García Pérez, Daniel

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García Pérez, Daniel

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Open Access
Pathogenesis of spinal intramedullary lipomas: two case reports
(BioMed Central, 2023-07-25) Moreno Gómez, Luis Miguel; García Pérez, Daniel; González‑León, Pedro Juan; Munarriz, Pablo M.; Castaño‑León, Ana María; Farmacología; Farmacia
Background: Spinal lipomas not associated with dysraphism are rare and have an unknown natural history. In this report, we describe two cases; they showed recurrence during long-term follow-up, which makes us doubt a benign malformative etiology. Case reports: Two patients, a 19-year-old South American woman and a 14-year-old boy with spinal lipomas, underwent surgical resection. The lipomas were not associated with dysraphism and were located in the cervicothoracic and craniocervical junctions. In both cases, we decided to operate due to clinical progression; the former had a progressive natural course, and the latter experienced clinical worsening after recurrence from previous surgeries. The surgery took place with the assistance of neurophysiological monitoring and intraoperative ultrasound; a partial resection and medullary decompression were done, following the more recent recommendations. Discussion: The natural history of these lesions is currently unknown due to their rarity and the heterogeneity in the long-term follow-up of previously reported cases. Although previous reports describe good outcomes after surgical resection, long follow-ups, especially in young subjects, may show differences in these outcomes with progression and recurrence. We contribute to this last piece of evidence by describing two more cases of progression and recurrence. Lessons: Long-term close follow-up should be done in young subjects with spinal lipomas, as they are more prone to an aggressive course. Metabolism and hormonal changes may be behind this progression. Reoperation must be considered if neurological decline is detected.
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Implant microbial colonization detected by sonication as a cause for spinal device failure
(Lippincott, Williams & Wilkins, 2021-11-01) García Pérez, Daniel; Lagares, Alfonso; Castaño León, Ana María; Panero, Irene; Munarriz, Pablo M.; Delgado Fernández, Juan; Jiménez Roldán, Luis; Pérez-Núñez, Ángel; Alén, Jose Antonio F.; Paredes, Igor; Farmacología
Study Design. A prospective single center observational study. Objectives. The aim of this study was to examine the potential role of sonication in the diagnosis of low-grade infections and its association with pedicle screw (PS) loosening, and to describe risk factors and radiological findings associated with spinal implant infection. Summary of Background Data. Although PS loosening has mainly been attributed to mechanical overload, implant colonization and biofilm formation have recently been suggested. Culturing of sonication fluid implants is promising in the field of spine instrumentation infection, but little data are available. Methods. We prospectively included all patients who were subjected to implant removal. PS loosening was assessed with computed tomography (CT) scan. Different clinical and radiological parameters which could serve as indicators of implant infection were studied. Results. Thirty-eight patients were included in the study and 11 of them (29%) had a positive sonication result. Patients with spinal implant infection were associated with screw loosening (P = 0.005). Particularly, those screws with a positive microbiological culture showed signs of screw loosening in the preoperative CT scan (P < 0.001). Our results also showed that radiological screw loosening at L1-L3 level, and loosened larger constructs were associated with screw microbial colonization. The most common isolated microorganisms were coagulase-negative staphylococci and Cutibacterium acnes. An implant-based multivariate analysis indicated that screw loosening, the absence of prophylactic cefazolin, ICU hospitalization, screw breakage, and L1-L3 spine level were independent risk factors for implant-associated infection. Our model exhibited a high predictive power with an area under the curve of 0.937. Conclusion. As clinical presentation of deep implant chronic infection is unspecific, consideration of these factors enables preoperative prediction and risk stratification of implant colonization, thus helping patient's management. Level of Evidence: 3
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.
Open Access
Opiate addiction: neuronal plasticity on brain reward system and emotional memory-related areas = Adicción a opiáceos : plasticidad neuronal en los circuitos neuronales de recompensa y en áreas de memoria emocional
(2015-12-01) García Pérez, Daniel; Núñez Parra, Cristina; Milanés Maquilón, María Victoria; Facultad de Medicina
Los opiáceos, como la morfina, son unos potentes analgésicos que se usan para tratar diversas formas de dolor agudo y crónico. Sin embargo, el uso crónico de opiáceos produce cambios neuroadaptativos a nivel cerebral que conllevan efectos indeseables, como la adicción. La creciente evidencia implica a varios mecanismos de regulación génica (incluyendo epigenéticos, moleculares, celulares y a nivel de circuitos neuronales) en los cambios que las drogas de abuso provocan en el cerebro, siendo el conocimiento de éstos una posible estrategia terapéutica para el tratamiento de la adicción. Hemos centrado el presente estudio en varios neurocircuitos implicados en la adicción a opiáceos: i) el eje hipotálamo-hipófisis-adrenal (HPA) y el sistema extrahipotalámico del estrés, ii) el sistema dopaminérgico de recompensa, y iii) circuitos relacionados con las memorias aversivas. 1. El primer objetivo consistió en examinar el papel de los glucocorticoides (GCs) en la expresión de ΔFosB en poblaciones neuronales específicas del sistema cerebral del estrés durante la dependencia de morfina. Para ello, la expresión de ΔFosB se cuantificó en ratas control (sham) y adrenalectomizadas (ADX) que desarrollaron dependencia de morfina. 2. Segundo objetivo: Dada la importante implicación de la transmisión dopaminérgica en los desórdenes adictivos, hemos centrado esta parte de nuestro estudio en identificar los marcadores dopaminérgicos que resultan alterados con la administración aguda y crónica de morfina, así como durante el síndrome de abstinencia inducido por naloxona, tanto en el área tegmental ventral (VTA) como el núcleo accumbens (NAc). Para ello, hemos determinado: i) la expresión del miR-133b y Agonauta 2 (Ago2) en el VTA; ii) el contenido de tirosina hidroxilasa (TH) y su actividad; iii) la actividad dopaminérgica (recambio de DA y activación de TH) en el sistema mesolímbico de ratas tratadas con morfina. 3. El tercer objetivo fue estudiar: i) posibles cambios en los niveles de mRNA y proteína de Nurr1 y Pitx3, así como la expresión de Ago2 y de TH en regiones específicas del sistema mesolímbico; ii) actividad dopaminérgica en el NAc; iii) co-localización cuantitativa de Nurr1 y Pitx3 en el VTA en las neuronas que expresan TH, iv) cambios en la plasticidad de subpoblaciones neuronales dopaminérgicas del VTA en respuesta a morfina aguda, crónica o durante el síndrome de abstinencia. 4. Cuarto objetivo: Los efectos del síndrome de abstinencia a morfina sobre la expresión de Nurr1 y Pitx3 nos llevó a investigar la expresión de otros genes y proteínas que están implicadas en la regulación de la función dopaminérgica, algunos de los cuáles son dianas de Nurr1 y Pitx3. Para ello, las ratas recibieron morfina de forma aguda o crónica. Otro grupo fue sometido a un síndrome de abstinencia a morfina. Se estudió: i) la expresión del transportador de dopamina (Dat)-DAT, transportador vesicular de monoaminas 2 (Vmat2)-VMAT2, receptor de DA tipo 2 (Drd2)-DRD2 y DRD1 en VTA/NAc; ii) la co-localización de Nurr1 y/o Pitx3 con neuronas que expresan TH en el VTA, así como el porcentaje de neuronas dopaminérgicas que expresan Nurr1 y Pitx3; iii) la posible correlación entre la expresión de Nurr1/Pitx3 y los niveles de los diferentes marcadores dopaminérgicos. 5. Quinto objetivo: Por otra parte, cada día es más evidente que las drogas de abuso producen alteraciones en el sistema inmune del CNS. Por ello, se ha propuesto que los astrocitos contribuirían a la plasticidad sináptica que se produce durante el desarrollo de la adicción mediante la síntesis y liberación de sustancias, como las citoquinas. Dado que pleiotrofina (PTN) y midkina (MK) tienen los mismos efectos que las neurotrofinas y que los astrocitos pueden liberar MK y PTN después de diversos estímulos, nuestro siguiente objetivo fue: i) estudiar posibles cambios en la expresión de PTN, MK, su receptor, así como alteraciones en sus vías de señalización intracelular en respuesta a morfina aguda, crónica o durante el síndrome de abstinencia en el VTA y NAc; ii) la posible activación de los astrocitos durante los tratamientos descritos; iii) identificar las subpoblaciones celulares que producen y secretan PTN y/o MK. Las conclusiones de nuestro trabajo son: 1. El presente trabajo demuestra que los GCs están críticamente involucrados en la acumulación de FosB/ΔFosB en el sistema cerebral del estrés durante la administración crónica de morfina, lo que resultaría en cambios duraderos en los patrones de expresión génica en las áreas relacionadas con el estrés. 2. Aunque no hallamos cambios significativos en los niveles de miR-133b en el VTA, proponemos el papel de Ago2 en combinación con otros miRs en la regulación de la estabilidad y/o traducción del mRNA de TH en respuesta a la administración crónica de morfina y al síndrome de abstinencia a opiáceos. Nuestros resultados sugieren un papel importante de Nurr1 y Pitx3 en los cambios en la expresión génica durante la dependencia y abstinencia a opiáceos, y que la regulación epigenética de TH puede estar asociada a los mecanismos moleculares que contribuyen a los cambios en la función dopaminérgica inducida por los opiáceos. 3. La dependencia de morfina y el síndrome de abstinencia a la misma están asociados con alteraciones de la mayoría de los marcadores dopaminérgicos (DAT, VMAT2, DRD2) en la vía mesolímbica de recompensa, que se correlacionan con alteraciones en los factores de transcripción encargados del mantenimiento de las neuronas dopaminérgicas (Nurr1 y Pitx3). 4. Debido a la activación glial en el VTA durante la administración aguda y crónica de morfina, junto con el incremento de los niveles de mRNA de MK y PTN, proponemos la importancia de estas citoquinas al mediar, al menos en parte, las adaptaciones tróficas que se observan durante el fenómeno de adicción. Opiate drugs, such as morphine, are a class of powerful analgesics that are used for treating many forms of acute and chronic pain. However, chronic use of opiates causes brain neuroadaptations that lead to undesirable effects, namely opiate addiction that is a significant medical and public health problem. Increasing evidence implicates various mechanisms of gene regulation (including epigenetic, molecular, cellular and circuit level effects) in the changes that drugs of abuse induce in the brain, indicating a potential therapeutic strategy for addiction therapy. We have focused the present study on several neurocircuits involved in opiate addiction: i) the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic stress systems; ii) the dopaminergic reward pathways; and iii) aversive memories-related neuronal circuits. 1. The first objective of the present study was designed after considering the above. We examined the role of glucocorticoids (GCs) in regulation of ΔFosB expression in specific populations of the brain stress system during morphine dependence. For that, expression of ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made dependent on morphine. 2. Second objective: Given the important implications of dopamine (DA) neurotransmission in addiction disorders, we have focused this part of our study on identifying the DA markers that are altered in association with acute and chronic morphine exposure, as well as with morphine withdrawal in the ventral tegmental area (VTA) and nucleus accumbens [NAc(medial shell)]. For that, we have determined i) the expression of miR-133b and Argonaute (Ago2) in VTA; ii) tyrosine hydroxylase (TH) content and activity; and iii) dopaminergic activity (DA turnover and TH activation) in the mesolimbic system. 3. The third objective was to study: i) Nurr1 and Pitx3 mRNAs and proteins changes as well as the expression of Ago2 and TH mRNA and protein levels in specific region of the mesolimbic system; ii) dopaminergic activity in the NAc; iii) quantitative co-localization of Nurr1 and Pitx3 in the VTA TH-positive neurons; and iv) the plasticity changes in VTA DA neurons subpopulations in response to morphine, morphine dependence and morphine withdrawal. 4. Fourth Objective: The long-lasting effects of opiate withdrawal on Nurr1 and Pitx3 expression prompted us to investigate expression of other genes and proteins that are involved in the regulation of DA function, some of which represent putative targets of Nurr1 and Pitx3. For that, rats were exposed to acute and chronic morphine administration as well as to morphine withdrawal and analized: i) the expression of dopamine transporter (Dat)-DAT, vesicular monoamine transporter 2 (Vmat2)-VMAT2, dopamine receptor 2 (Drd2)-DRD2 and DRD1 in VTA/NAc(shell), dysfunction of which is causally linked to addiction; ii) the co-localization of Nurr1 and/or Pitx3 with TH-positive neurons in the VTA as well as the percentage of DA neurons expressing Nurr1 and Pitx3; and iii) the possible correlation between Nurr1/Pitx3 expression and DA markers levels in the VTA and/or NAc(shell). 5. Fifth Objective: There is increasing evidence that drugs of abuse produce alterations in CNS immunology. Thus, it has been proposed that astrocytes contribute to the synaptic plasticity during the development of drug addiction by the synthesis and release of substances, such as cytokines. The present study was focused on: i) identifying whether the expression of pleiotrophin (PTN), midkine (MK), receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ) and their intracellular signaling pathways are altered in association with acute and chronic morphine exposure as well as with morphine withdrawal in the VTA and NAc; ii) the possible activation of astrocytes; iii) identify those cell subpopulations that produced and secreted PTN and/or MK and those that expressed RPTPβ/ζ in response to morphine administration or morphine withdrawal. The conclusions from the present work are: 1. Present work provides evidence that GCs are critically involved in FosB/ΔFosB accumulation in the brain stress system after chronic morphine exposure, which might result in lasting changes of gene expression pattern in stress-related areas. 2. Although no significant changes of miR-133b levels are detected in the VTA, a role for Ago2 and specific miRs is hypothesized in regulating TH mRNA stability and/or translation in response to chronic morphine administration and naloxone-induced morphine withdrawal. Moreover, morphine dependence and withdrawal are associated with consistent alteration of transcription factors involved in the maintenance of dopaminergic neurons in the mesolimbic drug-reward pathway. 3. Morphine dependence and withdrawal are associated with consistent alteration of most of the DA markers (DAT, VMAT2, DRD2) in the mesolimbic drug-reward pathway which correlated with alteration of transcription factors involved in the maintenance of dopaminergic neurons (Nurr1 and Pitx3). Moeover, the correlations between DA markers and Nurr1/Pitx3 add evidence onto previous results. 4. Because of the glial activation in the VTA during acute and chronic morphine administration besides the enhancement in MK and PTN mRNAs, we propose a role for these cytokines in mediating, at least in part, the trophic adaptations that are observed during drug addiction.
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Densitometric analysis of brain computed tomography as a new prognostic factor in patients with acute subdural hematoma
(Journal of Neurosurgery Publishing Group (JNSPG), 2021-07-31) García Pérez, Daniel; Panero Pérez, Irene; Eiriz Fernández, Carla; Moreno Gómez, Luis Miguel; Esteban Sinovas, Olga; Navarro Main, Blanca; Gómez López, Pedro A.; Castaño León, Ana M.; Lagares, Alfonso; Farmacología
OBJECTIVE Acute subdural hematoma (ASDH) is a major cause of mortality and morbidity after traumatic brain injury (TBI). Surgical evacuation is the mainstay of treatment in patients with altered neurological status or significant mass effect. Nevertheless, concerns regarding surgical indication still persist. Given that clinicians often make therapeutic decisions on the basis of their prognosis assessment, to accurately evaluate the prognosis is of great significance. Unfortunately, there is a lack of specific and reliable prognostic models. In addition, the interdependence of certain well-known predictive variables usually employed to guide surgical decision-making in ASDH has been proven. Because gray matter and white matter are highly susceptible to secondary insults during the early phase after TBI, the authors aimed to assess the extent of these secondary insults with a brain parenchyma densitometric quantitative CT analysis and to evaluate its prognostic capacity. METHODS The authors performed a retrospective analysis among their prospectively collected cohort of patients with moderate to severe TBI. Patients with surgically evacuated, isolated, unilateral ASDH admitted between 2010 and 2017 were selected. Thirty-nine patients were included. For each patient, brain parenchyma density in Hounsfield units (HUs) was measured in 10 selected slices from the supratentorial region. In each slice, different regions of interest (ROIs), including and excluding the cortical parenchyma, were defined. The injured hemisphere, the contralateral hemisphere, and the absolute differences between them were analyzed. The outcome was evaluated using the Glasgow Outcome Scale–Extended at 1 year after TBI. RESULTS Fifteen patients (38.5%) had a favorable outcome. Collected demographic, clinical, and radiographic data did not show significant differences between favorable and unfavorable outcomes. In contrast, the densitometric analysis demonstrated that greater absolute differences between both hemispheres were associated with poor outcome. These differences were detected along the supratentorial region, but were greater at the high convexity level. Moreover, these HU differences were far more marked at the cortical parenchyma. It was also detected that these differences were more prone to ischemic and/or edematous insults than to hyperemic changes. Age was significantly correlated with the side-to-side HU differences in patients with unfavorable outcome. CONCLUSIONS The densitometric analysis is a promising prognostic tool in patients diagnosed with ASDH. The supplementary prognostic information provided by the densitometric analysis should be evaluated in future studies.
Open Access
Duroplastia expansiva en paciente con lesión medular aguda traumática: la importancia del sellado de la duramadre para evitar fugas
(Editorial PowerRachel SLU, 2022) García Pérez, Daniel; García Posadas, Guillermo; Moreno, Luis Miguel; Esteban, Olga; Paredes, Igor; Farmacología
Open Access
Impact of the first wave of the SARSCoV-2 pandemic on the outcome of neurosurgical patients: a nationwide study in Spain
(BMJ Publishing Group, 2021-12-10) Paredes, Igor; García Pérez, Daniel; Farmacología; Farmacia
Objective To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. Settings The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. Participants This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. Interventions An exploratory factorial analysis was performed to select the most relevant variables of the sample. Primary and secondary outcome measures Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. Results Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/105 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade ≥3 (OR 2.5) and preoperative GCS 3–8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/105 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. Conclusions Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/105 people/week) was a statistically independent predictor of mortality.
Open Access
Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic
(Oxford University Press, 2023-04-13) Poon, Michael T.C.; García Pérez, Daniel; COVIDSurg Collaborative; British Neurosurgical Trainee Research Collaborative; WFNS Young Neurosurgeons Committee; NIHR Global Health Research Group on Acquired Brain and Spine Injury; Farmacología; Facultad de Farmacia
Open Access
Snorting the brain away: cerebral damage as an extension of cocaine-induced midline destructive lesions
(Oxford University Press, 2020-11-26) García Pérez, Daniel; Ruiz Ortiz, Mariano; Panero, Irene; Eiriz Fernández, Carla; Moreno, Luis Miguel; García Reyne, Ana; García, Alfredo; Martín Medina, Patricia; Salvador Álvarez, Elena; Hernández Lain, Aurelio; Serrano, Antonio; Gil Etayo, Francisco Javier; Castaño León, Ana María; Paredes, Igor; Pérez Núñez, Ángel; Farmacología
Cocaine consumption is associated with a variety of clinical manifestations. Though cocaine intranasal inhalation always determines nasal mucosal damages, extensive septum perforations, and midline destructions—known as cocaine-induced midline destructive lesions (CIMDL)—affect only a limited fraction of patients. CIMDL is viewed as a cocaine-associated autoimmune phenomenon in which the presence of atypical anti-neutrophil cytoplasmic antibody (ANCA) promotes and/or defines the disease phenotype. A 51-year-old man presented with an intracranial tumor-like lesion by its space-occupying effect. CT also revealed the destruction of the nasal septum and skull base. A diagnosis of CIMDL was made in light of the patient’s history as well as findings of the physical and endoscopic examinations, imaging studies, and laboratory testing. There was no evidence of other pathologies. Histopathological results from cerebral biopsy led us to consider the intracranial pathology as an extension of the CIMDL. CIMDL is the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of predisposed patients. The reported case is the first CIMDL consistent with brain extension mimicking a tumor-like lesion. While the presence of atypical ANCA seems to promote and/or define the disease phenotype, the specific role of these and other circulating autoantibodies needs further investigation.
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.