lnu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Wadenberg, Marie-LouiseORCID iD iconorcid.org/0000-0003-1806-307X
Publications (10 of 48) Show all publications
Wadenberg, M.-L., Manetti, D., Romanelli, M. N. & Arias, H. R. (2017). Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat. Behavioural Brain Research, 333, 129-134
Open this publication in new window or tab >>Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat
2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 333, p. 129-134Article in journal (Refereed) Published
Abstract [en]

Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of alpha 7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer's drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP) induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity. Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective alpha 7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that alpha 7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, alpha 7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the anti psychotic efficacy of atypical antipsychotics.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
alpha 7 Nicotinic acetylcholine receptor positive allosteric modulators, Risperidone, Attentional set-shifting, Conditioned avoidance response, Schizophrenia
National Category
Neurosciences
Research subject
Natural Science, Medicine
Identifiers
urn:nbn:se:lnu:diva-67964 (URN)10.1016/j.bbr.2017.07.001 (DOI)000408289600016 ()28684359 (PubMedID)
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2018-01-13Bibliographically approved
Snyder, G. L., Prickaerts, J., Wadenberg, M.-L., Zhang, L., Zheng, H., Yao, W., . . . Wennogle, L. P. (2016). Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats. Psychopharmacology, 233(17), 3113-3124
Open this publication in new window or tab >>Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats
Show others...
2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 17, p. 3113-3124Article in journal (Refereed) Published
Abstract [en]

Rationale: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.

Objective: The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).

Methods: ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1–10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments.

Results: ITI-214 inhibited PDE1A (Ki = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR.

Conclusions: ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.

Keywords
Conditioned avoidance response, Cyclic AMP, Cyclic GMP, Memory, Novel object recognition, Phosphodiesterase-1
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-56076 (URN)10.1007/s00213-016-4346-2 (DOI)000381586500005 ()27342643 (PubMedID)2-s2.0-84976276833 (Scopus ID)
Available from: 2016-09-16 Created: 2016-08-31 Last updated: 2018-01-10Bibliographically approved
Wadenberg, M.-L. (2014). Current Pro-Cognitive Therapeutic Strategies for Improved Pharmacological Treatment in Schizophrenia. Current pharmaceutical design, 20(31), 5045-5045
Open this publication in new window or tab >>Current Pro-Cognitive Therapeutic Strategies for Improved Pharmacological Treatment in Schizophrenia
2014 (English)In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 31, p. 5045-5045Article in journal, Editorial material (Other academic) Published
Abstract [en]

Cognitive impairment influencing memory, attentional focus and executive functions in schizophrenia have a significant impact on social functioning and quality of life. Cognitive functions depend on normal functioning of brain prefrontal cortex. Attempts to explain cognitive impairment in schizophrenia include hypotheses (based on among others post-mortem, genetic and imaging data) of dysfunctions involving dopamine, glutamate, GABA as well as acetylcholine neural transmission. Current antipsychotic drugs are not sufficiently effective against cognitive symptoms. Thus, while pharmacological treatment strategies earlier primarily focused on managing psychotic (so called positive) symptoms, current pharmacological strategies aim at identifying compounds with pro-cognitive properties, suitable for treatment of cognitive symptoms as manifested in schizophrenia. To this end, scientists are primarily working along two lines: i) developing animal models/tests in rodents with relevance either to cognitive symptoms as presented in schizophrenia and/or to brain abnormalities in schizophrenia believed to be causing these symptoms; ii) identifying pro-cognitive compounds with pharmacological properties acting on brain neurotransmitter functions believed to be involved in cognitive dysfunction in schizophrenia. The present special issue on ‘Current pro-cognitive therapeutic strategies for improved pharmacological treatment in schizophrenia’ includes presentation and discussion of the use of the attentional set-shifting test as a relevant model for attentional/executive functioning in schizophrenia as well as for the identification of pro-cognitive compounds with relevance to schizophrenia treatment Tait et al. [1] and Goetghebeur and Dias [2], presentation of the neurodevelopmental prenatal methylazoxymethanol acetate (MAM) model of schizophrenia by Gill and Grace [3], and discussion of the novel object recognition (NOR) task for memory functions by Rajagopal et al. [6]. In addition, putative procognitive treatment strategies for schizophrenia treatment such as the use of GABAA receptor agonists [3], the use of compounds acting at nicotinic acetylcholine receptors from a clinical perspective Boggs et al. [4], as well as the therapeutic significance of compounds (phosphodiesterase, PDE, inhibitors) influencing intracellular signaling Snyder and Vanover [5] are presented and discussed. Finally, data on the effects of atypical antipsychotics, as well as 5-HT1A partial agonists, 5-HT7 antagonists, and D1 agonists in the NOR test are reviewed by Rajagopal et al. [6]. The contributors are all distinguished scientists, and issues discussed in the articles are timely and of great importance for the advancement of effective schizophrenia treatment strategies. Therefore, this special issue will hopefully be well received and appreciated in the scientific community dealing with these issues.

National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-37361 (URN)10.2174/1568026613666131216120137 (DOI)000340816600011 ()2-s2.0-84906215802 (Scopus ID)
Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2018-01-11Bibliographically approved
Wadenberg, M.-L., Fjällström, A.-K., Federley, M., Persson, P. & Stenqvist, P. (2011). Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor. International Journal of Neuropsychopharmacology, 14(5), 644-654
Open this publication in new window or tab >>Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor
Show others...
2011 (English)In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 5, p. 644-654Article in journal (Refereed) Published
Abstract [en]

The acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer’s disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo-dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD haloperidol (Hal) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of Hal or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to Hal treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro-cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment.

Place, publisher, year, edition, pages
Cambridge University Press, 2011
Keywords
antipsychotics cholinergics conditioned avoidance response catalepsy rat
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-7395 (URN)10.1017/S1461145710000921 (DOI)000290109000007 ()2-s2.0-79956051888 (Scopus ID)
Available from: 2010-08-17 Created: 2010-08-17 Last updated: 2018-01-12Bibliographically approved
Wadenberg, M.-L. (2010). Active Avoidance. In: Ian P Stolerman (Ed.), Encyclopedia of Psychopharmacology: Part 1 (pp. 15-19). Heidelberg: Springer
Open this publication in new window or tab >>Active Avoidance
2010 (English)In: Encyclopedia of Psychopharmacology: Part 1 / [ed] Ian P Stolerman, Heidelberg: Springer, 2010, p. 15-19Chapter in book (Other academic)
Place, publisher, year, edition, pages
Heidelberg: Springer, 2010
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-4246 (URN)978-3-540-68698-9 (ISBN)3-540-68698-3 (ISBN)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2018-01-12Bibliographically approved
Wadenberg, M.-L. (2010). Conditioned avoidance response in the development of new antipsychotics.. Current pharmaceutical design, 16(3), 358-370
Open this publication in new window or tab >>Conditioned avoidance response in the development of new antipsychotics.
2010 (English)In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 16, no 3, p. 358-370Article, review/survey (Refereed) Published
Abstract [en]

Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-5113 (URN)
Available from: 2010-04-28 Created: 2010-04-28 Last updated: 2018-01-12Bibliographically approved
Wadenberg, M.-L., Fjällström, A.-K., Karlsson-Federley, M., Persson, P. & Stenqvist, P. (2010). Effects of adjunct galantamine to antipsychotics in animal models of antipsychotic activity and extrapyramidal side effect liability: Cholinergic muscarinic receptor mediation. Paper presented at 27th CINP Congress Meeting 2010, Hong Kong, PEOPLES R CHINA, JUN 06-10, 2010. International Journal of Neuropsychopharmacology, 13(Suppl. 1), 111
Open this publication in new window or tab >>Effects of adjunct galantamine to antipsychotics in animal models of antipsychotic activity and extrapyramidal side effect liability: Cholinergic muscarinic receptor mediation
Show others...
2010 (English)In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 13, no Suppl. 1, p. 111-Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-10262 (URN)000281281100399 ()
Conference
27th CINP Congress Meeting 2010, Hong Kong, PEOPLES R CHINA, JUN 06-10, 2010
Available from: 2011-01-20 Created: 2011-01-20 Last updated: 2018-01-12Bibliographically approved
Wiker, C., Schilström, B., Sandbäck, C., Wadenberg, M.-L. & Svensson, T. (2008). Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.. International Journal of Neuropsychopharmacology, 11(6), 845-850
Open this publication in new window or tab >>Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.
Show others...
2008 (English)In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 11, no 6, p. 845-850Article in journal (Refereed) Published
Abstract [en]

Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of α7 nAChR-selective allosteric potentiators for schizophrenia.

Place, publisher, year, edition, pages
Glasgow, UK: Cambridge Univ Press, 2008
Keywords
Antipsychotics, experimental
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:hik:diva-2961 (URN)10.1017/S1461145708008730 (DOI)000259706800009 ()
Available from: 2010-09-03 Created: 2010-03-04 Last updated: 2018-01-12Bibliographically approved
Wadenberg, M.-L. & Karlsson, M. (2008). Galantamine enhances antipsychotic-like effects. In: Schizophr Res 98 (Suppl): . Paper presented at Int Congr Schizophr Res.
Open this publication in new window or tab >>Galantamine enhances antipsychotic-like effects
2008 (English)In: Schizophr Res 98 (Suppl), 2008Conference paper, Published paper (Refereed)
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-5042 (URN)
Conference
Int Congr Schizophr Res
Note

Nummer:

Available from: 2010-04-28 Created: 2010-04-28 Last updated: 2017-02-10Bibliographically approved
Wadenberg, M.-L. & Karlsson (Federley), M. (2008). Galantamine enhances antipsychotic-like effects of low dose risperidone, with beneficial extrapyramidal side effect profile in rats. Paper presented at XIVth Biennial Winter Workshop on Schizophrenia and Bipolar Disorders, Montreux, Switzerland, 3–7 February 2008. Schizophrenia Research, 98(Suppl), 175
Open this publication in new window or tab >>Galantamine enhances antipsychotic-like effects of low dose risperidone, with beneficial extrapyramidal side effect profile in rats
2008 (English)In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 98, no Suppl, p. 175-Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

Background: The acetylcholine esterase inhibitor galantamine (GAL) is used clinically against cognitive impairment in Alzheimer's disease. We previously showed that in similarity to antipsychotic drugs, GAL (1.25–5 mg/kg) alone produced a dose-dependent, selective suppression of Conditioned Avoidance Response (CAR) in rats. The CAR test has high predictive validity for antipsychotic activity (indicated by selective suppression of CAR). GAL was also recently reported by others to increase both brain ventral tegmental dopamine (DA) cell firing activity and extracellular DA levels in the medial prefrontal cortex in rats. Interestingly, improvement of negative and cognitive symptoms, as well as significant amelioration of psychotic symptoms, in schizophrenia by adjunct treatment with GAL to the atypical antipsychotic risperidone has been reported in clinical studies and case reports.

Methods: The present study evaluated, in rats, the effect of adjunct GAL (1.25 mg/kg, sc) to risperidone (0.2 mg/kg, ip; estimated DA D2 receptor occupancy ≈ 45–50%) on CAR behavior. Extrapyramidal side effect (EPS) liability was evaluated by the catalepsy test.

Results: Risperidone alone produced a slight suppression of CAR. Pretreatment with GAL significantly enhanced risperidone-induced suppression of CAR in an antipsychotic-like manner. Consistent with previous observations, GAL (1.25 mg/kg) alone had no effects on CAR. In the catalepsy test, risperidone alone produced a slight, but significant (compared with vehicle treated animals) increase in catalepsy scores. Pretreatment with GAL did not significantly alter catalepsy scores. GAL alone had no effect on catalepsy scores.

Conclusions: In conclusion, the present data are in line with recent clinical reports, and suggest that GAL may indeed contribute to antipsychotic efficacy with retained beneficial EPS liability profile, if given as an add-on to antipsychotic medication.

Acknowledgement: Galantamine and risperidone were generously provided by Janssen-Cilag. The study was supported by University of Kalmar, intramural faculty funding.

Place, publisher, year, edition, pages
The Netherlands: Elsevier, 2008
Keywords
Antipsychotics, experimental
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:hik:diva-2960 (URN)10.1016/j.schres.2007.12.413 (DOI)
Conference
XIVth Biennial Winter Workshop on Schizophrenia and Bipolar Disorders, Montreux, Switzerland, 3–7 February 2008
Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2018-01-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1806-307X

Search in DiVA

Show all publications