digiscan Activity Monitor which provides a multivariate assessment of spontaneous motor activity. The rats with vestibular dysfunction (Group VNX) took significantly less time to fall off the platform (p less than 0.01). They also exhibited significantly more open-field ambulation but fewer rearing responses (ps less than 0.01). An examination of group correlation coefficients for open-field variables and the platform test scores revealed some interesting group differences (ps less than 0.05). In the Digiscan tests the atoxyl-treated rats exhibited fewer number of horizontal movements, but increased speed for these movements (ps less than 0.05). Vertical movements did not differ significantly in incidence, but these movements were greatly reduced in duration (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

MK801-Induced hyper activity: Duration of effects in rats

MK801, a noncompetitive NMDA antagonist, induces hyperactivity, the duration of which is unknown. Thus, the hyperactivity induced by three different doses of MK801 was measured for 4 h using an automated open-field system. Adult male rats were habituated to the monitors for 1 h immediately prior to data collection. Rats were then administered one of three doses (0.05 mg/kg, n = 15; 0.1 mg/kg, n = 14; 0.5 mg/kg, n = 11) of MK801 or equivalent volumes of saline (n = 14). Upon injection, individual monitors were activated, and 48 consecutive 5-min samples were collected. Results indicated that MK801 induced hyperactivity in a dose-dependent fashion, with the two lower doses being significantly different from saline controls, but not from each other. The 0.5 mg/kg dose indicated that the peak behavioral activation occurred approximately 30 min after administration. This was followed by either a slow decline or a plateau phase, dependent upon the measure examined. By approximately 3 h after administration all measures had returned to the level of saline controls.

Evidence for different neurochemical contributions to long-term potentiation and to kindling and kindling-induced potentiation: Role of NMDA and urethane-sensitive mechanisms

Long-term potentiation (LTP) and kindling share a number of features, and it has been suggested that LTP might constitute the cellular mechanism of kindling. This question was approached by assessing the effect of urethane anesthesia (0.75 or 1.5 g/kg) or blockade of NMDA receptors by local infusion of DL-2-amino-5-phosphonovaleric acid (APV; 7.5 micrograms) on LTP, partial kindling, and kindling-induced potentiation (KIP) in the perforant path-dentate gyrus circuit of the intact hooded rat. Urethane anesthesia attenuated but did not block LTP and completely blocked partial kindling and KIP. APV completely blocked LTP but did not block partial kindling or KIP in the unanesthetized rat. These results suggest that different neurochemical mechanisms can support LTP on the one hand, and kindling and KIP on the other. They are consistent with a contribution by NMDA-mediated LTP to kindling and KIP, but they indicate that this contribution is not crucial for kindling and KIP in this circuit.