Evidence for a role of brain serotonergic neurotransmission in avoidance learning.

This thesis has analyzed the role of brain serotonergic (5-HT) neurotransmission in avoidance learning in the male rat using neurochemical, pharmacological and behavioural approaches. The acute and long-term effects of p-chloroamphetamine (PCA) on one-way and two-way active avoidance (AA) acquisition and retention and passive avoidance (PA) retention and on central monoamine concentrations were examined in the male rat. The effects of PCA were compared with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). To characterize the effects of PCA the following neurotoxins were used: 5,6- and 5,7-dihydroxytryptamine (5,6- and 5,7-DHT) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). The concentrations of biogenic monoamines and their metabolites in discrete brain regions were determined by high pressure liquid chromatography with or without electrochemical detection. The effects on 5-HT receptors in vitro and in vivo were measured by ligand binding studies (using 3H-5-HT and 3H-ketanserin as radioligands) and with behavioural techniques, respectively. Administration of the 5-HT releasing compound PCA prior to training (pre-training) produced a dose- and time-related impairment of one-way AA acquisition and retention and PA retention. A series of studies indicated that the avoidance learning deficits caused by PCA are produced by release of 5-HT, resulting in stimulation of postsynaptic 5-HT receptors. For instance, the avoidance deficit was blocked by pretreatment with the 5-HT uptake inhibitors alaproclate and zimeldine, which inhibit the 5-HT release induced by PCA. The avoidance deficits could not be related to changes (direct or indirect) in NA and DA transmission. Lesion experiments in combination with biochemical analyses provided evidence that the avoidance deficit caused by PCA involves 5-HT terminals of the forebrain, while the descending 5-HT projections seem to play a minor role. The AA acquisition deficit induced by PCA appears to be mediated via stimulation of 5-HT2 receptors, whereas the PA retention is mediated via 5-HT1 receptors. Analysis of the PCA-induced AA deficit indicated that it is mediated by non-associative factors. Thus, the performance of the PCA-treated rats was susceptible to interference from extratask contextual stimuli. Pre-training administration of PCA was found to produce a time-dependent loss in memory retention (PA retention) in animals which had acquired the response. This finding indicates that serotonin also has a role in associative learning processes e.g. in the way information is processed in the rat brain following acquisition.(ABSTRACT TRUNCATED AT 400 WORDS)