Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, on cognitive dysfunction and social aversion in rats

Emilia Tarland,Robert T Franke,Heidrun Fink,Heinz H Pertz,Jan Brosda

doi:10.1007/s00213-017-4747-x

Emilia Tarland, Robert T Franke + Show 3 more

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https://doi.org/10.1007/s00213-017-4747-x

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Abstract

Rationale2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes.ObjectiveIn continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats.ResultsTreatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug.ConclusionsOur data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.

Highlights

The treatment of schizophrenia ideally involves reduction of positive symptoms, negative symptoms, and cognitive deficits
Information processing, and ability to filter out redundant environmental stimuli have been identified in patients with schizophrenia, and prepulse inhibition (PPI) has been extensively investigated in patients as well as in preclinical animal models
Based on the observation that the startle response magnitude is reduced when a startle eliciting acoustic stimulus is preceded by a weaker acoustic prepulse, the PPI paradigm in rodents represents a preclinical test with face, predictive, and construct validity (Swerdlow et al 1994; Geyer et al 2001; Leumann et al 2002)

Summary

Introduction

The treatment of schizophrenia ideally involves reduction of positive symptoms, negative symptoms, and cognitive deficits. Positive symptoms such as hallucinations and delusions can be treated more or less satisfactorily with currently available antipsychotic drugs (APDs). Negative symptoms (affective flattening, alogia, avolition, and anhedonia) and cognitive impairment often fail to respond to typical (first generation) APDs (Dunlop and Brandon 2015; Vreeker et al 2015). Most importantly, atypical APDs are apparently no more effective than typical APDs regarding negative and cognitive symptoms of schizophrenia (Leucht et al 2013)

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