The G Protein Biased Serotonin 5-HT2A Receptor Agonist Lisuride Exerts Anti-depressant Drug-like Activities in Mice

There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and -arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related lysergic acid diethylamide (LSD), the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), βArr1-knockout (KO), and βArr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both βArr lines of mice. Locomotion was decreased overall in βArr1-KOs and βArr2-KOs relative to wild-type controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was decreased in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Serotonin syndrome-associated responses were present at all lisuride doses in WTs, but they were reduced especially in βArr2-KO mice. Prepulse inhibition (PPI) was unaffected in βArr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in βArr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in βArr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in βArr1-KOs. Clozapine, SCH23390, and GR127935 restored PPI in both βArr1 genotypes. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride's actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.