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

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.

A2A Adenosine Receptor Partial Agonism Related to Structural Rearrangements in an Activation Microswitch

“…Development of partial agonist drugs is therefore of interest whenever overstimulation of a GPCR needs to be prevented by tuning the receptor response (Hauser et al, 2017). GPCR partial agonists currently used in the clinic or investigated for their therapeutic potential include drugs targeting opioid receptors (Browne et al, 2020;Chan et al, 2017;Fujimura et al, 2017;Khroyan et al, 2017;Schmid et al, 2017), adrenergic receptors (Calverley et al, 2007), dopamine receptors (Frank et al, 2017;Tarland et al, 2018), and serotonin receptors (Chen et al, 2018;Huang et al, 2017;Yoshinaga et al, 2018;Zheng et al, 2017). Partial agonists are also under consideration as potential treatments for obesity (Wargent et al, 2013) and heart failure (Greene et al, 2016).…”

Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats

“…Interestingly, an antipsychotic drug, aripiprazole, has shown some efficacy in preclinical studies against PCP-induced social interaction deficits (Bruins Slot et al 2005; Snigdha and Neill 2008). However, in the study of Tarland et al (2018), aripiprazole was unable to reverse the social interaction deficits. Aripiprazole has strikingly different receptor binding profile compared to atypical antipsychotics used in this study, including agonistic effect on D 2 receptors and relatively high affinity for serotonergic 5-HT 1A receptors, which may explain its positive effects on social interaction behavior (Bruins Slot et al 2005; Snigdha and Neill 2008).…”