Neuronal functioning serotonin action

FIGURE 5—44. This figure shows how norepinephrine can function as a brake for serotonin release. When norepinephrine is released from nearby noradrenergic neurons, it can diffuse to alpha 2 receptors, not only to those on noradrenergic neurons but as shown here, also to these same receptors on serotonin neurons. Like its actions on noradrenergic neurons, norepinephrine occupancy of alpha 2 receptors on serotonin neurons will turn off serotonin release. Thus, serotonin release can be inhibited not only by serotonin but, as shown here, also by norepinephrine. Alpha 2 receptors on a norepinephrine neuron are called autoreceptors, but alpha 2 receptors on serotonin neurons are called heteroreceptors. 

How precisely does cocaine achieve these effects in the brain As described in Chapter i, once a neurotransmitter is released from its neuronal terminal, its actions within the synapse are ended principally by reuptake into the presynaptic terminal. Cocaine primarily blocks the reuptake of dopamine but also acts similarly on norepinephrine and serotonin reuptake. If your neuronal terminals can be seen as acting like little vacuum cleaners, then cocaine essentially clogs the vacuum nozzle. As a consequence of this blockade, the concentrations of dopamine, norepinephrine, and serotonin within the synaptic cleft between two neurons increases dramatically. Withinmillions of synapses in the brain, these neurotransmitters are now free to continue to stimulate their receptors over and over, again and again. There are neuronal terminals for dopamine, norepinephrine, and serotonin scattered throughout the entire brain, and thus the consequences of cocaine on brain function are also widespread. 

It has been reported that serotonin can produce opposite and complementary action on neuronal functioning, maturation, proliferation and apoptosis, depending on the kind and the density of receptors synthesized by the cells [1]. There are at least fourteen different receptor subtypes described for 5-HT, 13 different heptahelical G-protein-coupled receptors and one ligand-gated ion channel (Table 3). The 5-HT receptor family has been, and is at present, subjected to intense research. Excellent and complete reviews of functional, molecular and pharmacological aspects of 5-HT receptors have been published [5-7]. 

Monoamine oxidase inhibitors MAO is found in neural and other tissues, such as the gut and liver. In the neuron, this enzyme functions as a "safety valve" to oxidatively deaminate and inacti vate any excess neurotransmitter molecules (norepinephrine, dopamine, or serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors2 may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumu late within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. 

Despite the recent advances in molecular biology, the mechanisms of action and the physiological functions of the anandamide system remain obscure. It would appear that the cannabinoid receptors and the anandamides reside within the neurons. Thus unlike the classical neurotransmitters noradrenaline and serotonin, the anandamides are not released into the synaptic cleft and are not involved in intemeuronal communication. Instead the anandamides modulate the excitability and inhibitory responsiveness of neurons by acting on cannabinoid hetero-ceptors located on inhibitory and excitatory terminals. In this way, the... 

In addition to its other functions BH4 enhances the release of dopamine and serotonin in the rat striatum when administered locally through the dialysis membrane. The enhancement of dopamine release persisted even when dopamine biosynthesis or dopamine reuptake was completely blocked, but it was abolished when hlockers of voltage-dependent Na" " or Ca " " channels were administered with BH4. Further experiments using selective inhibitors of tyrosine, TH, and NOS demonstrated that BH4 stimulates dopamine release directly, independent of its cofactor action on TH and NOS, by acting from the outside of neurons. The exact mechanism is not entirely clear but it has been shown that arginine also induces a concentration-dependent increase of dopamine release in the superfusate of rat striatum slices, and that it is dependent on the presence of BH4. ... 

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