Dopaminergic lnterference for Treatment of Schizophrenia and Alcohol Use Disorder - an experimental study in rats

Sammanfattning: The neurotransmitter dopamine is involved in several different physiological functions as well as pathological conditions. Two conditions that have been suggested to be related to a low dopaminergic tone in the ventral striatum are substance use disorder, and negative symptoms in schizophrenia, both of which are difficult to treat. In this thesis, we aimed to investigate in the rat the possibility of elevating dopamine in the ventral striatum (nucleus accumbens, nAc) in order to treat these conditions. To this end, we utilized in vivo microdialysis to sample and analyse extracellular dopamine, ex vivo electrophysiological field potential recordings to analyse effects on primarily excitatory neurotransmission, as well as behavioural methods to study ethanol consumption and behavioural sensitisation. In paper I, we show that the combination of the smoking cessation agent varenicline and the anti-depressant bupropion has an additive effect on nAc dopamine, and eliminates the alcohol deprivation effect in an ethanol consumption study. In paper II, we showcased the effects of protracted amphetamine treatment on both ventral and dorsal striatal (dorsomedial striatum, DMS) dopaminergic signalling. Results show that the nAc appears more sensitive to both acute and repeated amphetamine challenge, and that repeated amphetamine results in both reduced basal dopamine release and a qualitatively different signalling via dopamine D2 receptors in this region. In paper III, we investigated the effects of psychosis-generating and non-psychosis-generating addictive substances with regards of their effect on nAc and DMS dopamine. Key findings showed a distinct difference between amphetamine and cocaine, both strongly pro-psychotic, and nicotine, which has low psychosis-generating potential. Whereas amphetamine and cocaine both produced robust and similar elevations in dopamine in both the nAc and DMS, nicotine only had a noticeable effect in the nAc. In paper IV, findings from previous papers were combined in an effort to propose a way to selectively elevate dopamine in the nAc, without affecting DMS dopamine. We show that combining ethanol and nicotine produces an additive effect on nAc dopamine, with no marked interference on DMS dopamine, findings that we could then reproduce using varenicline and the glycine transport inhibitor Org24598. The combined findings presented in this thesis lend support to the possibility of raising nAc dopamine for treatment of alcohol use disorder and selectively raising nAc dopamine, for treatment of negative symptoms of schizophrenia.