Acute administration of lithium but not valproate

Authors: Rafal Rygula Joanna Golebiowska Jakub Kregiel Malgorzata Holuj Piotr Popik

Publish Date: 2014/12/25

Volume: 232, Issue: 12, Pages: 2149-2156

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Abstract

Both valproic acid VPA and lithium LI are wellestablished treatments for therapy of intense and sustained mood shifts which are characteristics of affective disorders such as bipolar disorder BP As mood and cognitive judgment bias have been found to be strongly interrelated the present study investigated in an animal model whether acute treatment with VPA or LI could affect cognitive judgment biasTo accomplish this goal two groups of rats received single injections of either VPA or LI after initial behavioral training and were subsequently tested with the ambiguouscue interpretation ACI test Both drugs were administered in three doses using the fully randomized Latin square designVPA 100 200 and 400 mg/kg had no significant effect on the interpretation of the ambiguous cue LI at the lowest dose 10 mg/kg had no effect at an intermediate dose 50 mg/kg it significantly biased animals towards positive interpretation of the ambiguous cue and at the highest dose 100 mg/kg it impaired the ability of animals to complete the testTo our knowledge this is the first study demonstrating lithium’s effects on increased optimistic judgment bias Future studies may focus on the ability of putative pharmacotherapies to modify the cognitive judgment bias dimension of patients at risk for bipolar disorder or depressionAlthough over 60 years have elapsed since its effects on mania were first described lithium LI is still a mainstay in the treatment of mood disorders and remains the standard against which new moodstabilizing or thymoleptic drugs are measured Price and Heninger 1994 LI treatment paradoxically relieves both mania and depression—conditions that appear to be opposites and additionally it has been reported to have specific antisuicidal effects Baldessarini et al 2006 Guzzetta et al 2007 However the mechanism by which LI effectively treats bipolar disorder BP and depression and reduces the risk of suicidal behaviors is largely unknownAnother wellestablished treatment for bipolar disorder is valproic acid VPA The drug is increasingly used for therapy of bipolar and schizoaffective disorders and neuropathic pain and for prophylactic treatment of migraines Johannessen 2000 Johannessen and Johannessen 2003 however similar to LI its mode of action especially on the systems level remains unknownTo date limited research has examined effects of LI and VPA on cognitive processes in laboratory animals Recent studies for instance reported that LI but not VPA significantly reduced impulsivity of mice in the threechoice serial reaction time task Ohmura et al 2012 and in the delay discounting task Halcomb et al 2013 Important insights regarding the mechanism of action of these drugs may arise from understanding the effects of LI and VPA on cognitive biases associated with affective disorders which themselves are closely interrelated with mood Optimistic cognitive judgment bias for instance is a prominent endophenotype of bipolar mania For example manic patients consistently display overoptimistic judgment bias leading to highrisk behaviors such as extravagant shopping sexual adventures or improbable commercial schemes Belmaker and Bersudsky 2004 Young et al 2011 Clinical studies have highlighted the importance of excessive optimism in this disorder Carver and Johnson 2009 Gamma et al 2008 Giovanelli et al 2013 Johnson 2005 Johnson and Jones 2009 Leahy 1999 and Beck and Weishaar 1995 argued that “overly optimistic expectations provide vast sources of energy and drive the manic individual into continuous goaldirected activity” Similarly pessimistic cognitive judgment bias is a wellknown endophenotype associated with depression According to the cognitive model proposed by Beck negatively biased acquisition and processing of information plays a primary role in the development and maintenance of depressive disorder Beck 1967 1987 2008 In this model negative and pessimistic processing of one’s self and context including interpretation and judgment of environmental stimuli become pervasive Clark et al 1999Given that cognitive judgment biases are characteristics of many psychopathologies it is surprising how little attention they have received in preclinical research Although a number of studies over the past decade have reported that “optimism” and “pessimism” can be induced in animals following different behavioral and pharmacological manipulations Bateson et al 2011 Bethell et al 2007 Brilot et al 2010 Doyle et al 2011 Enkel et al 2010 Harding et al 2004 Mendl et al 2010 Rygula et al 2012 very few of these studies Enkel et al 2010 Richter et al 2012 have investigated cognitive judgment bias in the context of psychiatric disorders and their treatment

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