Papers by Arnoud Herremans
Pharmacy World & Science, 1993
We previously found that [tzSI] ET-f (30 pM) labeled a homogeneous receptor population in the hum... more We previously found that [tzSI] ET-f (30 pM) labeled a homogeneous receptor population in the human coronary artery.[= z~ I] Sarafotoxin S6b (30 pM) labeled a similar receptor, but apparently also labeled a non-ET^, non-ET B receptor with relatively high affinity for both ...
Pharmacy World & Science, 1994
Metanocortins have various physiological actions on the brain. The recent cloning of neural melan... more Metanocortins have various physiological actions on the brain. The recent cloning of neural melanecortin 0//(2) receptors Opened new avenues to study the effect of these ncuropeptides on the nervous system. We investigated the structure activity relations (SARs) of peptides derived from adrenecorticotropo hormone (ACrH) on cloned MC3, MC4 and MC5 receptors in vitro. Analysis of the effects of various melanocortin peptides on cAMP accumulation in and on binding to cells that expressed either the rat MC3 receptor, the human MC4 receptor or the ovine MC5 receptor demonstrated that different ACTH fragments and analogs could selectively activate or inhibit the MC receptor subtype activities. The SAP.. of the MC4 receptor resembled that of the induction of excessive grooming behavior by melanocortin poptides. Antagonists that blocked the MC4 receptor were also tested to block a behavioral response induced by cc-MSH, a-MSH-induced excessive grooming behavi~ in rats was inhibited by [Pbe-IT]ACTH-(4-10), [D-ArgS]ACTH-(4-10) and [ProSa~ but not by [Ala6]ACTH-(4-10). From these 4 antagonists, only the latter compound did not antagonize the MC4 receptor in vitro. Therefore, we suggest that this behavioral response is mediated by MC4 receptors. ORG2766, an ACTH 4-9 analog that is very potent in an active avoidance task, did not activate, antagonize or bind to the MC receptors. This suggests the presence of still other MC receptors than the MC3, MC4 and MC5 receptors in the brain. In order to develop more selective MC (an0agonists, the interaction of melanoeortins and receptors at molecular level were investigated. Based upon a 3D-medel for MC receptors and the differences in primary ,structure of the MC receptors, receptormutagenesis was preformed in order to identify the amino acids in the receptors that underly the selectivity that these receptors display for the different melanecortins. Therefore, the MC4 receptor, which is not activated by low doses of yMSH, was genetically modified with sequences that occur in the MC3 receptor, which is activated by yMSH. Furthermore, amino acids that according to our model were important for peptide binding were mutated. Both the binding characteristics as well as the activation of the mutated MC4 receptors by melanecorims were altered. These studies may be employed for development of novel MC-receptor-spectfie ligands.
European Neuropsychopharmacology, 2001
Behavioural Pharmacology, Aug 1, 1998
receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT 2 receptor a... more receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT 2 receptor antagonists. PHARMACOL BIO-CHEM BEHAV 64 (2) 389-395, 1999.-Ten homing pigeons were trained to discriminate the selective 5-HT 1A receptor agonist flesinoxan (0.25 mg/kg PO) from its vehicle in a fixed-ratio (FR) 30 two-key operant drug discrimination procedure. The 5-HT 2 receptor antagonist mianserin (ED 50 ϭ 4.8 mg/kg) fully substituted for flesinoxan, whereas ketanserin, ritanserin, mesulergine, and SB200646A substituted only partially, suggesting an interaction between 5-HT 1A and 5-HT 2 receptors. However, the 5-HT 2 receptor agonists [DOI (0.6 mg/kg), TFMPP (10 mg/kg), mCPP (4 mg/kg)] were unable to antagonize the flesinoxan cue. The 5-HT 1A receptor antagonists DU125530 (0.5-13 mg/kg) and WAY100,635 (0.1-1 mg/kg) partially antagonized the generalization of mianserin to flesinoxan. Taken together, these results are in accordance with the hypothesis that 5-HT 1A receptor activation exerts an inhibitory effect on activation of 5-HT 2 receptors. These results are in broad agreement with existing theories on 5-HT 1A and 5-HT 2 receptor interaction. Furthermore, it is argued that the discriminative stimulus properties of a drug may undergo qualitative changes with prolonged training.
Neuroscience applied, 2022
Pharmacology, Biochemistry and Behavior, Oct 1, 1999
Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamin... more Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamine and its vehicle as assessed in a drug discrimination paradigm have been without success. The present experiments were, therefore, designed to assess in a conditioned taste aversion procedure (CTA) whether or not fluvoxamine possesses stimulus properties. Rats were exposed to a conditioned taste aversion (CTA) procedure. In Experiment I, subjects were given 15 mg/kg fluvoxamine PO or vehicle after drinking a novel tasting saccharin solution. In Experiment II, a comparison was made between the effects of 15 mg/kg fluvoxamine IP, 30 mg/kg fluvoxamine IP, NaCl, and lithiumchloride (LiCl). In Experiment III, subjects were treated with either 10 mg/kg fluoxetine IP, 30 mg/kg fluvoxamine IP, or LiCl. CTA was observed after treatment with LiCl, but never after treatment with fluvoxamine or fluoxetine, suggesting that fluvoxamine does not have clear stimulus properties, which can serve as a discriminative stimulus in operant procedures. In a crossfamiliarization CTA procedure in mice, however, fluvoxamine elicited a reliable CTA, suggesting that under certain conditions (species, dose?) selective serotonin reuptake inhibitors (SSRIs) may lead to certain discriminable effects. It is as yet unclear why SSRIs apparently produce such weak and species or situation-dependent discriminable effects.
Behavioural Pharmacology, 1998
European Neuropsychopharmacology, 2002
the patients group scores in psychological domain of Q0L decreased significantly during follow up... more the patients group scores in psychological domain of Q0L decreased significantly during follow up. Patients scored significantly worse than controls in all areas of SFS. During the year following first psychiatric hospitalization significant improvement in social engagement and a trend towards increase of pro-social activities were observed. Gender differences were detected. There was a trend towards younger age of male patients. In the first assessment women had higher scores in the area of social engagement of SFS. In the second assessment women scored significantly lower in general subscale and overall PANSS scale than men. Female gender was also associated with better social engagement, higher level of independence and employment in the second assessment. Associations between severity of symptoms after discharge and social functioning and perception of quality of life and own health were also found. Conclusion: The findings suggest presence of deficits in social functioning in the early course of schizophrenia and the role of gender and clinical symptoms of the illness as predictors of social adjustment. In the studied group decrease in psychological dimension of quality of life during follow up was observed.
Journal of Pain Research
Background: Evidence-based clinical guidelines consider physical exercise one of the best nonphar... more Background: Evidence-based clinical guidelines consider physical exercise one of the best nonpharmacological interventions for low-back pain (LBP), but it is necessary to clarify the exercise-induced hypoalgesia effect of different modalities of exercise in chronic pain populations. Purpose: This study focused on exploring acute changes in tactile and pressure-pain perception and lumbar strength and flexibility in patients with nonspecific chronic LBP (NSCLBP) after performing one of three 20-minute physical exercise modalities. Methods: A total of 81 patients with NSCLBP were pseudorandomly distributed into three groups of 20-minute physical exercise-1) aerobic (n=21, mean age 42±9.72 years, nine men), 2) stretching (n=21, mean age 40±11.37 years, ten men), and 3) strengthening (n=20, mean age 35.80±11.56 years, ten men)-and 4) a control group (n=19, mean age 38.64 ±10.24 years, eight men), and completed self-reported questionnaires during the same period. Tactile and pressure-pain thresholds and isometric lumbar muscle endurance and flexibility were assessed before and after this brief exercise-based intervention. Results: All groups were comparable in terms of sociodemographic and clinical data, cardiovascular capacity, and self-reported data onphysical disability, mood, motivation, psychological response to stimulus properties of physical exercise, and physical activity enjoyment. Our analyses revealed higher tactile sensitivity (p<0.001) and pressure-pain thresholds (p<0.001) at the forefinger than other body locations. We also found lower pain sensitivity (p=0.010) and pressure pain-intensity ratings (p=0.001) and higher lumbar flexibility (p<0.001) after intervention. After calculation of absolute pre-post differences, higher tactile sensitivity was observed at the gluteus medius muscle than the erector spinal muscle only after aerobic intervention (p=0.046). Conclusion: These results add some evidence about different modalities of exerciseinduced hypoalgesia in NSCLBP. However, the fact that we also found improvements in the control group limits our conclusions.
Frontiers in Psychiatry
Objective: Adolescent depression is a heterogeneous disorder, with a wide variety of symptoms and... more Objective: Adolescent depression is a heterogeneous disorder, with a wide variety of symptoms and inconsistent treatment response, and is not completely understood. A dysregulated stress system is a consistent finding, however, and exhaustion is a consistent trait in adolescent patients. The aim of this paper is to critically assess current hypotheses in adolescent depression research and reframe causes and treatment approaches. Methods: A mixed-method approach involved a review based on publications from PubMed, Embase and PsycInfo, and two exemplary adolescent cases. Results: Both cases show a spiral of stress and exhaustion, but with a different profile of symptoms and coping mechanisms. Reframing both cases from the perspective of coping behavior, searching for the sources of experienced stress and exhaustion, showed coping similarities. This proved essential in the successful personalized treatment and recovery process. In combination with recent evidence, both cases support the functional reframing of depression as the outcome of a stress-and exhaustion-related spiralling mechanism. Conclusions: We propose to open up a symptom-based, mood-centered view to a model in which adolescent depression is framed as a consecutive failure of stress coping mechanisms and chronic exhaustion. Addressing exhaustion and coping primarily as a treatment strategy in adolescents and young adults might work in synergy with existing treatments and improve overall outcomes. This perspective warrants further investigation.
Medicine
Depression is one of the most common mental health problems which affects more than 10% of the gl... more Depression is one of the most common mental health problems which affects more than 10% of the global population. The prevalence of this disorder is higher in fibromyalgia patients. However, the influence of the combination of depression and fibromyalgia in the brain processing is poorly understood. To explore the modifications of EEG power spectrum in women with fibromyalgia when depressive feelings are elicited. Twenty eight women with fibromyalgia participated in this cross-sectional study. They were classified as women with depression or women without depression according to the score in the Geriatric Depression Scale. This questionnaire was used to elicit depression symptoms during the EEG recording. Analyses were performed with the standardized LOw Resolution Electric Tomography (sLORETA) software. Power spectrum were compared in the following frequency bands: delta, theta, alpha-1, alpha-2, beta-1, beta-2, and beta-3. Fibromyalgia patients with untreated depression showed a hypoactivation of the left hemisphere when compared with fibromyalgia patients without depression. In addition, when compared fibromyalgia patients without depression and women with both fibromyalgia and depression who were taking antidepressant medications, differences in EEG power spectrum in the studied frequency bands were not found. The current study contributes to the understanding on the influence of the combination of fibromyalgia and depression in the brain activity patterns. Patients with untreated depression showed a hypoactivation of the left hemisphere while eliciting depression symptoms. However, further research is needed, antidepressant medication might reduce the differences between patients with depression and those who do not suffer from depression symptoms.
Journal of Medicinal Chemistry, 2002
A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was... more A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (K(i) = 0.01 nM) and selectivity for the hA(3) versus A(1), A(2A), and A(2B) receptors (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA(3) receptor indicated a K(B) value of 0.20 nM.
European Neuropsychopharmacology, 2003
Physical (PS) and emotional (ES) stress have opposite long-term effects on open field behaviour, ... more Physical (PS) and emotional (ES) stress have opposite long-term effects on open field behaviour, i.e., response to novelty. PS induced a long-term reduction in locomotor activity, while ES increased it. Additionally, sensitivity to rewarding stimuli was differentially affected by PS and ES. Whether the stress effects were specific for locomotor activity and reward or if these two stress treatments also have differential effects on other behaviours and brain functions is not known. In the present study, temperature regulation, sensory gating, learning capacity, locomotor activity and coping style were examined. PS consisted of a repeated mild foot shock treatment, which the ES animals witnessed. The tests pose additional challenges, to which all groups can respond differently depending on their previous experience. All tests were performed several days after the last stress treatment. Stress effects were specifically observed on locomotor activity, startle response and prepulse inhibition (PPI). The PS animals showed a potentiated inhibition of the startle when a prepulse (PPI) was used, although the initial startle response was already significantly lower than that of controls. ES animals did not differ from controls on PPI and startle. Additionally PS animals showed an initial decrease in activity, which turned into an increase when the tests continued. ES showed a constant increase in activity compared to controls. Stress effects on the tests for other brain processes and behaviour were not found. In addition, PS animals appeared to be less sensitive to the dopamine agonist apomorphine than control animal. In summary, physical and emotional stress induce differential changes on locomotor activity, startle response and PPI. Underlying mechanisms explaining the differences in stress effects are discussed, i.e., the role of the mesolimbic dopamine system and opioid systems.
European Journal of Pharmacology, 1997
Twelve homing pigeons were trained to discriminate the 5-HT receptor agonist flesinoxan 0.25 mgrk... more Twelve homing pigeons were trained to discriminate the 5-HT receptor agonist flesinoxan 0.25 mgrkg p.o. from its vehicle in a 1A 1A
Behavioural Pharmacology, 1998
receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT 2 receptor a... more receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT 2 receptor antagonists. PHARMACOL BIO-CHEM BEHAV 64 (2) 389-395, 1999.-Ten homing pigeons were trained to discriminate the selective 5-HT 1A receptor agonist flesinoxan (0.25 mg/kg PO) from its vehicle in a fixed-ratio (FR) 30 two-key operant drug discrimination procedure. The 5-HT 2 receptor antagonist mianserin (ED 50 ϭ 4.8 mg/kg) fully substituted for flesinoxan, whereas ketanserin, ritanserin, mesulergine, and SB200646A substituted only partially, suggesting an interaction between 5-HT 1A and 5-HT 2 receptors. However, the 5-HT 2 receptor agonists [DOI (0.6 mg/kg), TFMPP (10 mg/kg), mCPP (4 mg/kg)] were unable to antagonize the flesinoxan cue. The 5-HT 1A receptor antagonists DU125530 (0.5-13 mg/kg) and WAY100,635 (0.1-1 mg/kg) partially antagonized the generalization of mianserin to flesinoxan. Taken together, these results are in accordance with the hypothesis that 5-HT 1A receptor activation exerts an inhibitory effect on activation of 5-HT 2 receptors. These results are in broad agreement with existing theories on 5-HT 1A and 5-HT 2 receptor interaction. Furthermore, it is argued that the discriminative stimulus properties of a drug may undergo qualitative changes with prolonged training.
Behavioural Brain Research, 2011
Cannabinoid CB1 receptor (CB1R) signaling has been shown to play a role in the regulation of addi... more Cannabinoid CB1 receptor (CB1R) signaling has been shown to play a role in the regulation of addictive behavior. In the present study, our aim was to investigate whether the CB1R antagonist SLV330 could reduce ethanol and nicotine self-administration and cue-induced reinstatement of ethanol and nicotine seeking behavior in Wistar rats.In operant chambers, rats were learned to emit a specific response
Behavioural Brain Research, 1997
Effects of bilateral infusions of cholinergic drugs into the dorsal part of the medial prefrontal... more Effects of bilateral infusions of cholinergic drugs into the dorsal part of the medial prefrontal cortex (dmPFC) on performance in a delayed conditional discrimination (DCD) task were examined in rats. Scopolamine dose-dependently impaired performance. No delay-dependent effect was found indicating that scopolamine did not specifically affect working memory (WM). Physostigmine alone induced a slight improvement of DCD performance independent of delay and co-administration of physostigmine with scopolamine attenuated the scopolamine-induced impairment of DCD performance. Infusion of the muscarinic M2 antagonist AQRA-471, the M 3 antagonist 4-DAMP and the mixed M1-M 3 antagonist UH-AH 37 did not affect performance in the DCD task, suggesting that the effect of scopolamine is not mediated by a single muscarinic receptor subtype. The results furthermore indicate that the cholinergic system in the dmPFC does not play a specific role in WM processes in the DCD task. Furthermore, the results suggest that the dmPFC cholinergic system plays a role in the attentional processes involved in the DCD task.
Behavioral Neuroscience, 1995
The centrally acting cholinergic antagonist scopolamine (0.025-0.10 mg/kg ip) and the peripherall... more The centrally acting cholinergic antagonist scopolamine (0.025-0.10 mg/kg ip) and the peripherally acting cholinergic antagonist methyl-scopolamine (0.01-0.10 mg/kg) dose dependently impaired discriminability independent of delay in a delayed conditional discrimination task that precludes use of mediating behavior. This indicates that scopolamine does not specifically affect working memory. Drugs that enhance cholinergic transmission neither improved discriminability nor attenuated scopolamine-induced impairments. In a post hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner in rats that performed at a high level in pretest sessions. Methyl-scopolamine impaired performance independently of delay in these rats. The authors suggest that a ceiling effect at short delays produced this Drug x Delay interaction of scopolamine in the best performing rats.
![Research paper thumbnail of SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug](https://attachments.academia-assets.com/82980707/thumbnails/1.jpg)
Neuropsychopharmacology, 2007
Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve ef... more Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D 2/3 antagonist and 5-HT 1A agonist. SLV313 possessed high affinity at human recombinant D 2 , D 3 , D 4 , 5-HT 2B , and 5-HT 1A receptors, moderate affinity at 5-HT 7 and weak affinity at 5-HT 2A receptors, with little-no affinity at 5-HT 4 , 5-HT 6 , a 1 , and a 2 (rat), H 1 (guinea pig), M 1 , M 4 , 5-HT 3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT 1A receptors (pEC 50 ¼ 9.0) and full antagonist activity at hD 2 (pA 2 ¼ 9.3) and hD 3 (pA 2 ¼ 8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT 1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT 1A antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT 1Adependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT 1A receptor agonist and full D 2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.
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Papers by Arnoud Herremans