Novel pharmacological treatment alternatives for schizophrenia
Author: Wiker, Charlotte
Date: 2007-12-07
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna
Time: 09.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
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thesis.pdf (1.274Mb)
Abstract
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 papers:
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
Pubmed
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 alpha2 adrenoceptor blockade: experimental evidence." Int J Neuropsychopharmacol 10(2): 191-202
Pubmed
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): 43-53
Pubmed
V. Wiker C, Schilström B, Sandbäck C, Wadenberg ML, Svensson TH. (1970). "Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats." International Journal of Neuropsychopharmacology (Manuscript)
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
Pubmed
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 alpha2 adrenoceptor blockade: experimental evidence." Int J Neuropsychopharmacol 10(2): 191-202
Pubmed
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): 43-53
Pubmed
V. Wiker C, Schilström B, Sandbäck C, Wadenberg ML, Svensson TH. (1970). "Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats." International Journal of Neuropsychopharmacology (Manuscript)
Issue date: 2007-11-16
Rights:
Publication year: 2007
ISBN: 978-91-7357-343-6
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