Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline Héctor González-Pardo a , Nélida M. Conejo a , Jorge L. Arias a , Santiago Monleón b , Concepción Vinader-Caerols b , Andrés Parra b, ⁎ a Laboratory of Neuroscience, Faculty of Psychology, University of Oviedo, Plaza Feijoo s/n, E-33003 Oviedo, Spain b Department of Psychobiology, University of Valencia, Blasco Ibáñez, 21, E-46010 Valencia, Spain Received 7 September 2007; received in revised form 14 January 2008; accepted 31 January 2008 Available online 8 February 2008 Abstract The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline. © 2008 Elsevier Inc. All rights reserved. Keywords: Amitriptyline; Tricyclic antidepressants; Inhibitory avoidance; Cytochrome oxidase; Limbic system; Mouse Tricylic antidepressants (TCAs) are often prescribed for the pharmacological management of severe major depression, particularly in cases with physical symptoms or pain (Mann, 2005). Amitriptyline is one of the most prescribed of the available TCAs (Barbui and Hotopf, 2001). Although the mechanisms underlying the therapeutic action of antidepressant drugs remain largely unknown, the reuptake inhibition of norepinephrine and serotonin is believed to be related with the antidepressant effects of TCAs. Compared to other TCAs, amitriptyline has a higher anticholinergic potency and a con- siderably high antihistaminergic effect (Cusack et al., 1994; Richelson, 1994). These properties have been associated with effects in the CNS, where they cause memory impairment and sedation after acute administration. Paradoxically, memory impairment is a common symptom among patients suffering from major depression, and is believed to be restored after chronic treatment with antidepressants (Burt et al., 1995). We have hypothesized that memory impairment is related to the therapeutic action of antidepressants (Parra, 2003). Several studies have examined the effect of antidepressants on memory in rodents (Yau et al., 1995, 2001; Monleón et al., 2002; Parra et al., 2002; Everss et al., 2005; Naudon et al., 2007), however, Available online at www.sciencedirect.com Pharmacology, Biochemistry and Behavior 89 (2008) 456 – 462 www.elsevier.com/locate/pharmbiochembeh ⁎ Corresponding author. Tel.: +34 963 864 302; fax: +34 963 864 668. E-mail address: andres.parra@uv.es (A. Parra). 0091-3057/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2008.01.022