Annals of Neurosciences, Vol 16, No 1 (2009)
Annals of Neurosciences, Volume 16, Issue 1 (January), 2009
Neuropsychopharmacology 2009 ; 34 : 1057-1066
Acute electrical stimulation of ventral tegmental area improves depressive behavior
Correspondence : The Mina and Everard Goodman Faculty of Life Sciences and Leslie and Susan Gonda (Goldschmied)
Multidisciplinary Brain Research Center, Bar-Ilan University, Geha Road, Ramat-Gan 52900, Israel. Tel: +972 3 531 8123;
Fax: +972 3 635 4965; E-mail: Yadidg@mail.biu.ac.il
Dept. of Pharmacology and Experimental Therapeutics,University of Maryland School of Medicine, Baltimore, MD 21201, USA
Research article of A. Friedman et al http://www.nature.com/npp/journal/v34/n4/abs/npp2008177a.html
Background
Depression is a common and devastating neuropsychiatric disorder, affect approximately 5% of the population and a better understanding of its pathophysiology is needed to improve diagnosis, treatment and prevention. Research has revealed some promising approaches that hold considerable therapeutic promise for the treatment of a range of neuropsychiatric disorders which include deep-brain stimulation (DBS), chronic administration of BDNF in mediating antidepressant effects and stimulation of mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA). Ventral tegmental area (VTA) neuronal activity plays an important role in reward-related learning and motivation. It is the origin of dopaminergic neuron cell bodies in the mesolimbic system and represents a reasonable site for intervention through DBS.
Study Design
In this study, the Friedman et al have tested a new method for intervention in depressive disorders, based on DBS of the VTA, as a source of incentive motivation and hedonia, in comparison to chemical antidepressants which may require several weeks to produce their clinical effects. They used acute electrical stimulation (AES), a modified version of DBS, which applies short-term low frequency programmed stimulation instead of continual DBS. They have tested this method on the male Flinder Sensitive Line (FSL) rats (genetic animal model of depression) as well as SD rats (as controls) and compared it to conventional antidepressant treatments.
In first set of experiment Friedman et al demonstrated the VTA neuronal firing and estimated the AES pattern. They used single unit recordings from VTA neurons of SD and FSL rats by inserting recording electrode streotaxically and quantified the firing pattern of dopaminergic cells. They found that VTA of SD rats has the capability of firing burst with large amount of spikes, whereas FSL rats rarely showing this pattern. Thus they picked a defined electrical template from the recorded and analyzed SD VTA cell-firing data and applied this pattern of stimulation, shaped to mimic the firing pattern of the normal rat, in the VTA of the FSL rats.
The authors then explored the normalization of FSL depressive like behavior after AES. The effect of AES on depressive-like behavioral expressions was monitored by a battery of five behavioral tests. Rats were first trained for behavioral tests and baseline was recorded. Depressive like behavior was again tested two weeks after implantation of bipolar electrode into the VTA of FSL and control rats, followed by AES of FSL through electrode and again monitored for same behavior paradigm. Treatment with AES resulted in improved grooming, eating and drinking as compared to non treated FSL rats. The level of depression was measured by immobility in the swim test and they found that immobility was higher in depressive rats than in controls. AES not only attenuated the degree of immobility in FSLs but also showed a significant faster onset and long-term effect compared to other treatment. They demonstrated this by stimulating FSL rat brain in a nonspecific region which resulted in no effect on depressive behavior. Then they confirmed whether AES to the VTA may have acted as an antidepressant, or it may have had a stimulant effect. They measured the locomotor activity of rats in open field test. Naive FSL rats have lower locomotor activity than the control SD rats, and treatment with AES did not improve locomotor activity supporting the rationale AES has an antidepressant, and not stimulant function.
The results of sucrose self-administration test (measure of anhedonia) clearly demonstrated that FSL rats exhibited anhedonic-like behavior, measured by a low number of presses on the active lever as compared to controls. But AES treatment improved self administration task in AES-treated FSL rats. They validated whether this disrupted behavior was due to cognition deficit or their high level of anhedonia in FSL rats. They confirmed this by measuring water self-administration following water deprivation in FSL and control rats and found that naive FSL rats did not show significant differences in active lever responses for water reinforcement as compared to controls which confirmed the effects of DBS on hedonic motivation without involvement of cognitive deficit or any other impairment in physical performance.
In a social interaction test FSL rats showed submissive behavior before treatment in comparison to SD rats, whereas following AES treatment, they found inverse relationship. In novelty exploration behavior FSL rats show a low level of ‘interest’ in the new object, whereas AES treatment normalized object exploration.
In last set of experiments, Friedman and colleagues investigated BDNF expression in different brain regions following AES by realtime PCR and western blot analysis. Surprisingly, AES significantly normalizes BDNF mRNA levels in the PFC, and also in the Nucleus accumbens. However, in the VTA, no differences were found between groups which indicates that BDNF transcription levels are correlated with depressive-like behavior and are not a result of neuronal lesion or electrical stimulus. On the basis of those results, they suggest a significant therapeutic effect of AES on depressive behavior, in addition to the functional role of BDNF in mediating the antidepressant effects of AES.
Implications
As with any new paradigm Friedman et al data revealed that AES has several advantages, specifically, fast onset of action, a selective effect within specific brain sites, and greater efficacy in correcting depressive behavior. Specifically, they showed that AES exerts its effect immediately within one short treatment session, whereas antidepressants or ECT require between 7 and 14 treatment sessions. The remedial effect of AES persists for up to 1 month after a single stimulation. A possible limitation confronting the future implementation of this procedure would be the sensitive location of the VTA. They raised interesting question for future research which shall determine whether this is a viable and practical mode of treatment in humans. But in light of the current findings it holds potential to become possible treatment of major depression.
doi : 10.5214/ans.0972.7531.2009.160106
* Monika Vinish is working as a post doctoral fellow at University of Maryland School of Medicine, Baltimore, USA.
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