Milanés Maquilón, María Victoria

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Milanés Maquilón, María Victoria

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Open Access
Unraveling the molecular mechanisms involved in alcohol intake and withdrawal in adolescent mice exposed to alcohol during early life stages.
(2021) Montagud-Romero, Sandra; Cantacorps, Lídia; Fernández Gómez, Francisco José; Núñez, Cristina; Miñarro, Jose; Rodriguez-Arias, Marta; Valverde, Olga; Milanés Maquilón, María Victoria; Farmacología
Open Access
Acute morphine, chronic morphine and morphine withdrawal differently affects pleiotrophin, midkine and receptor protein tyrosine phosphatase β/ζ regulation in the ventral tegmental area
(Springer, 2016-01-07) García Pérez, Daniel; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultad de Medicina
Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.
Open Access
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.
Open Access
Binge ethanol and MDMA combination exacerbates HSP27 and Trx-1 (biomarkers of toxic cardiac effects) expression in right ventricle
(Elsevier, 2019-01) Navarro-Zaragoza, Javier; Ros-Simó, Clara; Valverde, Olga; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
Aims Oxidative stress caused by exposure to drugs of abuse such as ethanol or 3, 4 methylenedioxymethamphetamine (MDMA) may derive from direct or indirect effects in many organs including the heart. The aim of the present work was to evaluate cardiac sympathetic activity and the expression and activation of two antioxidant proteins: heat shock protein27 (HSP27) and thioredoxin-1 (Trx-1) after voluntary binge ethanol consumption, alone and in combination with MDMA. Material and Methods Adolescent mice received MDMA, ethanol or both. Drinking in the dark (DID) procedure was used as a model of binge. HSP27 expression and phosphorylation at serine 82 (pHSP27), Trx-1 expression, tyrosine hydroxylase (TH) and TH phosphorylated at serine 31 (pTH) were evaluated in adolescent mice 48h and 7 days after treatments in the right ventricle. TH, HSP27 expression and phosphorylation and Trx-1 expression were measured by quantitative blot immunolabeling using specific antibodies. Key Findings The expression of HSP27, pHSP27, Trx-1, total TH and pTH in the right ventricle was increased after binge ethanol or MDMA alone. In addition, the combination of binge ethanol+MDMA enhanced TH expression and phosphorylation versus their individual administration. Significance These results indicate that this combination could produce higher activation of sympathetic pathways, which could trigger an increased cell stress. On the other hand, increased HSP27, 3 pHSP27 and Trx-1 expression in the right ventricle by ethanol+MDMA could be a protective mechanism to reduce the adverse effects of oxidative stress caused by both drugs of abuse.
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Expression of heat shock protein 27 and troponin T andtroponin I after naloxone-precipitated morphine withdrawal
(Elsevier, 2015-10-09) Martínez Laorden, Elena; Almela Rojo, Pilar; Milanés Maquilón, María Victoria; Laorden Carrasco, María Luisa; Farmacología; Facultad de Medicina
Open Access
Role of glucocorticoids on noradrenergic and dopaminergic neurotransmission within the basolateral amygdala and dentate gyrus during morphine withdrawal place aversion
(Wiley, 2019-02-19) García Pérez, Daniel; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
Aversive memories related to drug withdrawal can generate a motivational state leading to compulsive drug taking. However, the mechanisms underlying the generation of these withdrawal memories remain unclear. Limbic structures, such as the basolateral amygdala (BLA) and the dentate gyrus (DG) of the hippocampus, play a crucial role in the negative affective component of morphine withdrawal. Given the prominent role of glucocorticoids (GCs), noradrenaline (NA), and dopamine (DA) in memory-related processes, in the present study, we employed the conditioned place aversion (CPA) paradigm to uncover the role of GCs on NA and DA neurotransmission within the BLA and NA neurotransmission within the DG during opiate-withdrawal conditioning (memory formation consolidation), and after reexposure to the conditioned environment (memory retrieval). We observed that adrenalectomy impaired naloxone-induced CPA. Memory retrieval was associated with an increase in dihydroxyphenylacetic acid (DOPAC) levels in the BLA in morphine-addicted animals in a GC-independent manner. Importantly, NA turnover was related with the expression of withdrawal physical signs during the conditioning phase and with locomotor activity during the test phase. On the other hand, reduced DA concentration in the BLA was correlated with the CPA score. Our results indicate that while noradrenergic system is more associated with the somatic consequences of withdrawal, dopaminergic neurotransmission modulates the affective state. Nevertheless, it seems necessary that both systems work together with GCs to enable aversive-memory formation and recall.
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Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress
(MDPI, 2021-03-18) Guerrero-Bautista, Rocío; Franco-García, Aurelio; Hidalgo, Juana M.; Fernández-Gómez, Francisco José; Núñez, Cristina; Ribeiro do Couto, Bruno; Milanés Maquilón, María Victoria; Farmacología; Anatomía Humana y Psicobiología
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Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons
(Wiley, 2009-08-10) Martín Sánchez, María Rosario Fátima; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
The transcription factor cAMP response element binding protein (CREB) has been implicated in the actions of drugs of abuse in several brain areas. However, little is known about CREB regulation in the nucleus tractus solitarius (NTS)-A2 catecholaminergic cell group, one of the key regions of the brain stress system. Morphine withdrawal modulates gene expression in the NTS through various second- messenger signal transduction systems including activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase C (PKC). In the current study we used immunoblotting and immunohistochemistry to investigate changes in CREB phosphorylation in the NTS and kinases that may mediate the morphine withdrawal-triggered activation of CREB and hypothalamo- pituitary-adrenocortical (HPA) axis (another stress system circuit) response after naloxone-induced morphine withdrawal. We found an increased phosphorylation of REB (pCREB) selectively within tyrosine hydroxylase (TH) immunoreactive neurons in the NTS from morphine- withdrawn rats, which parallel elevated corticosterone levels. We also measured expression levels of TH and phosphorylated ERK1/2 (pERK1/2), and found that both are up-regulated following morphine withdrawal. SL327, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK1/2 levels, did not attenuated the rise in pCREB and TH immunoreactivity or plasma corticosterone secretion during morphine withdrawal, indicating that ERK kinase/ERK pathway was not directly needed for either activation of CREB and TH expression in the NTS or HPA axis hyperactivity. In contrast, PKC inhibitor calphostin C reduced the withdrawal-triggered rise in pCREB, pERK1/2, TH expression and corticosterone secretion. The results indicate that PKC mediates both CREB activation and HPA response by morphine withdrawal and might suggest that CREB activation in the NTS is related to TH expression associated with morphine withdrawal.
Open Access
Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons
(Wiley, 2013-08-08) García Pérez, Daniel; López Bellido, Roger; Hidalgo, Juana M.; Rodríguez, Raquel E.; Núñez Parra, Cristina; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction.
Open Access
Dysregulation of dopaminergic regulatory mechanisms in the mesolimbic pathway induced by morphine and morphine withdrawal
(Springer, 2015) López Bellido, Roger; Rodríguez, Raquel E.; Núñez Parra, Cristina; García Pérez, Daniel; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. The aim of our study was to investigate abnormalities in the mesolimbic pathway associated with morphine dependence and withdrawal. Using quantitative real-time PCR, immunofluorescence, HPLC and Western blotting, here we studied the effects of single morphine administration, morphine dependence and morphine withdrawal on Nurr1 and Pitx3 expression as well as on the DA marker tyrosine hydroxylase (TH) and the turnover of DA in the ventral tegmental area (VTA) and/or nucleus accumbens. We showed that the three experimental conditions caused induction of Nurr1 and Pitx3 in the VTA, which correlated with changes in TH expression during chronic morphine administration. Present data also confirmed the colocalization of Nurr1 and Pitx3 with TH-positive neurons in the posterior VTA. Furthermore, during morphine dependence, Nurr1 was detected in the nucleus compartment of VTA TH-positive neurons, whereas Pitx3 was strongly detected in the nucleus of TH-positive neurons after single morphine administration and during morphine withdrawal. The number of TH neurons, number of Nurr1 or Pitx3-positive cells, and the number of TH neurons expressing Nurr1 or Pitx3 were not modified in the subpopulations of DA neurons. Present data provide novel insight into the potential correlation between Nurr1 and Pitx3 and DA neurons plasticity during opiate addiction in the mesolimbic pathway.