Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats.
BACKGROUND
Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST).


METHODS
The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness.


RESULTS
Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness.


CONCLUSIONS
Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.
Hamani
Clement
C
Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada. clement.hamani@uhn.on.ca
Diwan
Mustansir
M
Macedo
Carlos E
CE
Brandão
Marcus L
ML
Shumake
Jason
J
Gonzalez-Lima
Francisco
F
Raymond
Roger
R
Lozano
Andres M
AM
Fletcher
Paul J
PJ
Nobrega
José N
JN
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D017115:Catheter Ablation / Q000009:adverse effects; D046690:Deep Brain Stimulation / Q000379:methods*; D003863:Depression / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D018755:GABA Agonists / Q000633:toxicity; D006380:Helplessness, Learned; D007051:Ibotenic Acid / Q000633:toxicity; D008297:Male; D017551:Microdialysis / Q000379:methods; D009118:Muscimol / Q000633:toxicity; D017397:Prefrontal Cortex / Q000293:injuries / Q000502:physiology*; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity; D013550:Swimming / Q000502:physiology
D018663:Adrenergic Agents; D001596:Benzylamines; D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D018490:Serotonin Agents; D007051:Ibotenic Acid; D009118:Muscimol; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; C012102:DSP 4