Place Learning

Place learning in the Morris water maze is a test extensively used in the evaluation of hippocampal learning and memory (McNamara and Skelton 1993).

Tecott et al. (1998) did not observe differences during the training between mutant mice, lacking 5-HT2C receptors, and wild-type mice in the Morris water maze. However, in the probe trial effected the last day of training, mutant mice did not show any preference for the target quadrant where the escape platform had been located, whereas the wild-type mice preferred this quadrant. This lack of preference for the escape platform quadrant indicates that the mutant mice probably used a nonhippocampal strategy to solve the training tasks (Tecott et al. 1998). In fact, animals can solve these tasks by using cue learning or egocentric learning as efficiently as place learning (Olvera-Cortes et al. 2004). In the same study, Tecott et al. (1998) used cerebral slices from mutant mice to evaluate the induction of LTP in different hippocampal regions and observed that only the LTP in the perforant path-dentate gyrus synapse was attenuated. This finding indicates a perturbation in dentate gyrus functioning that could impede the animals to use a hippocampal-dependent strategy, since it has been reported that the selective lesion of granular dentate cells impairs early phases of acquisition in hippocampal-dependent learning (Schuster et al. 1997) and that LTP has been proposed as a mechanism underlying memory formation (Lynch 2004). On the other hand, 5-HT2C deficient mice are prone to spontaneous convulsions, and it has been suggested that these receptors mediate the tonic inhibition of neuronal network excitability (Heisler et al. 1998;

Tecott et al. 1995). However, in the previously described work, the 5-HT2C receptor mutation was generalized, and therefore functional alterations in other regions relevant to spatial learning such as the medial septum, which is the pacemaker of hippocampal electrical activity and the source of acetylcholine release in the hippocampus, cannot be discarded. Acetylcholine modulation of learning has been extensively established (Altman et al. 1990; McNamara and Skelton 1993; Albert 1996; Lamberty and Gower 1991).

With regard to the evaluation of the effect of compounds with affinity for 5-HT2C receptors, Kant et al. (1996) evaluated the effect of the 5-HT2C receptor agonist TFMPP (5.0 mg/kg IP) on rat learning by using a water maze test in which the rats are challenged to learn to swim through alleyways and doors to reach a platform, in order to evaluate working spatial memory. Both the time required to find the platform and the number of errors made were the variables considered. The different tests in rats receiving TFMPP showed an increase of the time required by the rats to solve the task, but the number of errors were not affected, though these effects seem to be better explained by alteration of motor functions instead of learning process, as was suggested by the same authors in other work in which DOI (0.1 and 0.25 mg/kg IP) had a slowing effect on movement and the latencies to find the platform increased) without an increase in the number of errors (Kant et al. 1998). Thus, hypolocomotion has been observed after acute administration of mCPP (2.5 mg/kg IP) in rats evaluated in a novel open field test (exploration-associated locomotion), where the animals displayed a low number of turns and rears (Fone et al. 1998). Similar observations were made after the administration of TFMPP and DOI (Lucki et al. 1989; Pranzatelli et al. 1992). Therefore, it is important to mention that 5-HT2C receptors seem not to be involved in the working spatial memory.

Recently, Khaliq et al. (2008) tested place learning of rats after the administration of mCPP and observed a negative correlation between memory function and 5-HT2C receptor stimulation. The mCPP (1.0, 3.0, and 5.0 mg/kg IP) impaired memory function in a dose-dependent manner, increasing the latency to find a sunken platform in the water maze in a 24-h posttraining memory test. The authors stated that this detrimental effect was not related to hypolocomotion because passive avoidance tests produced similarly impaired retention at all doses tested.

However, passive avoidance implicates an absence of response, whereas the swimming speed in any water maze could be influenced by hypolocomotion; hence, a measure of pathway lengths must be conducted to assert the influence of motor alterations, which may be relevant because hypolocomotion has been consistently observed when locomotor activity was evaluated. Further experimental work must be done to eliminate motor influences and to obtain conclusive results about 5-HT2C receptor regulation in place learning ability.

In a spatial working memory test with delay (delayed nonmatching to position task [DNMTP]), cerebral serotonin depletion induced by the administration of 5,7-DHT in rats had no effects. After the authors applied DOI (100 and 300 mg/kg IP), no effects on choice accuracy were observed (Ruotsalainen et al. 1998). Thus, evidence on 5-HT2C receptor directly affecting hippocampal-dependent test was not obtained. Although tests of working memory are prefrontally driven, the spatial component of this function implies hippocampal-prefrontal interactive relationships, and no effects after serotonin manipulation were observed.

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