title: The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS₁ receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.
abstract: Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs.
authors.affiliation: Psychology Department, Northern Michigan University.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Hillhouse
authors.affiliation: Psychology Department, Northern Michigan University.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Shankland
authors.affiliation: Psychology Department, Northern Michigan University.
authors.forename: Katelin S
authors.initials: KS
authors.lastname: Matazel
authors.affiliation: Psychology Department, Northern Michigan University.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Keiser
authors.affiliation: Psychology Department, Northern Michigan University.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Prus
mesh_terms: D000478:Alkylation; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003865:Major Depressive Disorder / Q000188:drug therapy*; D003987:Dibenzothiazepines / Q000737:chemistry* / Q000627:therapeutic use; D004195:Disease Models, Animal; D008297:Male; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069348:Quetiapine Fumarate; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000819:agonists*; D012054:Reinforcement, Psychology
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; C117269:PD 149163; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D000069348:Quetiapine Fumarate; D009496:Neurotensin