SUMMARY “Serotonergic modulation of dopamine and GABA inputs to A9 and A10 dopamine neurons and its role in antipsychotic drug efficacy”.

This thesis investigated differential (modulatory) effects of serotonin on A9 and A10 dopamine neurons in the rat brain. As these neurons are implicated in the therapeutic effects as well as the extra-pyramidal side-effects of antipsychotic drugs, the existence of possible differences in the regulation of the actvity of these neurons might provide new targets or a more refined treatment of schizophrenia using antipsychotic drugs.

In Chapters 2 and 3 the (differential) effect of antipsychotic drugs and serotonin (5-HT) on dopamine neuron firing activity was determined. These chapters show that not only does serotonin enhance dopamine D 2 receptor-mediated auto-inhibition, but that the 5-HT 2 receptor is differentially involved in this effect. Furthermore, this differential involvement of the 5-HT 2 receptor was shown to be (partly) responsible for the difference in effect that atypical antipsychotics have in an amphetamine-model for schizophrenia.

Chapter 4 further explored the cellular mechanisms behind the 5-HT-mediated enhancement of dopamine D 2 receptor mediated-auto-inhibition as well as a possible modulatory effect of serotonin on GABA B receptor-mediated inhibition of the firing activity. The results in this chapter indicated that serotonergic effects on dopamine and GABA B receptor-mediated inhibition impinged on the G protein coupled inward rectifying potassium (GIRK) channel, although the cellular locations were the involved 5-HT receptors exerted their effects are (likely) very different.

Concluding, the work described in this thesis showed that 5-HT modulates dopamine neuron firing activity via a differential involvement of 5-HT receptors in A9 and A10. Not only do these results support the hypothesis that 5-HT 2 receptor affinity of antipsychotic drugs is an important feature of these drugs for the reduction of extra-pyramidal side-effect probability, they also uncovered a previously unknown modulatory role for 5-HT on GABAB receptor-mediated inhibition.