Does the future of antidepressants lie in anesthetics?
Mood disorders like depression are among the leading causes of mental disability in the U.S. Because the therapeutic effects of traditional interventions and pharmacological treatments have shown to be limited in terms of efficacy, new therapies that are rapid acting and have increased efficacy in treatment-resistant populations are actively being sought out. Today, I was surprised to learn that the volatile anesthetic isoflurane has been shown to have antidepressant effects in humans since 1985 (Langer et al.) Given that I use isoflurane to knock my rats out while I implant cannulas and our lab studio the development of depressive-like behavior following early life abuse, I was floored.
Although clinical literature has provided hints into the use of anesthetics, whether isoflurane could also exert antidepressant-like effects in conventional animal models of depression had not been determined until recently. Paul Shepard’s lab at the Maryland Psychiatric Research Center (MPRC) have behavioral evidence suggesting that a short period of acute isoflurane inhalation is sufficient to impede the development of depressive-likebehavior in rats.
For this study, the group administered isoflurane (2% in 100% O2) to adult male Sprague Dawley rats continuously for two hours through a nose cone attached to a standard stereotaxic apparatus. Two weeks following exposure to isoflurane, rats entered a conventional two-day learned helplessness paradigm. Learned helplessness is a term that refers to the condition of an organism (human or animal) that has learned to behave helplessly and fails to respond even in the presence of opportunities for it to help itself. Another way of thinking about it is as a perceived loss of control over the outcome of a situation on the organism’s part. Specifically, the group used the shuttle box avoidance task, in which an animal must move from one compartment to the other in order to gain either gain a reward or avoid an aversive stimulus such as a shock.
As shown in the figure above, isoflurane-treated rats (n=12) had fewer failure trials (Fig. 1A) and a faster mean escape latency (Fig. 1B) in the shuttle box avoidance task compared to naïve-controls (n=12). To specify this effect, a separate group of rats was exposed to an equivalent dose (1.5% in 100% O2) of another anesthetic agent, halothane, for two hours, and evaluated in an identical learned helplessness paradigm after the same two week recovery period. Halothane-treated rats (n=12) performed similarly to naïve-controls (n=10; Fig. 1C-D), suggesting that the reduced expression of learned helplessness is specific to isoflurane rather than a general effect associated with exposure to volatile anesthetics. Importantly, these results support and extend on previous findings indicating that isoflurane has antidepressant effects in humans and provide new insights and opportunities regarding alternate targets for development of rapid pharmacological treatments for depression.
Obviously, more work needs to be done in order to clarify the mechanism of action and the timing in which isoflurane inhalation could prove to be useful. For example, would isoflurane work if it were given during infancy or adolescence? Could it be sufficient to prevent the depressive-like behavior even in the face of early life adversity? Moreover, research designed at determining the minimum exposure of isoflurane necessary for this effect would also be useful. Would animals, like the clinical population exhibit individual differences in terms of what dose is effective? We don’t know, but I certainly hope we find out.
This work was presented on Tuesday, October 16th 2012 by L. Wang as a poster titled Isoflurane impedes the development of a depression-like phenotype in rats.
