Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion

Abstract

Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits.

Keywords: animal model of schizophrenia; dopamine; noradrenaline; therapy; ventral hippocampal lesion; xanthine.

Figure 1

Example of lesions according to MRI. The contrasts of the pictures were inverted so that, opposite to the usual MRI images, the white matter and bone appear clear and the gray matter dark. With this inversion, the lesions replaced by cerebrospinal fluid appear black and the sclerosis, white. They are pointed by black arrows. The pictures in each row correspond to different coronal slices, the approximate anteriority relative to the bregma is indicated below. The three rows show an example of a triplet of lesions. Each row corresponds to one rat before it was treated either with vehicle, veh; or caffeine, caf; or RX821002. The identity of the rat was printed on the left most MRI picture (respectively CARX01,02, and 17) followed by the reference of its experimental group (veh, caf, and RX).

Figure 2

Locomotion under drug or vehicle. Bar graphs represent means + S.E.M. of the beam crossings during 20 min. The 6 bars on the left hand side represent the initial 20 min of the test. The 6 bars on the right hand side represent the last 20 min. In each group of 6 bars, the 3 left ones were obtained with sham-lesioned rats and the 3 right ones with NVHL rats (as indicated below the bars). The white bars represent the effect of the vehicle, the green one of caffeine and the brown one for RX821002. The dotted lines ending with two arrows indicate the differences between the groups that were statistically significant (** p < 0.01; *** p < 0.001).

Figure 3

Effect of the treatments in the associative learning test. The two graphs show the duration of nose poking in the food magazine during the 5 s before food was delivered (ceiling = 5 s). The X-axis depicts the sequence of daily training sessions in which 10 s of the cue preceded food delivery. The Y-axis presents the mean nose poke duration for each daily session (1–8 days). Data of sham-lesioned rats were represented as circles and dotted lines, those of NVHL rats as squares and full lines. The white symbols correspond to the reference data (vehicle), the green symbols to the effect of caffeine, and the brown symbol to the effects of RX821002. The standard errors were not plotted for clarity (see statistical computations in the Result section). The dark backgrounds signal respectively the initial learning and final stable performances. The arrows point to the changes (left graph: effect of caffeine on the final performance and, right graph: effect of RX821002 on the learning stage).

Figure 4

Results of the Plus Maze Test. Presence of the rats in open arms is shown in the left bar graph, and number of entries into the arms in the right bar graph. Each bar represents the mean + S.E.M. The groups of drugs and rats are similar to those described in Figures 2, 3. The white bars represent the effect of the vehicle, the green ones that of caffeine and the brown ones those for RX821002. The dotted lines ending with two arrows indicate the differences between the groups that were statistically significant (* p < 0.05; *** p < 0.001).