Browsing by Subject "Morphine dependence"

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    Different contribution of glucocorticoids in the basolateral amygdala to the formation and expression of opiate withdrawal-associated memories
    (Elsevier, 2016-10-08) Ferenczi, Szilamer; Kovács, Krisztina J.; Núñez Parra, Cristina; García Pérez, Daniel; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
    Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval). We examined the influence of glucocorticoids (GCs) for a morphine-withdrawal CPA paradigm, along with plasticity changes in the BLA, in sham-operated and adrenalectomized (ADX) animals. We demonstrated that sham + morphine animals robustly displayed CPA, whereas ADX-dependent animals lacked the affective-like signs of opiate withdrawal but displayed increased somatic signs of withdrawal. Glucocorticoid receptor (GR) actions promote memory consolidation but highly depend on increases in GC levels. Interestingly, we observed that GCs were only increased in sham-dependent rodents during aversive-withdrawal memory consolidation, and that GR expression correlated with phosphorylated cAMP response element binding (pCREB) protein, early growth response 1 (Egr-1) and activity-regulated cytoskeletal-associated (Arc) mRNA induction in this experimental group. In contrast, ADX-animals displayed reduced (pCREB). GCs are also known to impair memory retrieval. Accordingly, we showed that GCs levels remained at basal levels in all experimental groups following memory retrieval, and consequently GRs no longer acted as transcriptional regulators. Importantly, memory retrieval elicited increased pCREB levels in sham + morphine animals (not in ADX + morphine group), which were directly correlated with enhanced Arc mRNA/protein expression mainly in glutamatergic neurons. In conclusion, context-withdrawal associations are accompanied plasticity changes in the BLA, which are, in part, regulated by GR signaling. Moreover, dysregulation of CREB signaling, in part through Arc expression, may enhance reconsolidation, resulting in the maintenance of excessive aversive states. These findings might have important implications for drug-seeking behavior.
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    Glucocorticoid homeostasis in the dentate gyrus is essential for opiate withdrawal-associated memories
    (Springer, 2016-10-11) García Pérez, Daniel; Ferenczi, Szilamer; Kovács, Krisztina J.; Núñez Parra, Cristina; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultad de Medicina
    Drug-withdrawal-associated aversive memories might trigger relapse to drug-seeking behavior. However, changes in structural and synaptic plasticity, as well as epigenetic mechanisms, which may be critical for long-term aversive memory, have yet to be elucidated. We used male Wistar rats and performed conditioned-place aversion (CPA) paradigm to uncover the role of glucocorticoids (GCs) on plasticity-related processes that occur within the dentate gyrus (DG) during opiate-withdrawal conditioning (memory formation-consolidation) and after reactivation by re-exposure to the conditioned environment (memory retrieval). Rats subjected to conditioned morphine-withdrawal robustly expressed CPA, while adrenalectomy impaired naloxone-induced CPA. Importantly, while activity-regulated cytoskeletal-associated protein (Arc) expression was induced in sham- and ADX-dependent animals during the conditioning phase, Arc and early growth response 1 (Egr-1) induction was restricted to sham-dependent rats following memory retrieval. Moreover, we found a correlation between Arc induction and CPA score, and Arc was selectively expressed in the granular zone of the DG in dopaminoceptive, glutamatergic and GABAergic neurons. We further found that brain-derived neurotrophic factor was regulated in the opposite way during the test phase. Our results also suggest a role for epigenetic regulation on the expression of glucocorticoid receptors and Arc following memory retrieval. Our data provide the first evidence that GC homeostasis is important for the expression of long-term morphine-withdrawal memories. Moreover, our results support the idea that targeting Arc and Egr-1 in the DG may provide important insights into the role of these signaling cascades in withdrawal-context memory re-consolidation. Together, disrupting these processes in the DG might lead to effective treatments in drug addiction thereby rapidly and persistently reducing invasive memories and subsequent drug seeking.
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    Naloxone-precipitated morphine withdrawal evokes phosphorylation of heat shock protein 27 in rat heart through extracellular signal-regulated kinase
    (Elsevier, 2011-04-17) Almela, P.; Martínez Laorden, Elena; Atucha, N.M.; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU
    Heat shock protein 27 (Hsp27) is a well-known stress response protein that becomes phosphorylated through extracellular signal-regulated kinase (ERK). Different drugs of abuse, such as morphine and/or its withdrawal, induce severe stress situations. In this study, we investigated Hsp27 and phospho-Hsp27 expression during morphine dependence and withdrawal and evaluated the involvement of ERK in the phosphorylation of Hsp27 in the rat right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by injection of naloxone (2 mg/kg, s.c.). ERK1/2, Hsp27 and phospho-Hsp27 at Ser15 were determined by quantitative blot immunolabeling using specific antibodies. Hsp27 expression was increased 30, 60, 90 and 120 min (144.5 ± 14.2%, P < 0.0001; 128.9 ± 4.6%, P = 0.04; 177.4 ± 12.7, P < 0.0001; and 136.2 ± 11.0%, P = 0.042, respectively) after saline injection to rats dependent on morphine. Naloxone-precipitated morphine withdrawal also increased the phosphorylation of Hsp27 at Ser15 at those time points (146.8 ± 19.8%, P = 0.034; 143.9 ± 17.9%, P = 0.032; 161.2 ± 33.3%, P = 0.029; and 152.2 ± 25.5%, P = 0.008, respectively). However, there were no changes in Hsp27 phosphorylation in the morphine dependent group injected with saline. In addition, there was an increase in the phosphorylation of ERK 60 min after naloxone injection in morphine dependent rats (pERK1: 116.3 ± 4.2%, P = 0.015 and pERK2: 117.2 ± 1.5%, P = 0.05). Pretreatment with SL327, an inhibitor of ERK phosphorylation, decreased activation (phosphorylation) of both ERK and Hsp27 (pERK1: 4.5 ± 3.6%, P < 0.0001; pERK2: 42.3 ± 3.3%, P < 0.0001; and pHsp27: 97.6 ± 1.5%, P = 0.008), suggesting that ERK activation triggers Hsp27 phosphorylation. The present findings demonstrate that morphine withdrawal is capable of inducing the activation of Hsp27 in the heart and suggest that phosphorylation of Hsp27 is closely linked to and also dependent on the ERK pathway.