Werner, F.-M. and Covenas, R.

Euro-Schulen Pößneck, Pößneck, Germany


Introduction: In schizophrenia a glutamate and GABA deficiency is encoded in the genes GAD 67, neuregulin-1 and dysbindin-1, and dopamine and serotonin hyperactivity occurs through a reduced presynaptic inhibition. Other neurotransmitters, neuropeptides and the corresponding specific subreceptors play a role in pathogenesis of schizophrenia. A neuronal network is developed to derive novel therapeutical options.

Material/Methods: The neuronal network can be decribed as follows: In the mesolimbic system GABAergic neurons weakly inhibit via GABAA receptors D2 dopaminergic neurons which exert a high activity. Tachykinin neurons activate dopaminergic neurons via NK3 receptors. Encoded in the suceptibility genes, glutaminergic neurons weakly inhibit via NMDA receptors serotonergic neurons which exert a high activity via 5-HT2A receptors. Dopamine and serotonin hyperactivity is increased, because in the A10 cell group serotonergic and dopaminergic neurons activate each other via 5-HT2A and D2 receptors. GABAergic neurons send projections to neurotensin neurons in the prefrontal cortex, which transmit a weak activating impulse to glutaminergic neurons via NTS1 receptors. GABAergic neurons are connected as well to cholecystokinin (CCK) neurons in the prefrontal cortex, which activate glutaminergic neurons via CCKA receptors. CCK deficiency can induce accustic hallucinations. The glutaminergic neurons inhibit serotonergic neurons in the mesolimbic system. Cannabinoid neurons inhibit CCK neurons via CB1 receptors and are therefore hallucinogenic. In the prefrontal cortex D1 dopaminergic neurons with a high activity are combined through presynaptic GABAergic and glutaminergic neurons with M4 muscarinic cholinergic neurons, which have a low activity.

In the hippocampus dopaminergic and serotonergic neurons are connected with each other through presynaptic GABAergic and glutaminergic neurons, while nicotinic cholinergic neurons activate GABAergic neurons via alpha4beta2 and alpha7 nAch receptors. Other serotonergic neurons with a high activity activate serotonergic neurons via 5-HT7 receptors.

Results: In addition to the treatment with atypical antipsychotic drugs, the following therapeutic options could be administered:
-     NK3 antagonists which inhibit D2 dopaminergic neurons,
-     M4 agonists which reduce dopamine hyperactivity in the prefrontal cortex,
-     NTS1 agonists or neurotensin analogs,
-     CCKA receptors agonists to treat accustic hallucinations,
-     CB1 receptor antagonists which increase CCK levels,
-     Alpha4beta2 and alpha7 nicotinic cholinergic agonists in order to improve cognitive function,
-     5-HT7 antagonists in order to improve cognitive function.

Conclusion: It is important to examine the involved neuronal networks and to investigate whether the mentioned new drugs can improve or not the treatment of positive and negative schizophrenic symptoms.