title: Chronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels.
abstract: Several animal models are currently utilised in the investigation of major depressive disorder; however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100μg/day; 14 days) blocks the immobility-reducing 'antidepressant' effects of a single dose of imipramine (10mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100μg/day; 14 days) blocks the antidepressant effects of imipramine (10mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.
authors.affiliation: School of Psychology, Deakin University, Melbourne Burwood Campus, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Walker
authors.forename: Sandy A
authors.initials: SA
authors.lastname: Burnett
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hasebe
authors.forename: Jane A
authors.initials: JA
authors.lastname: McGillivray
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gray
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Tye
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006120:Grooming / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming; D013997:Time Factors
chemical_list: D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; D010446:Peptide Fragments; C038513:ACTH (1-14); D000324:Adrenocorticotropic Hormone; D007099:Imipramine; D003345:Corticosterone