Research in our group revolves around biogenic amines in the brain: molecular biology, biochemistry and physiology, with special reference to drug development in neuropsychopharmacology.
Our research projects continue and extend our ongoing work aiming at the development of novel and improved pharmacological treatments of schizophrenia, major depression and tobacco dependence. These disorders represent some of the most costly medical problems known in the industrialized world, both at the level of the individual and at the level of the society.
Our research, which originates in clinical problems and observations, utilizes an advanced set of basic scientific methodologies including transgenic mice, extra- and intracellular recordings, microdialysis and several behavioral techniques, in combination with various selective pharmacological tools to identify critical sites of action for new treatment strategies in this medical area.
|Monica Marcus||Senior lab manager|
|Torgny Svensson||Professor, senior|
|Joep Titulaer||R&D trainee, Student|
Research project 1:
Focuses on identification of principles for development of improved antipsychotic drug treatment. During the nineties a number of new antipsychotic drugs have been introduced, with advantageous effect against negative and cognitive symptoms in schizophrenia and less neurological side effects, the so-called second generation antipsychotic drugs or atypical antipsychotics.
This project aims at defining their critical mechanisms of action, with special emphasis on certain neurotransmitter systems in the brain, in particular glutamate and dopamine, and specifically some receptors, namely dopaminergic D1 receptors, alpha2 adrenoceptors, 5-HT2A receptors and several types of cholinergic receptors, i.e. muscarinic m1 and m4 receptors and nicotinic alpha7 receptors, as well as glycine reuptake inhibitors.
All these receptors have previously been shown to generally modulate both dopaminergic and glutamatergic neurotransmission in the brain, particularly important in the prefrontal cortex, where these neurotransmitters seem to play a pivotal role in the control of negative and cognitive symptoms of schizophrenia.
The present work will continue to utilize the phencyclidine model of schizophrenia and a series of typical and atypical antipsychotic drugs as well as various receptor selective ligands, to delineate the specific roles of different receptor affinities of antipsychotic drugs and glutamatergic modulation per se for clinical efficacy.
Research project II:
Focuses on the functional roles of nicotinic receptor subtypes in the control of midbrain dopamine neurons using transgenic mice, and the potential utility of conjugate vaccines, i.e. active immunization against nicotine, and dopamine stabilizers in the treatment of nicotine dependence.
Our previous work has shown that nicotinic alpha7 receptors as well as certain muscarinic receptors may serve to modulate the glutamatergic input to midbrain dopamine neurons. Our continued studies will, partly in collaboration with Jean-Pierre Changeux (Paris) and Lars Olson (Stockholm), further characterize the role of other nicotinic and muscarinic receptor subtypes in the regulation of the mesocorticolimbic dopamine system.
In other studies we will continue our ongoing characterization and development of a conjugate vaccine for active immunization against nicotine dependence, as well as clarify the potential utility of dopamine stabilizers in nicotine dependence.
Research project III:
Aims at delineating basic mechanisms for novel augmentation strategies in the treatment of major depression. With particular emphasis on serotonergic autoreceptor functioning during treatment with escitalopram, which shows a shortened latency of onset of action, and the significance of dopaminergic modulation via methylphenidate and GR II receptor antagonists in enhancement of SSRIs. Drug combinations that already show promising clinical results.
Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.
Eur Neuropsychopharmacol 2013 Jul;23(7):709-20
Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat.
Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Oct;39(1):143-8
Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission.
Psychopharmacology (Berl.) 2012 May;221(1):115-31
Smoking, quitting, and psychiatric disease: a review.
Neurosci Biobehav Rev 2012 Jan;36(1):271-84
Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat.
Synapse 2011 May;65(5):357-67
Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias.
Exp. Neurol. 2010 Oct;225(2):408-15
Reboxetine enhances the olanzapine-induced antipsychotic-like effect, cortical dopamine outflow and NMDA receptor-mediated transmission.
Neuropsychopharmacology 2010 Aug;35(9):1952-61