Theoretical reflections about the reciprocal influence of neurotransmitters upon each other

In the reticular formation, serotonin and noradrenaline are competitive neurotransmitters in the regulation of the sleep-waking cycle. A balance exists between the two neurotransmitters: serotonin is preponderant during sleep and noradrenaline during wakefulness. Adrenergic neurons transmit an excitatory impulse to glutaminergic neurons via alpha1 receptors. These neurons have an inhibitory effect on serotonergic neurons through NMDA receptors. By contrast, serotonergic neurons exert a sleep-inducing and soothing effect through 5-HT1A receptors. These neurons have a postsynaptic excitatory effect upon GABAergic neurons, which presynaptically inhibit adrenergic neurons via GABAA recpetors. This model describes a feedback circuit of the four neurotransmitters that depend on the circadian rhythm. In the pathogenesis of schizophrenia, new research has revealed hyperactivity of dopamine and serotonin in the mesolimbic system. Atypical neuroleptics are D2 and 5-HT2A antagonists are used to treat positive and also negative psychotic symptoms. However, other neurotransmitters, such as glutamate and GABA, are also involved in the pathogenesis of schizophrenia. In animal experiments, glutamate antagonists cause schizophrenic behaviour, which can be relieved by 5-HT2A antagonists. In healthy subjects, a possible neuronal combination could be that dopaminergic neurons would transmit a postsynaptic excitatory impulse to glutaminergic neurons which presynpatically inhibit serotonergic neurons. The serotonergic neurons, in turn, would transmit a postsynpaptic excitatory impulse to GABAergic neurons, which presynaptically inhibit dopaminergic neurons. The presynaptic inhibition prevents hyperactivity of either the dopaminergic or serotonergic system. In schizophrenic patients, 5-HT2A receptors could be localized on dopamine cells so that there is no presynpatic inhibition. Consequently, hyperactivity of dopaminergic and serotonergic neurons is possible. As a result of this, new neuroleptics should have an optimal ratio of D2/5-HT2A receptor occupancy. It is possible that agonism against NMDA and GABAA might improve schizophrenic symptoms.