From DEPARTMENT OF PHYSIOLOGY AND PHARMACOLOGY Karolinska Institutet, Stockholm, Sweden NOVEL PHARMACOLOGICAL TREATMENT ALTERNATIVES FOR SCHIZOPHRENIA

Antipsychotic drugs are commonly divided into typical (first generation) and atypical (second generation) antipsychotic drugs. Clinically effective doses of typical antipsychotic drugs generate a striatal dopamine D2 receptor occupancy of about 70 – 80%, approaching a level that is associated with a high risk of extrapyramidal side effects. Typical antipsychotic drugs are mostly effective against positive symptoms, but have a more limited effect on and may even exacerbate negative and cognitive symptoms. In contrast, some, but not all, atypical antipsychotic drugs are clinically effective at lower D2 receptor occupancy. Clozapine, which may be considered as the prototypical atypical antipsychotic drug, thus displays only around 45% D2 receptor occupancy and generates virtually no extrapyramidal side effects. Compared with typical antipsychotic drugs, atypical antipsychotics have been found to improve not only positive symptoms, but also negative symptoms and cognitive impairment. Several atypical antipsychotic drugs are, however, associated with other major side effects, such as for example weight gain, diabetes, heavy sedation and even agranulocytosis. Clozapine has a broad spectrum of receptor affinities and acts as an antagonist at several dopamine receptors (i.e. D2, D3 and D4 receptors), but also at e.g. α1 and α2 adrenoceptors, 5-HT2A and 5-HT2C receptors, muscarinic and histaminergic (H1) receptors. In contrast to a typical antipsychotic drug such as haloperidol most atypical antipsychotic drugs have been found to increase dopamine in the medial prefrontal cortex of rodents. Moreover, most atypicals that generate improved cognitive function also enhance prefrontal glutamatergic transmission and increase extracellular levels of acetylcholine in the cerebral cortex. Since treatment outcome is critically dependent on the degree of cognitive impairment, the putative cognitive enhancing effects of antipsychotic drugs are of considerable interest. Generally, the currently available drugs for schizophrenia are insufficient in this regard. Therefore, the development of more effective and better tolerated antipsychotic drugs with less side effects is highly warranted. This development may be facilitated by evaluation of so-called augmentation strategies using combinations of existing antipsychotics and other psychoactive drugs, such as for example antidepressants and various selective ligands for specific neurotransmitter-related targets in the brain. In this thesis we have experimentally evaluated several augmentation strategies employing a combination of behavioral, biochemical and electrophysiological techniques. Our results show that the addition of two antidepressant drugs, reboxetine or mianserin, significantly augment the antipsychotic-like effect induced by raclopride without affecting the raclopride-induced catalepsy, concomitant with a preferentially increased prefrontal dopamine output. We have also shown that adjunctive treatment with the selective α2 adrenoceptor antagonist idazoxan when added to a typical (haloperidol) or an atypical (olanzapine) antipsychotic drug, significantly enhances the suppression of conditioned avoidance response (CAR) without increasing catalepsy and produces a substantial increase in dopamine output in the medial prefrontal cortex. Moreover, we have found that galantamine, a cognitive enhancing drug used in Alzheimer’s disease, facilitates the excitability of VTA dopamine neurons via allosteric potentiation of nicotinic acetylcholine receptors of the α7 subtype, and that galantamine through this mechanism, rather than through acetylcholine esterase inhibition, increases prefrontal dopamine outflow. Subsequently, we observed that addition of galantamine to raclopride can significantly enhance the raclopride-induced suppression of CAR without increasing catalepsy, effects that could not be reproduced by adjunctive treatment with donepezil, a selective acetylcholine esterase inhibitor. Our data support the view that increasing prefrontal dopamine and noradrenaline output either by blocking the noradrenaline transporter or the noradrenergic autoreceptor may represent viable strategies to augment the efficacy of antipsychotic drugs without increasing extrapyramidal side effect liability. Our previous results also provide evidence that this strategy may secondarily facilitate cortical glutamatergic transmission and cognitive functioning, e.g. working memory. Our data finally provide support for the adjunctive use of galantamine together with antipsychotic drugs in schizophrenia, not only to improve cognition and negative symptoms, but also to potentially enhance the antipsychotic effect per se. By inference, these results support the development of selective allosteric potentiators of α7 nicotinic acetylcholine receptors for the treatment of schizophrenia. LIST OF PUBLICATIONS I. Linnér L, Wiker C, Wadenberg ML, Schalling M, Svensson TH (2002) Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat. Neuropsychopharmacology, 27(5):691-8. II. Wiker C, Linnér L, Wadenberg ML, Svensson TH (2005) Adjunctive treatment with mianserin enhances effects of raclopride on cortical dopamine output and, in parallel, its antipsychotic-like effect. Neuropsychiatric disease and treatment, 1(3):153-60. III. Wadenberg ML, Wiker C, Svensson TH (2007) Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive 2 adrenoceptor blockade: experimental evidence. International Journal of Neuropsychopharmacology, 10(2):191-202. IV. Schilström B, Ivanov VB, Wiker C, Svensson TH (2007) Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology, 32 (1): 4353. V. Wiker C, Schilström B, Sandbäck C, Wadenberg ML, Svensson TH (2007) Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats. Manuscript under revision in International Journal of Neuropsychopharmacology. All previously published papers were reproduced with permission from the publisher.