Modulation of the endogenous opioid system after morphine self-administration and during its extinction: A study in Lewis and Fischer 344 rats Pilar Sa ´nchez-Cardoso 1 , Alejandro Higuera-Matas 1 , Sonsoles Martı ´n, Nuria del Olmo, Miguel Migue ´ns, Carmen Garcı ´a-Lecumberri, Emilio Ambrosio * Departamento de Psicobiologı ´a, Facultad de Psicologı ´a, UNED, C/Juan del Rosal n  10, Ciudad Universitaria, Madrid 28040, Spain Received 21 July 2006; received in revised form 16 October 2006; accepted 18 October 2006 Abstract Lewis (LEW) and Fischer 344 (F344) rats show differential morphine self-administration rates. In this study, after animals of both strains self-administered morphine (1 mg/kg) or extinguished this behaviour for 3, 7 or 15 days, we measured the binding to, and functional state of m opioid receptors (MORs) as well as proenkephalin (PENK) mRNA content in several brain regions. The results showed that in most brain areas: 1) LEW rats had less binding to MORs in basal conditions than F344 rats; 2) after morphine self-administration, either one of the strains or both (depending on the brain area) showed increased levels of binding to MORs as compared to basal groups; and 3) these binding levels in morphine self-administration animals came down in each extinction group. Moreover, F344 rats exhibited, in general, an increased functionality of MORs after morphine self-administration, as compared to basal groups, which also went down during extinction. Finally, the basal content of PENK mRNA was lower in LEW rats than in F344 rats and it decreased more after self-administration; during extinction, the levels of PENK mRNA got normalized in this strain. This differential modulation of the endogenous opioid system might be related to the different rates of morphine self-administration behavior exhibited by both inbred rat strains. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Lewis; Fischer 344; Morphine; Self-administration; Extinction; Opioid system Abbreviations: AID, agranular insular cortex, dorsal part; AIV, agranular insular cortex, ventral part; APT, anterior pretectal nucleus; BLA, basolateral amyg- daloid nucleus, anterior part; BMP, basomedial amygdaloid nucleus, porterior part; BSTMA, bed nucleus of stria terminalis, medial division, anterior part; BSTMV, bed nucleus of the stria terminalis, medial division, ventral part; CA1, field CA1 of hippocampus; CA2, field CA2 of hippocampus; CA3, field CA3 of hippocampus; Cg1, cingulate cortex, area 1; CL, centrolateral thalamic nucleus; CP, caudate-putamen; CPDL, caudate-putamen, dorsolateral division; CPDM, caudate-putamen, dorsomedial division; CP-Matrix, caudate-putamen, matrix; CP-Patches, caudate-putamen, patches; CPVL, caudate-putamen, ventrolat- eral division; CPVM, caudate-putamen, ventromedial division; DEn, dorsal endopiriform nucleus; DG, dentate gyrus; DM, dorsomedial hypothalamic nucleus; G1, glomerular layer of the olfactory tubercle; La, lateral amygdala; LAVM, lateral amygdaloid nucleus, ventromedial part; LC, locus coeruleus; LDDM, laterodorsal thalamic nucleus, dorsomedial part; LDVL, laterodorsal thalamic nucleus, ventrolateral part; LGP, lateral globus pallidus; LHbM, lateral habenular nucleus, medial part; LPMR, lateral posterior thalamic nucleus, mediorostral part; LSI, lateral septal nucleus, intermediate part; LSS, lateral stripe of the striatum; LSV, lateral septal nucleus, ventral part; M1, primary motor cortex; M2, secundary motor cortex; MDC, mediodorsal thalamic nucleus, central part; MDM, mediodorsal tha- lamic nucleus, medial part; Me, medial amygdaloid nucleus; MGD, medial geniculate nucleus, dorsal part; MePD, medial amygdaloid nucleus, posterodorsal part; MePV, medial amygdaloid nucleus, posteroventral part; MGM, medial geniculate nucleus, medial part; MGV, medial geniculate nucleus, ventral part; NAcc-Shell, nucleus accumbens, shell division; NAcc-Core, nucleus accumbens, core division; OT, nucleus of the optic tract; PAG, periaqueductal gray; PBP, parabrachial pigmented nucleus; PIR, piriform cortex; Po, posterior thalamic nuclear group; PPT, posterior prectectal nucleus; PV, paraventricular thalamic nucleus; Re, nucleus reuniens; Rh, rhomboid thalamic nucleus; RMC, red nucleus magnocellular part; RN, raphe nucleus; RPC, red nucleus parvicellular part; SNC, substantia nigra, compact part; SNR, substantia nigra, reticular part; S1J, primary somatosensory cortex, jaw region; SuG, superficial gray layer of the superior colliculus; Tu, olfactory tubercle; VRe, nucleus reuniens, ventral part; VTA, ventral tegmental area. * Corresponding author. Tel.: þ34 9 1398 7974; fax: þ34 9 1398 6287. E-mail address: eambrosio@psi.uned.es (E. Ambrosio). 1 These authors equally contributed to the present work. 0028-3908/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2006.10.011 Neuropharmacology 52 (2007) 931e948 www.elsevier.com/locate/neuropharm