Attenuation of chronic mild stress-induced 'anhedonia' by asenapine is not associated with a 'hedonic' profile in intracranial self-stimulation.
Chronic mild stress (CMS)-induced 'anhedonia' is a predictive model of antidepressant activity. We assessed the reversal of CMS-induced behavioral changes by asenapine, the antidepressant imipramine, and the atypical antipsychotics olanzapine and risperidone. Secondarily, the ability of these agents to facilitate intracranial self-stimulation (ICSS) was assessed to ensure that any attenuation of CMS-induced anhedonia was not associated with an overt hedonic profile. After 2 weeks of CMS, male Wistar rats were administered asenapine (0.06-0.6 mg/kg), olanzapine (2 mg/kg), risperidone (0.5 mg/kg), or imipramine (10 mg/kg) by intraperitoneal injection over 5 weeks to examine their ability to reverse CMS-induced reductions in the intake of a sucrose solution. For the ICSS study, rats were trained to deliver an electrical stimulus to the ventral tegmental area. The effects of acute doses of subcutaneous asenapine (0.01-0.3 mg/kg), olanzapine (0.3 and 1 mg/kg), risperidone (0.1 and 0.3 mg/kg), and intraperitoneal imipramine (3-30 mg/kg), cocaine (5.0 mg/kg), or amphetamine (1.0 mg/kg) on ICSS were then examined. CMS significantly reduced sucrose intake (P < 0.001). All active agents (0.6 mg/kg asenapine, 2 mg/kg olanzapine, 0.5 mg/kg risperidone, and 10 mg/kg imipramine) reversed the effect of CMS (all P < 0.001). In the ICSS protocol, asenapine (0.01 and 0.03 mg/kg), olanzapine (1 mg/kg), and risperidone (0.3 mg/kg) impaired ICSS performance, whereas positive controls (5 mg/kg cocaine, 1 mg/kg amphetamine) facilitated ICSS. Asenapine reversed CMS-induced anhedonia without facilitating ICSS, providing support for a role of asenapine in treating bipolar disorder and aspects of negative and/or affective symptoms in schizophrenia.
Marston
Hugh M
HM
Merck Research Laboratories, MSD, Newhouse, Lanarkshire, Scotland, UK. hugh.marston@spcorp.com
Martin
Frederic Dc
FD
Papp
Mariusz
M
Gold
Lisa
L
Wong
Erik Hf
EH
Shahid
Mohammed
M
D059445:Anhedonia / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use; D001921:Brain / Q000502:physiology*; D002908:Chronic Disease; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018967:Risperidone / Q000627:therapeutic use; D012653:Self Stimulation; D013315:Stress, Psychological / Q000150:complications*
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D001569:Benzodiazepines; C522667:asenapine; D018967:Risperidone; D000077152:Olanzapine; D007099:Imipramine