Psychopharmacology (2005) 181: 309–318 DOI 10.1007/s00213-005-2240-4 ORIGINAL INVESTIGATION H. Luna-Munguía . L. Manuel-Apolinar . L. Rocha . A. Meneses 5-HT 1A receptor expression during memory formation Received: 10 October 2004 / Accepted: 8 February 2005 / Published online: 19 March 2005 # Springer-Verlag 2005 AbstractRationale:It has been reported that 5-HT 1A re- ceptors modulate learning and memory and diverse phar- macological and genetic evidence supports this notion. Nevertheless, there are few works about expression of these receptors during memory formation. Objective: We aimed to determine 5-HT 1A receptor expression in brain areas of untrained, passive, and autoshaping trained groups of rats. Methods:Ex vivo receptor autoradiography using the li- gand agonist [ 3 H]8-hydroxy-2-[di-n-propylamino]tetralin] (8-OH-DPAT) was used. Results:The trained group rela- tive to untrained animals showed increases of 5-HT 1A receptor expression in 14 brain areas, decrements in 7, and no changes in 12. Thus, in contrast to untrained rats, 5-HT 1A receptor expression of autoshaping trained rats was aug- mented in the tubercule olfactory, septal nucleus, nucleus accumbens, caudate putamen, globus pallidus, striate, and parietal (1 and 2), temporal cortex (1 and 3), granular ret- rosplenial cortex (1), amygdala, and median and dorsal raphe nuclei. In contrast, in the latter group, receptors were decreased in the CA1 area, hypothalamus dorsal, frontal cortex (1 and 3), occipital cortex, cingulate cortex (1 and 2), and cuneiform nucleus. There were significant differences between passive vs trained groups, butnotregarding un- trained rats, in the lateral olfactory tract, dentate gyrus, CA3 area, ventromedial hypothalamic, lateral hypothala- mus, preoptic medial, frontal cortex (2), granular retrosple- nial cortex (2), entorhinal cortex (1 and 2), piriform cortex, and substantia nigra. Conclusions: These data suggest that upregulated, downregulated, and “silence” of 5-HT 1A re- ceptors in brain areas form part of neural circuits engag in memory formation by demonstrating a high degree o specificity and memory mapping. KeywordsAutoshaping . 5-HT . [ 3 H]8-OH-DPAT . Memory . Learning . Receptors . Rat Introduction Normal and impaired memory involves several brain are (Buckner 2004;Murray and Wise 2004), neurotransmit- ters,and signal systems. Growing evidence indicates that the serotonin (5-hydroxytryptamine, 5-HT) system modu- lates normal, pathophysiological, and therapeutic aspects of learning and memory (Meneses 1999). Indeed, the et ogy of Alzheimer’s disease (AD) includes dysfunctions of the mesolimbic acetylcholine (ACh) system. Serotonin modulates the cortical ACh tone through multiple 5-HT receptors (Jacobs and Azmitia, 1992;Jeltsch et al. 2004; Terry 2004). AD and/or aging apparently is associated w changes in diverse 5-HT markers, including 5-HT 1A recep- tors (Meneses 1999, 2003). In patients suffering from AD the level of cognitive impairment is highly correlated wit cortical 5-HT and 5-HIAA tissue concentrations (Meneses 1999, for a review). Traditionally, the search for brain ar involved in learning and memory has been centered on aminations of amnesic and AD patients, cerebral lesions, and,more recently, neuroimaging (Squire 2004).In this regard, a complementary alternative consists in using ra- dioligands. For instance, age-related changes in [ 125 I]DOI (a 5-HT 2A receptor agonist) in cortical areas (e.g., prefron cortex,entorhinal area),and parahippocampal gyrusof rhesus monkeys (from 5 to 32 years) were correlated wi performance on the executive function, working memory, and recognition memory, respectively (Pugh et al. 2004). Lai et al. (2003) found that the frontal cortex of patients AD prospectively assessed with the Mini-Mental State Examination (MMSE) showed reduced 5-HT levels and increased 5-HT 1A receptor density associated with acceler- ated cognitive decline. Moreover, positron emission tom H. Luna-Munguía . L. Manuel-Apolinar . L. Rocha . A. Meneses (*) Departo. Farmacobiología, CINVESTAV-IPN, Tenorios 235, Granjas Coapa, México City, 14330, Mexico e-mail: ameneses@msn.com Tel.: +52-55-50612869 Fax: +52-55-50612863 L. Manuel-Apolinar Escuela Superior de Medicina, IPN, Mexico City, Mexico