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  • 1. Eltayb, A
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Schilstrom, B
    Svensson, T H
    Malmerfelt, Anna
    Adjunctive treatment with topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride2005In: Naunyn-Schmiedeberg's Archives of pharmacology, Vol. 372, no 3, p. 195-202Article in journal (Refereed)
  • 2.
    Eltayb, Amani
    et al.
    Karolinska Institutet.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Schilström, Björn
    Karolinska Institutet.
    Svensson, Torgny
    Karolinska Institutet.
    Antipsychotic-like effect by combined treatment with citalopram and WAY 100635: involvement ofthe 5-HT2C receptor.2007In: The Int J neuropsychopharmacol, ISSN 1461-1457, Vol. 10, no 3, p. 405-410Article in journal (Refereed)
    Abstract [en]

    Catalepsy occurs following high dopamine (DA) D2 blockade by typical antipsychotic drugs (APDs). We showed that a combination of a high dose of citalopram, a selective serotonin reuptake inhibitor (SSRI) and the selective 5-HT1A receptor antagonist WAY 100635 produces significant catalepsy in rats, similar to APDs. Here, we investigated the potential antipsychotic activity of lower doses of citalopram+WAY 100635, using the conditioned avoidance response (CAR) test. Cataleptogenic liability of the combination was evaluated with the catalepsy test. Citalopram and WAY 100635 in combination, but not when givenalone, prod uced a significant antipsychotic action in CAR without significant catalepsy, similar to the effect selective 5-HT2C receptor antagonist, SB , completely prevent 242084ed the citalopram/WAY 100635-induced suppression of CAR indicating an involvement of the 5-HT2C receptor. In summary, treatment with an SSRI/5-HT1A antagonist combination might prove beneficial in psychiatric disorders withpsychotic/depressive symptoms. 

  • 3. Eltayb, Amani
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Svensson, Torgny
    Enhanced Cortical Dopamine Output and Antipsychotic-like Effect of Raclopride with Adjunctive Low-Dose L-dopa.2005In: Biol Psychiatry, Vol. 58, p. 337-343Article in journal (Refereed)
  • 4. Jardemark, Kent
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Grillner, Pernilla
    Svensson, Torgny
    Dopamine D3 and D4 receptor antagonists in the treatment of schizophrenia.2002In: Curr Opinion in Investigational Drugs, Vol. 3, no 1, p. 101-105Article, review/survey (Other academic)
    Abstract [en]

    The findings that dopamine D3 and D4 receptors are highly expressed in limbic and cortical areas (D4 more than D3), and the fact that the atypical drug clozapine has preferential affinity for the D4 receptors have suggested an involvement of these receptors in schizophrenia. Subsequently, many pharmaceutical companies have pursued the approach of developing selective dopamine D3 or D4 antagonists as potential antipsychotics. This review will discuss the current status of selective dopamine D3 and D4 receptor antagonists for the treatment of schizophrenia.

  • 5. Kapur, Shitij
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Seeman, Philip
    McClelland, RA
    VanderSpek, SC
    Baker, G
    Nobrega, Jose
    Zipursky, RB
    Increasing D2 affinity results in the loss of clozapine’s atypical antipsychotic action.2002In: NeuroReport, Vol. 13, p. 831-835Article in journal (Refereed)
  • 6. Linner, Love
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wiker, Charlotte
    Schalling, Martin
    Svensson, Torgny
    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.2002In: Neuropsychopharmacology, Vol. 27, p. 691-698Article in journal (Refereed)
  • 7. Marcus, M M
    et al.
    Jardemark, K E
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Langlois, X
    Hertel, P
    Svensson, T H
    Combined alpha(2) and D-2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat2005In: International journal of neuropsychopharmacology, Vol. 8 (3), p. 315-327Article in journal (Refereed)
  • 8.
    Snyder, Gretchen L.
    et al.
    Intra-Cellular Therapies Inc, USA.
    Prickaerts, Jos
    Maastricht University, The Netherlands.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zhang, Lei
    Intra-Cellular Therapies Inc, USA.
    Zheng, Hailin
    Intra-Cellular Therapies Inc, USA.
    Yao, Wei
    Intra-Cellular Therapies Inc, USA.
    Akkerman, Sven
    Maastricht University, The Netherlands.
    Zhu, Hongwen
    Tianjin Hospital, China.
    Hendrick, Joseph P.
    Intra-Cellular Therapies Inc, USA.
    Vanover, Kimberly E.
    Intra-Cellular Therapies Inc, USA.
    Davis, Robert
    Intra-Cellular Therapies Inc, USA.
    Li, Peng
    Intra-Cellular Therapies Inc, USA.
    Mates, Sharon
    Intra-Cellular Therapies Inc, USA.
    Wennogle, Lawrence P.
    Intra-Cellular Therapies Inc, USA.
    Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 17, p. 3113-3124Article in journal (Refereed)
    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.

  • 9. Svensson, Torgny
    et al.
    Mathe, Jan
    Nomikos, George
    Marcus, Monica
    Hygge-Blakeman, Karin
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Brain dopaminergic dysfunction in psychotic behaviour: stabilization by 5-HT2A and a1-receptor antagonistic drugs1999In: Interactive Monoaminergic Disorders / [ed] T Palomo, R Beninger & T Archer, Spain: Foundacion Cerebro Y Mente , 1999Chapter in book (Other academic)
  • 10.
    Wadenberg, Marie-Louise
    Karolinska Inst, Sect Neuropsychopharmacol, Stockholm, Sweden.
    A Review of the Properties of Spiradoline: A Potent and Selective Kappa-Opioid Receptor Agonist.2003In: CNS Drug Reviews, Vol. 9, no 2, p. 187-198Article, review/survey (Other academic)
  • 11.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Active Avoidance2010In: Encyclopedia of Psychopharmacology: Part 1 / [ed] Ian P Stolerman, Heidelberg: Springer, 2010, p. 15-19Chapter in book (Other academic)
  • 12.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy produced by raclopride or SCH 23 390 in the rat.1992In: J Neural Transm, Vol. 89, p. 49-59Article in journal (Refereed)
  • 13.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bifeprunox: a novel antipsychotic agent with partial agonist properties at dopamine D2 and serotonin 5-HT1A receptors2007In: Future Neurology, ISSN 1479-6708, Vol. 2, no 2, p. 153-165Article in journal (Refereed)
  • 14.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Conditioned avoidance response in the development of new antipsychotics.2010In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 16, no 3, p. 358-370Article, review/survey (Refereed)
    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.

  • 15.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Current Pro-Cognitive Therapeutic Strategies for Improved Pharmacological Treatment in Schizophrenia2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 31, p. 5045-5045Article in journal (Other academic)
    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.

  • 16.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Drug Evaluation: Iloperidone1998In: Curr Res in Serotonin, Vol. 3, p. 66-69Article, review/survey (Other academic)
  • 17.
    Wadenberg, Marie-Louise
    UNIV STOCKHOLM, DEPT PSYCHOL, S-10691 STOCKHOLM, SWEDEN.
    Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat.1996In: Neurosci and Biobehav Reviews, Vol. 20, p. 325-339Article, review/survey (Other academic)
    Abstract [en]

    The present paper reviews a series of experiments aimed at elucidating the interaction between specific dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors in the mediation of extrapyramidal motor functions in the rat. There is strong evidence to suggest that (1) the catalepsy produced by dopamine D-1 or D-2 receptor antagonists can be completely antagonized by the administration of 5-HT1A receptor agonists acting at 5-HT autoreceptors in the median raphe nucleus; (2) the catalepsy produced by a dopamine D-2 receptor antagonist can be completely antagonized by treatment with a 5-HT2A/C receptor agonist; and (3) the catalepsy produced by blockade of either dopamine D-1 or D-2 receptors is not affected by the administration of a 5-HT2A/C receptor antagonist. The emerging picture of DA/5-HT receptor interactions in the mediation of extrapyramidal motor functions is of great interest in relation to present efforts to develop new atypical neuroleptics with affinity for brain 5-HT receptor subtypes, and also for the observations that new serotonin selective re-uptake inhibiting antidepressants can produce parkinson-like symptoms in vulnerable individuals.

  • 18.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ahlenius, Sven
    Antagonism by the 5-HT2A/C receptor agonist DOI of raclopride-induced catalepsy in the rat.1995In: Eur J Pharmacol, Vol. 294, p. 247-251Article in journal (Refereed)
  • 19.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm .
    Ahlenius, Sven
    Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: Enhancement of antipsychotic-like effects without catalepsy.1991In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 83, p. 43-53Article in journal (Refereed)
    Abstract [en]

    The administration of the 5-HT1A agonist 8-OH-DPAT,0.1 mg kg- 1 sc - - 20 min, produced a moderate suppression of conditionedavoidance behavior (60% of controls) in the rat. This effect, however, was notseen after administration of higher doses, 0.4 and 1.6 mg kg- 1 sc. The numberof intertrial crosses were not affected by the lower dose but significantly increasedby administration of the two higher doses of 8-OH-DPAT. The dopamineD 2 receptor blocking agent raclopride, 0.05 mgkg-t, by itself did notsuppress the avoidance behavior, but in combination with 8-OH-DPAT producedsuppression of avoidance behavior (30% of controls) as well as intertrialcrosses. Open field locomotor activity was suppressed by raclopride,0.1 mg kg- 1 sc, or by 8-OH-DPAT, 0.1 mg kg- 1 sc. The combined treatmentproduced a further suppression of locomotor activity and a marked increasein "immobility" (stationary movements). Treadmill locomotion, however, wasnot affected by either compound by itself, whereas the combined treatmentimpaired treadmill performance. Suppression of treadmill performance by ahigher dose of raclopride, 0.4mgkg-~sc, was not altered by the additionaltreatment with 8-OH-DPAT, 0.1 mg kg- 1. In contrast to the additive effects of8-OH-DPAT and raclopride on conditioned avoidance behavior, open fieldlocomotion and treadmill performance, the catalepsy produced by raclopride,16mgkg -1 was completely antagonised by treatment with 8-OH-DPAT0.1 mg kg-1. Taken together, the present findings demonstrate strong interactionsbetween a 5-HT agonist and a DAD 2 antagonist on some critical testsfor antipsychotic-like actions and extrapyramidal motor effects in rats, andsuggest new possibilities in the search for new antipsychotic drugs with higherclinical efficacy and less extrapyramidal side effects. 

  • 20.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm .
    Ahlenius, Sven
    Effects of raclopride and haloperidol on spontaneous motor activity and on conditioned avoidance behavior in rats: A comparison of potency, efficacy and time-course of action.1991In: Arzneimittel-Forschung / Drug Res, ISSN 0004-4172, Vol. 41, no 7, p. 692-695Article in journal (Refereed)
    Abstract [en]

    The spontaneous locomotor activity of rats was used as an index of centrally mediated of raclopride (CAS 84225-95-6). The results indicate a duration of less than 2 h after s.c administration of 2 μmol kg-1. In support of a rapid first-pass metabolism in the rat, the effect was considerably weaker after i.p. administration. This difference was further supported by comparing the dose-effect curves after s.c. and i.p. raclopride administration. Halopéridol appears to be slightly more potent than raclopride 

  • 21.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm.
    Ahlenius, Sven
    Suppression of conditioned avoidance by 8-OH-DPAT in the rat.1988In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 74, no 3, p. 195-198Article in journal (Refereed)
    Abstract [en]

    Rats were trained to perform an aversely motivated discriminative task in a shuttle-box. The conditioned avoidance response was selectively suppressed by 8-OH-DPAT in a dose-dependent manner (25–100 g·kg–1). There were no statistically significant deficits in discriminative performance. The present results suggest antipsychotic-like properties of 8-OH-DPAT. 

  • 22.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ahlenius, Sven
    Svensson, Torgny
    Potency mismatch for behavioral and biochemical effects by dopamine receptor antagonists: implications for the mechanism of action of clozapine.1993In: Psychopharmacology, Vol. 110, p. 273-279Article in journal (Refereed)
  • 23.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Cortizo, Lourdes
    Evidence for specific 5-HT1A and dopamine D2 receptor interactions in the mediation of extrapyramidal motor functions in the rat.1994In: Pharmacol Biochem Behav, Vol. 47, p. 509-513Article in journal (Refereed)
  • 24.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Elia, Yesmino
    The selective dopamine D-4 receptor antagonist L-745,870 produces antipsychotic-like effects in the presence of a weak dopamine D2 receptor blockade in rats.2001In: Nord J Psychiat, Vol. 55Article in journal (Refereed)
  • 25.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm .
    Ericsson, Eva-Lena
    Magnusson, Olle
    Ahlenius, Sven
    Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat.1990In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 28, no 4, p. 297-307Article in journal (Refereed)
    Abstract [en]

    The local application of (−)sulpiride, 200 ng side−1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompained by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (−)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [(DO-PAC+HVA) DA−1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-) sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum. 

  • 26.
    Wadenberg, Marie-Louise
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fjällström, Ann-Kristin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Federley, Malin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Pernilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Stenqvist, Pia
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor2011In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 5, p. 644-654Article in journal (Refereed)
    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.

  • 27.
    Wadenberg, Marie-Louise
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fjällström, Ann-Kristin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson-Federley, Malin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Pernilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Stenqvist, Pia
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effects of adjunct galantamine to antipsychotics in animal models of antipsychotic activity and extrapyramidal side effect liability: Cholinergic muscarinic receptor mediation2010In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 13, no Suppl. 1, p. 111-Article in journal (Other academic)
  • 28.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hertel, P
    Fernholm, Rita
    Svensson, TH
    Hygge-Blakeman, Karin
    Ahlenius, Sven
    Enhancement of antipsychotic-like effects by combined treatment with the α1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats2000In: J Neural Transm, Vol. 107, p. 1229-1238Article in journal (Refereed)
  • 29.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychiatry, Scott & White Clinic, Temple, TX 75608, USA..
    Hicks, Paul
    The conditioned avoidance response test re-evaluated: Is it a sensitive test also for the detection of potentially atypical antipsychotics?1999In: Neurosci and Biobehav Reviews, Vol. 23, no 6, p. 851-862Article, review/survey (Other academic)
    Abstract [en]

    The present review discusses the history and paradigm of the conditioned avoidance response (CAR) in rats for the detection of potential antipsychotic activity of drugs. In addition, the role of dopamine (DA) D2, serotonin (5-HT)2A/2C, alpha1, 5-HT1A, DA D4, muscarinic and glutamate receptors in the suppression of CAR induced by various classes of drugs is evaluated. Finally, data investigating brain sites of action for the mediation of CAR behavior is discussed. It is concluded that the CAR test, originally found to be sensitive for the detection of antipsychotic drugs with high affinity as antagonists for brain dopamine receptors, is also sensitive for the detection of potentially antipsychotic compounds acting primarily via neurotransmitter receptors other than the DA D2 receptor. Furthermore, the review confirms the importance of the nucleus accumbens(shell) in the mediation of effects on CAR produced by traditional, as well as atypical antipsychotic drugs.

  • 30.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hicks, Paul
    Young, Keith
    Richter, Travis
    Effects of local application of 5-hydroxytryptamine (5-HT) into the dorsal or median raphe nuclei on haloperidol-induced catalepsy in the rat.1999In: Neuropharmacology, Vol. 38, p. 151-156Article in journal (Refereed)
  • 31.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hicks, Paul
    Young, Keith
    Richter, Travis
    Enhancement of antipsychotic-like properties of raclopride in rats using the selective 5-HT2A receptor antagonist MDL 100,9071998In: Biol Psychiatry, Vol. 44, p. 508-515Article in journal (Refereed)
  • 32.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hicks, Paul
    Young, Keith
    Trompler, R
    Zavodny, Randall
    Richter, Travis
    A novel computer controlled conditioned avoidance apparatus for rats.1998In: Pharmacol & Toxicol Methods, Vol. 38, p. 211-215Article in journal (Refereed)
  • 33.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hicks, PB
    Antagonism at 5-HT2A receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats2001In: Pharmacol Biochem & Behav, Vol. 68, p. 363-370Article in journal (Refereed)
  • 34.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hillegaart, Viveka
    Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat1995In: Neuropharmacology, Vol. 34, p. 495-499Article in journal (Refereed)
  • 35.
    Wadenberg, Marie-Louise
    et al.
    Department of Psychology, University of Stockholm.
    Hillegaart, Viveka
    Ahlenius, Sven
    Effects of 8-OH-DPAT on motor activity in the rat.1989In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 32, no 3, p. 797-800Article in journal (Refereed)
    Abstract [en]

    The administration of 8-OH-DPAT to rats produced a dose-dependent suppression of spontaneous locomotor activity in an open field arena. 8-OH-DPAT was administered in the dose range 12.5–1,600 μg·kg−1 SC. Vertical activity ("rearing") was more sensitive to the treatment than horizontal activity ("locomotion"), both in terms of potency and efficacy. The activity along the walls of the open field arena ("peripheral activity") was increased, and the rearing activity was decreased, relative to total horizontal activity and total activity, respectively. There were no effects by 8-OH-DPAT on treadmill locomotion. The rectal temperature was decreased by 8-OH-DPAT administration, not only in animals tested in the open field, but also in animals with an increased body temperature, produced by treadmill locomotion. 

  • 36.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hillegaart, Viveka
    Berge, Odd-Geir
    Supraspinal mediation of dopamine-serotonin interactions in extrapyramidal motor functions in the rat.1993In: NeuroReport, Vol. 4, p. 59-61Article in journal (Refereed)
  • 37.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Kapur, S
    Remington, G
    Are animal studies appropriately dosed? – Lessons from the bedside to the bench.2000In: Can J Psychiat, Vol. 45, p. 241-246Article in journal (Refereed)
  • 38.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Kapur, S
    Soliman, A
    Jones, C
    Wilson, AA
    Vaccarino, F
    Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats.2000In: Psychopharmacology, Vol. 150, p. 422-429Article in journal (Refereed)
  • 39.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Karlsson (Federley), Malin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Galantamine enhances antipsychotic-like effects of low dose risperidone, with beneficial extrapyramidal side effect profile in rats2008In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 98, no Suppl, p. 175-Article in journal (Refereed)
    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.

  • 40.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Karlsson, Malin
    Galantamine enhances antipsychotic-like effects2008In: Schizophr Res 98 (Suppl), 2008Conference paper (Refereed)
  • 41.
    Wadenberg, Marie-Louise
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Manetti, Dina
    Univ Florence, Italy.
    Romanelli, Maria Novella
    Univ Florence, Italy.
    Arias, Hugo R.
    Calif Northstate Univ, USA.
    Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat2017In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 333, p. 129-134Article in journal (Refereed)
    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.

  • 42.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Salmi, Peter
    Jimenez, Patricia
    Svensson, Torgny
    Ahlenius, Sven
    Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist raclopride by the additional treatment with the 5-HT2 receptor blocking agent ritanserin in the rat.1996In: Eur Neuropsychopharmacol, Vol. 6, p. 305-310Article in journal (Refereed)
  • 43.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Seeman, Philip
    Clozapine pretreatment enhances raclopride catalepsy.1999In: Eur J Pharmacol, Vol. 377, p. R1-R2Article in journal (Refereed)
  • 44.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Sills, T
    Kapur, S
    Fletcher, PJ
    Antipsychotic-like effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats.2000In: Biol Psychiat, Vol. 47:670-676Article in journal (Refereed)
  • 45.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wiker, Charlotte
    Svensson, Torgny
    Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunct alpha2 adrenoceptor blockade: experimental evidence.2007In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 10, p. 191-202Article in journal (Refereed)
  • 46.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wiker, Charlotte
    Karolinska Institutet.
    Svensson, Torgny
    Karolinska Institutet.
    Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunct alpha2 adrenoceptor blockade: experimental evidence.2007In: The Int J Neuropsychopharmacol, ISSN 1461-1457, Vol. 10, p. 191-202Article in journal (Refereed)
  • 47.
    Wiker, Charlotte
    et al.
    Karolinska Institutet.
    Schilström, Björn
    Karolinska Institutet.
    Sandbäck, Carina
    Karolinska Institutet.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Svensson, Torgny
    Karolinska Institutet.
    Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.2008In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 11, no 6, p. 845-850Article in journal (Refereed)
    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.

  • 48. Wiker, Charlotte
    et al.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Linner, Love
    Svensson, Torgny
    Adjunctive treatment with mianserin enhances raclopride-induced cortical dopamine output and, in parallel, its antipsychotic-like effect.2004In: Neuropsychiatric Disease and Treatment, Vol. 1, p. 253-260Article in journal (Refereed)
1 - 48 of 48
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