The role of norepinephrine and serotonin in behavioral models of depression

523

Symposum Abstract\

THE ROLE OF DEPRESSION

NOREPINEPHRINE

AND

SEROTONIN

IN BEHAVIORAL

MODELS

OF

Inwn LuckI*. John F Cr)an. Lynn G. Kirby and Ashutosh Dalvt Dcpartmcnts of Psychiatry and Pl~amwzology. Unwcrsity of Penns! Ivania. Philadelphia. PA 19lOJ USA Antldcprcssnnt drugs that \‘:~a in their selectivity for norcpincphrinc (NE) and scrotonm (5-HT) produce ditTcrcnt behavioral paitems m the rat forced swunnung test (FST). a model of stress-induced dcprcsslon All of the antidcprcssant drugs tcstcd reduced munobility scows but wth different patterns. Sclcct~vc NE rcuptnkc inhibitors (SNRls). such as dcslpraminc and rcbosciine, reduce immobility and mcrcascd onI) climbing behavior. In contest. the sclcctivc scrotonin rcupt,akc inhibitors (SSRIs) reduced inunobtlity and incrcnscd only wimrnlng bclwior. Changes III diffcrcnt types of escape behaviors. c.g climbing and s~+inuning, nuy bc nicdiatcd by norndrcncrgic and scrotoncrgx mcchnnisms. rcspcctivclq. Signlticaat strain ditTcrcnccs tbat exist in the response to SNRls and SSRls could provide models for the genetic regulation of pl~nnrmcologicall~-sclcctl~c antidcprcwnts. Wistar-Kyoto (WKY) rats. a strain vulnerable to the cffccts of stress. show craggerated inmlobllity and corticosterone secretion in (he FST. WKY rats responded to the SNRI dcslpranline but failed to response to the SSRI lluosetinc. In addition. a sunq of &bred mouse strains indicates that SNRIs product behwiornl effects in mouse strains that arc unrcsponsivc to SSRls. SNRIs also mcdiatc ncwocndoumc responses during antidepressant behavioral tats Chronic administration of desipnminc (IO u@kg s II d;l!s) rcduccd inunobility and increased clintbing in the FST The forced swinuning strcssor also produced a IO-fold ~ncrcase m plasnu ~~rt~~~~ter~ne that was s~gniticantl) nttcnuatcd by chronic, but not acute. trcntmcnt wth dcsiprnnlinc Thcsc resells support the Idea that dlffcrcnt ncurotnnsn~ittcrs mediate distmct roles for antidcprcssant dmgs m bclwioral models of stress-induced dcprcssion

Noreoineohrine Dysfuncc~on in Anxiety and Depression

There is abundant clinical evidence suggesting a role for norepmephrine in the pathophysiology and treatment of depression and anxiety. Using a variety of experimental paradigms, our research group has found evidence for enhanced responsiveness of noradrenergic systems in patients with panic disorder and post traumatic stress disorder. These findings have important implications for the pathophysiology and treatment of these disorders. Recently our research has studied the behavioral effects of reducing norepinephrme and dopamine levels by admimstration of the tyrosine hydroxylase inhibitor alpha-methylparatyrosine (AMPT) to depressed patients. AMPT produces a transient return of depressive symptoms in remitted patients maintained on norepinephrine reuptake inhibitors (desipramine, mazindol), but not serotonin reuptake inhibitor drugs. Futther, in drug free remitted depressed patients AMPT produces a brief return of depressive symptoms, an effect not seen in healthy subjects. These findmgs suggest that the integrity of norep~nephrine neuronal systems is critical to the mechanism of antidepressant drugs with promment norepmephrine reuptake inhibitor properties and the vulnerabihty to AMPT-induced depressive symptoms may reflect a trait disturbance in norepinephrine function in depressed pattents. Chamey DS, Grillon C, Bremner JD: The Ncurobiological Basis of Anxiety and Fear: Circuits, Mechanisms. and Neurochemical Interactions (Part I). The Neeuroscienrist, 1998; 4135-44. Chamey DS, Grillon C, Bremner JD: The h’eurobiological Basis of Anxiety and Fear: Circuits, Mechanisms, andNeurochemical Interactloos (Pan II). & .Vtwoscienrisr, 1998; 4:122-132. Berman RM, Narasimhan M, Miller HL, Anand A, Cappiello A, Oren DA, Heninger GR, Chmey DS: Tramlent Depressive Relapse Induced by Catecholamine Depletion. Archrvcs ofGenera/ Psvrhmwy, 1999; 56:395-JO3