Role of 5HT in Memory Global Strategies

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Serotonergic projections from the raphe nuclei, where cell bodies are concentrated, are widespread and terminate in brain structures thought to underly memory processes such as the hippocampus, the prefrontal cortex, cortical associative areas, basal ganglia, or thalamus. The projections to the frontal cortex predominantly originate in the dorsal raphe nucleus (DRN), whereas the projections to the hippocampus arise from the median raphe nucleus (MRN). The DRN regulates the excitability of prefrontal cortical neurons,104 while the MRN plays a direct

Metabolism Neurotransmitter

Figure 2. Metabolism and receptor transduction systems ofserotonin. Top-halfofthe figure. 5-HT synthesis is realized in soma and terminals. Tryptophan hydroxylase is specific of 5-HT neurons and is the rate limiting enzyme for 5-HT synthesis. As tryptophan cannot be synthesized by the metabolism, 5-HT synthesis is very sensitive to the presence of this amino acid in the diet. 5-HT degradation takes place in neurons and glial cells. 5-HT uptake is specific for 5-HT neurons and exists in all membrane compartments of the neuron (soma, dendrites, axon terminals). Black dots show the steps which can be experimentally controlled in global strategy approaches to modify the extracellular level of5-HT. Bottom-halfofthe figure. Once released in the intercellular space, 5-HT may act on several specific receptor types or subtypes, which are differentiated by their protein structure, and by their intracellular effectors in the target neuron. The multiplicity of effector systems for each receptor type, as well as several common intracellular pathways for different receptor types, increase the diversity of functional effects of the fourteen 5-HT receptor subtypes.

Figure 2. Metabolism and receptor transduction systems ofserotonin. Top-halfofthe figure. 5-HT synthesis is realized in soma and terminals. Tryptophan hydroxylase is specific of 5-HT neurons and is the rate limiting enzyme for 5-HT synthesis. As tryptophan cannot be synthesized by the metabolism, 5-HT synthesis is very sensitive to the presence of this amino acid in the diet. 5-HT degradation takes place in neurons and glial cells. 5-HT uptake is specific for 5-HT neurons and exists in all membrane compartments of the neuron (soma, dendrites, axon terminals). Black dots show the steps which can be experimentally controlled in global strategy approaches to modify the extracellular level of5-HT. Bottom-halfofthe figure. Once released in the intercellular space, 5-HT may act on several specific receptor types or subtypes, which are differentiated by their protein structure, and by their intracellular effectors in the target neuron. The multiplicity of effector systems for each receptor type, as well as several common intracellular pathways for different receptor types, increase the diversity of functional effects of the fourteen 5-HT receptor subtypes.

role in the desynchronization of the electroencephalograph^ activity of the hippocampus,129 with possible consequences for memory-associated functions of the frontal cortex and the hippocampus, respectively. In the adult rat brain, hippocampal dependent learning increases the number of newborn cells which differentiate into neurons.50 Depletion of serotonin with 5,7-dihydroxytryptamine (5,7-DHT) reduces neurogenesis, thus serotonin might be a factor stimulating granule cell production.20

Nonspecific strategies, which concern much of the earlier studies on the role of serotonin in cognition, used global strategies, by which the effects of increasing or reducing central 5-HT neurotransmission were observed in various learning models (Fig. 2, top-half).

Given the known role of 5-HT in mood disorders such as anxiety, "emotional memory" deserves to be analysed per se in relation to 5-HT. Thus, a change in 5-HT metabolism occurs in the prefrontal cortex, the nucleus accumbens, and the amygdala of rats subjected to the conditioned fear stress (CFS).65 CFS-induced freezing behavior decreases following treatment with a selective serotonin reuptake inhibitor (SSRI), which is supposed to enhance 5-HT level in the brain.66 In contrast, global 5-HT lesions induce specific impairments of contextual conditioning in rats, while sparing discrete cue-conditioning.133 Interestingly, selective lesions of the DRN induce impairments of unconditioned (innate) fear, a response mediated by the DRN-periaqueductal gray (PAG) projection, but have facilitatory effects on learned fear, a response mediated by the DRN-amygdala and DRN-frontal cortex pathways.51

Reducing central 5-HT synthesis through L-tryptophan restriction specifically impairs short-term and long-term memory performance in rats and humans.49,111 Depletion of 5-HT by using the tryptophan hydroxylase inhibitor, parachlorophenylalaline (PCPA), during synaptogenesis decreases synaptic density in the adult rat hippocampus, while inducing spatial learning deficits associated with failure to extinction and, consequently, relearning.87 In contrast, 5-HT depletion following 5,7-DHT lesioning has been found to facilitate acquisition and performance of various learning tasks in rats such as spatial discrimination,3 conditional visual discrimination (presumably by reducing proactive interference),131 and temporal discrimination under certain conditions such as when the task difficulty is increased.4 Fluoxetine, a SSRI, was found to weaken associative memory in the rat,97 but aged rats treated with a low dose of the 5-HT precursor (5-hydroxytryptophan, 5-HTP) improved their performance (over controls) in a spatial memory task.110

From the above studies inconsistencies emerge about the mechanisms by which 5-HT might be involved in memory functions or dysfunctions. These are attributable, in part, to the application of this global experimental strategy, which modifies the entire serotonergic system and its interactions with other neurotransmitters, such as the cholinergic system.

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