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  • 1.
    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.

  • 2.
    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.

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