Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

Abstract

Rationale The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive. Objectives The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms. Methods Male C57BL/6 J mice and Sprague–Dawley rats were examined in five independent experiments. We assessed APH199 (0.1–5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light–dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats. Results APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats. Conclusions Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache

“…A door positioned between the two chambers allowed the animals to freely access both compartments. To initiate the test, a mouse was placed in the dark chamber facing the wall, and its behavior was tracked for a period of 5 minutes [ 27 ].…”

Exploring Structural Determinants of Bias among D4 Subtype-Selective Dopamine Receptor Agonists

“…Studies investigating the pharmacological effects of biased agonism at the D 4 receptor are, however, still scarce. Among D 4 receptor ligands, which are specifically labeled as “biased”, only APH199 was so far evaluated in an animal model, in which it was shown to have indeed an influence on amphetamine induced psychosis-like symptoms …”