Effect Of Antidepressant Medication Use On dopamine Neurotransmitter Processing In Major Depressive Disorder (MDD) In Female Mice

Acute Administration Of Anti Depressant Medication Increases Emotional Information Processing For PositiveInformation In Both Depressed And Healthy Persons. This Effect Is Likely Relevant To The Therapeutic Actions OfThese Medications,But It Has Not Been Studied In Patients With Major Depressive Disorder Taking Anti DepressantsAs Typically Prescribed In The Community. Antidepressant Drugs Produce Therapeutic Actions And Many Of TheirSide Effects Via Blockade Of The Plasma Membrane Transporters For Serotonin (SERT/SLC6A2), Norepinephrine(NET/SLC6A1) And Dopamine (DAT/SLC6A3). Many Antidepressants Block Several Ofthese Transporters; SomeAre More Selective. Mouse Gene Knockouts Of These Transporters Provide Interesting Models For Possible Effects OfChronic Antidepressant Treatments. To Examine The Role Of Monoamine Transporters In Models Of DepressionDAT, NET And SERT KO Mice And Wildtype Littermates Were Studied In The Forced Swim Test (FST), The TailSuspension Test (TST) And For Sucrose Consumption. In Order To Dissociate General Activity From The PotentialAntidepressant Effects Three Types Of Behavior Were Assessed In The FST: Immobility, Climbing And Swimming. InConfirmation Of Previous Reports, Both DAT KO And NET KO Mice Exhibited Less Immobility Than WildtypeLittermates While SERT KO Mice Did Not. Effects Of DAT Deletion Were Not Simply Due To Hyperactivity AsDecreased Immobility Was Observed In DAT +/- Mice That Were Not Hyperactive As Well As In DAT -/- Mice ThatDisplayed Profound Hyperactivity. Climbing Was Increased, While Swimming Was Almost Eliminated In DAT -/-Mice, While A Modest But Similar Effect Was Seen In NET KO Mice, Which Showed A Modest Decrease InLocomotor Activity. Combined Increases In Climbing And Decreases In Immobility Are Characteristic Of ForcedSwim Test Results In Antidepressant Animal Models, While Selective Effects On Swimming Are Associated With TheEffects Of Stimulant Drugs. Therefore, An Effect On Climbing Is Thought To More Specifically Reflect AntidepressantEffects, As Has Been Observed In Several Other Proposed Animal Models Of Reduced Depressive Phenotypes. ASimilar Profile Was Observed In The TST, Where DAT, NET And SERT Knockouts Were All Found To ReduceImmobility, But Much Greater Effects Were Observed In DAT KO Mice. However, To Further Determine WhetherThese Effects Of DAT KO In Animal Models Of Depression May Be Due To The Confounding Effects OfHyperactivity, Mice Were Also Assessed In A Sucrose Consumption Test. Sucrose Consumption Was Increased InDAT KO Mice Consistent With Reduced Anhedonia, And Inconsistent With Competitive Hyperactivity; No IncreasesWere Observed In SERT KO Or NET KO Mice. In Summary, The Effects Of DAT Knockout In Animal Models OfDepression Are Larger Than Those Produced By NET Or SERT KO, And Unlikely To Be Simply The Result Of TheConfounding Effects Of Locomotor Hyperactivity; Thus, These Data Support Reevaluation Of The Role That DATExpression Could Play In Depression And The Potential Antidepressant Effects Of DAT Blockade. The DopamineHypothesis Of Schizophrenia And The Emphasis On Other Neurotransmitters, Most Notably Norepinephirne,Serotonin, And Acetylcholine, In The Pathogenesis Of Depression, Have Focused Attention Away From SubstantialEvidence Implicating Dopamine In Affective Disorders. The Clinical Evidence Includes Alterations In DepressiveSymptoms With Aging (Concomitant With Possible Changes In Dopamine Metabolism). We Conclude That DopamineLikely Contributes Significantly To The Pathophysiology Of Depression. However, The Role Of Dopamine In ThisSyndrome Must Be Understood In The Context Of Existing Theories Involving Other Neurotransmitters Which MayAct Independently, And Interact With Dopamine And Other Neurochemicals, To Contribute To Depression.Method: The Authors Used Eye Tracking To Examine The Effects Of Antidepressant Medication On SelectiveAttention For Emotional Stimuli In A Sample Of 47 Patients With Major Depressive Disorder (21 Medlcated And 26Unmedicated) And 47 Matched Comparison Subjects Without Depression. Participants Completed A Passive ViewingEye Tracking Task Assessing Selective Attention For Positive, Dysphoric, Threatening, AndNeutral Stimuli In Addition To Providing Medication Information And Self-Report Measures Of Depression AndAnxiety Severity.Results: Depressed Participants Currently Taking Antidepressants And Nondepressed Comparison SubjectsDemonstrated Greater Total Gaze Duration And More Fixations For Positive Stimuli Compared With UnmedicatedDepressed Participants. Depressed Participants On Medication Also Had Fewer Fixations For Dysphoric StimuliCompared With Depressed Participants Not On Medication.Conclusions: Antidepressants, As Prescribed In The Community To Patients With Depression, Appear To ModifyEmotional Information Processing In The Absence Of Differences In Depression Severity. These Results AreConsistent With Previous Work And Indicate A Robust Effect For Antidepressants On Positive Information Processing.They Also Provide Further Evidence For Modification Of Information Processing As A Potential Mechanism Of ActionFor Antidepressant Medication.

کلیدواژه ها:

Depression ، Dopamine ، Norepinephrine ، Neurotransmitter