Behavioral characterization of dopamine D5 receptor null mutant mice.

To study behavioral functions of the D5 subtype, mice were generated with null mutations in the D5 gene. This 1st behavioral characterization of D5 null mutant mice (D5-/-) indicated normal general health, sensory abilities, and neurological reflexes. Under basal conditions, D5-/- mice were generally normal on locomotor activity, the rotarod test, acoustic startle response, prepulse inhibition, elevated plus-maze, light <--> dark exploration, Morris water maze, and cued and contextual fear conditioning. In the Porsolt forced swim test for antidepressant activity, male D5-/- mice showed lower levels of immobility. D5-/- mice showed some evidence of reduced responses to the hyperactivity-inducing effects of the D1/D5 receptor agonist SKF 81297. The ability of SKF 81297 to disrupt acoustic startle and prepulse inhibition appeared to be attenuated in D5-/- mice. These results suggest that the D5 receptor is not essential for many dopamine-mediated behaviors but may contribute to the pharmacological activation of dopaminergic pathways relevant to exploratory locomotion, startle, and prepulse inhibition.

Rat strain differences in response to galanin on the Morris water task.

Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague-Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long-Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory.

Galanin inhibits performance on rodent memory tasks.

Central administration of galanin produces performance deficits on a variety of rodent learning and memory tasks. Galanin impairs acquisition and/or retention of the Morris water task, delayed nonmatching to position, T-maze delayed alternation, starburst radial maze, and passive avoidance in normal rats. A primary site of action is the ventral hippocampus, with an additional modulatory site in the medial septum-diagonal band. The behavioral actions of galanin at rat septohippocampal sites mediating cognitive processes are consistent with previous reports of inhibitory actions of galanin on acetylcholine release and cholinergically activated transduction at the M1 muscarinic receptor in rat hippocampus. The peptidergic galanin receptor antagonist M40 blocks the inhibitory actions of galanin on memory tasks. Treatment combinations of M40 with an M1 agonist, TZTP, improves performance on delayed nonmatching to position, in rats with 192IgG-saporin-induced cholinergic lesions of basal forebrain neurons. Nonpeptide, bioavailable, subtype-selective galanin receptor antagonists may provide tools to test the hypothesis that antagonism of endogenous galanin, which is overexpressed in the basal forebrain in Alzheimer's patients, can contribute to the alleviation of the cognitive deficits associated with Alzheimer's disease.

Entorhinal-hippocampal connections and object memory in the rat: acquisition versus retention.

Investigations of the neurobiology of memory using experimental animals have modeled many of the characteristic features of amnesia seen in human clinical populations. To examine long-term memory, however, animal models of amnesia often employ extended measures of acquisition, which stand in contrast to the retention measures used with humans. To determine the role of entorhinal-hippocampal circuitry on both information acquisition and long-term retention, rats with bilateral transections of the angular bundle were trained on three object discrimination problems and then retrained two weeks later to measure retention. Animals with discrete lesions of the angular bundle, which disrupted perforant path connections from the entorhinal cortex to the hippocampus and efferent hippocampal-cortical projections, acquired the object discrimination problems normally but showed a marked deficit in retention. These findings are important because they indicate that the role of entorhinal-hippocampal connections may be limited to maintaining some types of information (e.g., single object discriminations) for retention. This dissociation, moreover, suggests that behavioral paradigms that include a measure of retention may be particularly important for characterizing the mnemonic functions of the hippocampal/parahippocampal region.

Landmark discrimination in the rat: a measure of allocentric spatial ability.

A landmark discrimination task similar to that previously used with monkeys was adapted to measure allocentric spatial ability in rats. Rats were trained to approach one of two food wells, placed 36 cm apart, based on the proximity of the landmark. During initial training, the landmark was adjacent to the baited food well (0 cm). As training progressed, the distance of the landmark from the baited food well was increased in 1.25-cm increments. Results show that rats were able to successfully use a landmark as an external referent up to a distance of 11 cm (when the midpoint between food wells was 18 cm). Following the stepwise training phase, a 64-trial test of mixed distances was administered, and performance was above 80% up to and including 12.5 cm from the near landmark. The results suggest that this landmark discrimination task provides a means to assess allocentric spatial ability in rats and to explore underlying neural mechanisms across species.

Role of the parahippocampal region in spatial and non-spatial memory: effects of parahippocampal lesions on rewarded alternation and concurrent object discrimination learning in the rat.

Rats with aspiration or excitotoxic (NMDA) lesions of the parahippocampal region were trained on a series of behavioral tasks which consisted of: (1) a test of spatial memory (discrete trial rewarded alternation), (2) a black-white discrimination, and (3) a test of non-spatial memory commonly used in primate models of amnesia (visual concurrent object discrimination). Rats in both lesion groups were severely impaired on the concurrent discrimination, even though they were able to learn the black-white discrimination normally. Animals with aspiration lesions were also impaired on the spatial memory task, whereas those with NMDA lesions did not differ from controls. The results indicate that concurrent object discrimination is a particularly sensitive measure of hippocampal/parahippocampal functions and suggest that these structures in the rat may serve mnemonic functions which are qualitatively similar to those of human and non-human primates.