Helplessness, learned

Petty, F, Kramer, G, Wilson, L and Jordan, S (1994) In vivo serotonin release and learned helplessness. Psychiatry Res. 52 285-293. 

This behavioural syndrome, rather emotively called learned helplessness", is widely believed to share many features of depression, not least because both culminate in psychomotor retardation and both are linked with experience of uncontrollable, unpredictable stress. Whether or not learned helplessness really is an analogue of depression remains controversial (Maier 1993). Nevertheless, escape deficits in rats are prevented by pretreatment with antidepressants from different generic groups. Other psychotropic agents, such as CNS stimulants and neuroleptics, are generally ineffective. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

In short, the widespread neurochemical disruption during learned helplessness suggests that antidepressant drugs could prevent this syndrome by targeting any of several different neurotransmitter systems. 

Obviously one limitation of all this work is that the drug effects have been tested in normal animals. So far, the neurochemical changes induced by long-term drug treatment have not been tested in combination with procedures such as learned helplessness, but it cannot be assumed that they will be the same as those in normal (non-depressed) subjects. 

Maier, SF (1993) Learned helplessness, relationships with fear and anxiety. In Stress from Synapse to Syndrome (Eds Stanford, SC and Salmon, P), Academic Press, London and New York, pp. 207-243. 

Depue, R. A., Monroe, S. M. (1978). Learned helplessness in the perspective of the depressed disorders Conceptual and definitional issues. Journal of Abnormal Psychobgy, 87, 3-20. 

Porsolt RD, Martin P, Lenegre A, Fromage S, Drieu K. (1990). Effects of an extract of Ginkgo biloba (EGB 761) on "learned helplessness" and other models of stress in rodents. Pharmacol Blochem Behav. 36(4) 963-71. 

Tejedor-Real P, Mico JA, Maldonado R, Roques BP, Gibert-Rahola J. (1995). Implication of endogenous opioid system in the learned helplessness model of depression. Pharmacol Biochem Behav. 52(1) 145-52. 

Unpredictability also is a central feature in the concept of learned helplessness. This concept, using uncontrollable shock, was introduced by Overmier and Seligman (1967) and is based on the observation that animals exposed to an invariable stressor such as electric foot shock, which, due to the experimental set-up, is uncontrollable in nature, developed behavioral deficits. As first shown by Weiss (1968), rats exposed to uncontrollable shock showed significant weight loss due to decreased food and water intake. Moreover, these animals spent more time immobile in the forced swim test, and they revealed altered sleep patterns as well as a weakened response to previously rewarding brain stimulation, i.e., anhedonia (Henn et al. 1985 Weiss 1991). Importantly, these changes are not seen in animals that receive the same shocks but can exert control over their duration. 

Seligman MEP, Beagley G (1975) Learned helplessness in the rat. J Comp Physiol Psychol 88 534-541... 

Pernar L, Curtis AL, Vale WW, Rivier JE, Valentino RJ (2004) Selective activation of corticotropin-releasing factor-2 receptors on neurochemicaUy identified neurons in the rat dorsal raphe nucleus reveals dual actions. J Neimosci 24 1305-1311 Petty F, Kramer G, Wilson L, Jordan S (1994) In vivo serotonin release and learned helplessness. Psychiatry Res 52 285-293... 

Stressful stimuli of many types produce marked increases in brain noradrenergic function. Stress produces regional selective increases in NE turnover in the locus coeruleus (LC), limbic regions (hypothalamus, hippocampus, and amygdala), and cerebral cortex. These changes can be elicited with immobilization stress, foot-shock stress, tail-pinch stress, and conditioned fear. Exposure to stressors from which the animal cannot escape results in behavioral deficits termed learned helplessness. The learned helplessness state is associated with depletion of NE, probably reflecting the point where synthesis cannot keep up with demand. These studies have been reviewed elsewhere in detail (Bremner et al. 1996a,b). 

Upregulation of CREB could play an important role in the actions of antidepressant treatment. To directly test this hypothesis, the influence of CREB expression in models of depression has been examined. For these studies, the expression of CREB or a dominant-negative mutant of CREB (mCREB) is increased by viral mediated gene transfer or by inducible transgenic expression. In addition, the influence of null mutation of one isoform, a-CREB, on behavior has been studied. Viral expression of wild-type CREB in the hippocampus, where antidepressant treatment increases CREB, results in an antidepressantlike effect in the forced swim (FST) and learned helplessness (LH) paradigms (Chen et al. 2001). The results demonstrate that increased expression of CREB is sufficient to produce an antidepressant effect and support the hypothesis that this transcription factor is an important target of antidepressant treatment. 

Ron an PJ, Kramer GL, Petty F (2001) Corticotropin releasing factor and arginine vasopressin effects in the learned helplessness animal model. Soc Neurosci Meeting Abstr 414.20 Rosen JB, Schulkin J (1998) From normal fear to pathological anxiety. Psychol Rev 105 325-350... 

Sayamwong Hammack Jom earned his Ph.D. from the University of Colorado studying how the serotonin system is altered in the learned helplessness model, which produces an anxiety-like state. He continues to research serotonin influences on anxiety in his current position as a postdoctoral fellow at Emory University. His work has been published in such journals as The Journal of Neuroscience, Neuroscience, and Behavioral Neuroscience. He currently lives in Atlanta, Georgia, with his wife. Heather. He would like to dedicate his contribution to this book to his parents. 

Sheehan M, de Belleroche J Facilitation of GABA release by cholecystokinin and caerulein in rat cerebral cortex. Neuropeptides 3 429-434, 1983 Sherman AD, Petty F Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 35 344-353, 1982 Sherman WR Lithium and the phosphoinositide signaling system, in Lithium and the Cell. Edited by Birch NJ. London, Academic Press, 1991, pp 121-157 Sherman WR, Munsell LY, Gish BG, et al Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis. J Neurochem 44 798-807, 1985... 

Another, somewhat comparable paradigm is the so-called learned helplessness test. Initially the rat is confronted with mild foot-shocks from which it cannot escape. Once it has learned that there is no way to avoid the unpleasant... 

If the answer to the last question is positive, dysthymia could represent a phenomenon consistent with the concept of learned helplessness, which would underscore the importance of early detection and aggressive therapy of MDD. 

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