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array:25 [ "pii" => "S2173580821001395" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2018.12.024" "estado" => "S300" "fechaPublicacion" => "2022-07-01" "aid" => "1270" "copyright" => "Sociedad Española de Neurología" "copyrightAnyo" => "2019" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Neurologia. 2022;37:459-65" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0213485319300106" "issn" => "02134853" "doi" => "10.1016/j.nrl.2018.12.004" "estado" => "S300" "fechaPublicacion" => "2022-07-01" "aid" => "1270" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Neurologia. 2022;37:459-65" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 450 "formatos" => array:2 [ "EPUB" => 18 "PDF" => 432 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVISIÓN</span>" "titulo" => "La plasticidad sináptica mediada por endocannabinoides y «trastornos por consumo de drogas»" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "459" "paginaFinal" => "465" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Endocannabinoid-mediated synaptic plasticity and substance use disorders" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1398 "Ancho" => 1943 "Tamanyo" => 110166 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Fenómenos bioquímicos que suceden durante la supresión de la liberación GABA en el hipocampo mediada por endocannabinoides. La liberación de glutamato activa receptores de kainato postsinápticos, que inducen la entrada de sodio y la producción de endocannabinoides. Los endocannabinoides son liberados al espacio sináptico y actúan sobre receptores CB<span class="elsevierStyleInf">1</span> unidos a proteínas G de terminales que liberan GABA. Ello induce la disminución de la entrada presináptica de calcio y una menor liberación de GABA.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">++</span>: calcio; CB<span class="elsevierStyleInf">1</span>R: receptor CB<span class="elsevierStyleInf">1</span>; eCB: endocannabinoide; G: proteína G; GABAR: receptor de GABA; Na<span class="elsevierStyleSup">+</span>: sodio.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Fernández-Espejo, L. Núñez-Domínguez" "autores" => array:2 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Fernández-Espejo" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Núñez-Domínguez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173580821001395" "doi" => "10.1016/j.nrleng.2018.12.024" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580821001395?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485319300106?idApp=UINPBA00004N" "url" => "/02134853/0000003700000006/v1_202206300632/S0213485319300106/v1_202206300632/es/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2173580820301553" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2020.08.001" "estado" => "S300" "fechaPublicacion" => "2022-07-01" "aid" => "1241" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Neurologia. 2022;37:466-79" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Axonal pathology in early stages of Guillain-Barré syndrome" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "466" "paginaFinal" => "479" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Patología axonal en la fase precoz del síndrome de Guillain-Barré" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 1540 "Ancho" => 2342 "Tamanyo" => 1140926 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Ischaemic lesions to proximal nerve trunks in AIDP.<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">70</span></a></p> <p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">A) Semithin transverse section of the third lumbar nerve, showing a wedge-shaped area (arrows) of pronounced loss of myelinated fibres. Toluidine blue stain; ×62 before reduction.</p> <p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">B) Semithin transverse section of the lumbosacral trunk, with the centrofascicular area presenting loss of myelinated fibres (arrows). Toluidine blue stain; ×62 before reduction. Note the diffuse reduction in the density of myelinated fibres in both A and B.</p> <p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">C) Detailed view of the lumbosacral trunk, showing marked loss of large myelinated fibres; small, thinly myelinated axons; preserved unmyelinated axons (arrowheads); and numerous mononuclear inflammatory cells, some with perivascular distribution (arrows). Toluidine blue stain; ×375 before reduction.</p> <p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">D) This subperineurial region of the lumbosacral trunk displays numerous de-remyelinated fibres and mononuclear cells. The extensive de-remyelination explains, to a great extent, the apparent loss of myelinated fibres in A and B. Toluidine blue stain; ×475 before reduction.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Berciano" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Berciano" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485318301762" "doi" => "10.1016/j.nrl.2018.06.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485318301762?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580820301553?idApp=UINPBA00004N" "url" => "/21735808/0000003700000006/v1_202206300536/S2173580820301553/v1_202206300536/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2173580821000730" "issn" => "21735808" "doi" => "10.1016/j.nrleng.2019.04.004" "estado" => "S300" "fechaPublicacion" => "2022-07-01" "aid" => "1322" "copyright" => "Sociedad Española de Neurología" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Neurologia. 2022;37:450-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "The role of vagus nerve stimulation in the treatment of refractory epilepsy: clinical outcomes and impact on quality of life" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "450" "paginaFinal" => "458" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Papel de la estimulación del nervio vago en el tratamiento de la epilepsia refractaria. Resultados clínicos e impacto en la calidad de vida" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 937 "Ancho" => 1667 "Tamanyo" => 54883 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Improvement in quality of life.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Martorell-Llobregat, P. González-López, E. Luna, M. Asensio-Asensio, R. Jadraque-Rodríguez, G. García-March, P. Moreno-López" "autores" => array:7 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Martorell-Llobregat" ] 1 => array:2 [ "nombre" => "P." "apellidos" => "González-López" ] 2 => array:2 [ "nombre" => "E." "apellidos" => "Luna" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Asensio-Asensio" ] 4 => array:2 [ "nombre" => "R." "apellidos" => "Jadraque-Rodríguez" ] 5 => array:2 [ "nombre" => "G." "apellidos" => "García-March" ] 6 => array:2 [ "nombre" => "P." "apellidos" => "Moreno-López" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485319300805" "doi" => "10.1016/j.nrl.2019.04.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485319300805?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580821000730?idApp=UINPBA00004N" "url" => "/21735808/0000003700000006/v1_202206300536/S2173580821000730/v1_202206300536/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Endocannabinoid-mediated synaptic plasticity and substance use disorders" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "459" "paginaFinal" => "465" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "E. Fernández-Espejo, L. Núñez-Domínguez" "autores" => array:2 [ 0 => array:4 [ "nombre" => "E." "apellidos" => "Fernández-Espejo" "email" => array:1 [ 0 => "efespejo@us.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "L." "apellidos" => "Núñez-Domínguez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro Médico Diagnóstico, Pamplona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La plasticidad sináptica mediada por endocannabinoides y «trastornos por consumo de drogas»" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1320 "Ancho" => 1674 "Tamanyo" => 119597 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Biochemical phenomena occurring during endocannabinoid-mediated long-term depression. Glutamate release activates postsynaptic ionotropic receptors and type 5 metabotropic glutamate receptors. The latter induce the production of endocannabinoids through Homer proteins and ryanodine receptors in calcium-storing vesicles and the endoplasmic reticulum. Endocannabinoids are released into the synaptic space and act on G protein–coupled CB<span class="elsevierStyleInf">1</span> receptors on terminals that release glutamate. This induces a decrease in presynaptic glutamate release.</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">++</span>: calcium; CB<span class="elsevierStyleInf">1</span>R: CB<span class="elsevierStyleInf">1</span> receptor; eCB: endocannabinoid; G: G protein; iGluR: ionotropic glutamate receptors; mGluR5: type 5 metabotropic glutamate receptors; RyR: ryanodine receptor.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">While it is clear that drugs can be addictive, “addictive” is a difficult word to define. Several terms have been used to define the psychobiological effect caused by drugs of abuse; these include addiction, dependence, abuse (Diagnostic and Statistical Manual of Mental Disorders-IV [DSM-IV]), and harmful use (International Classification of Diseases, 10th revision [ICD-10]).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Addiction is defined as a chronic and recurrent disease of the brain, characterised by searching for and compulsively consuming drugs, despite their harmful consequences.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Dependence would be a broader term than addiction, encompassing mild (for example, dependence on caffeine) to compulsive needs (an established addiction), according to 6 criteria.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Abuse (DSM-IV terminology), or harmful use (ICD-10 terminology), is based on a list of somatic and psychological effects of drug use. Today, the DSM-V<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> no longer uses these terms; instead, it includes “substance use disorders” (SUD), defined according to 11 criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and ranging from mild (presence of fewer than 3 criteria) to severe (more than 6 criteria).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">From a neurobiological viewpoint, drugs or addictive substances have an impact on the brain’s reward circuits, originating in the ventral tegmental area (VTA), as well as on limbic and memory-related regions including the amygdala and the hippocampus. Brain reinforcement mechanisms and synaptic plasticity in these circuits are essential in the development of addiction and addictive behaviour.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,4–6</span></a> Basic neuroplasticity events occur in mesolimbic reward circuits, which include the nucleus accumbens and ventral striate, the prefrontal cortex, and the VTA in the midbrain, as mentioned previously. These limbic structures consolidate the abnormal behaviour, associating numerous internal and external events with drug-related reward (conditioning). These conditioned effects are critical in the development of addiction, both in the active consumption phase and in the abstinence phase.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In terms of neurobiological effects, the neurotransmitters dopamine, GABA, and glutamate are key factors in mesolimbic neuroplasticity; the increasing relevance of such other neuromessengers as endocannabinoids is also worth mentioning. Endocannabinoids are known to cause retrograde modulation of synaptic signals, especially in glutamatergic and GABAergic synapses, and play a crucial role in synaptic neuroplasticity phenomena. SUDs are associated with a disruption of endocannabinoid-mediated plasticity. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the distribution of endocannabinoids in the human brain.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Endocannabinoids</span><p id="par0015" class="elsevierStylePara elsevierViewall">The first endocannabinoid to be discovered was anandamide (N-arachidonoylethanolamine, AEA), followed by 2-arachidonoylglycerol (2-AG) 2 years later.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> Other cannabinoid molecules have subsequently been identified, including 2-arachidonoylglycerol ether, N-arachidonoyl dopamine, virodhamine, N-homo-gamma-linolenoylethanolamine, and N-docosatetra-7,10,13,16-enoylethanolamine.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–13</span></a> Because endocannabinoids are lipidic compounds, synaptic vesicular storage is impossible due to their high liposolubility. Therefore, they are synthesised on demand by membrane precursors. After acting, endocannabinoids are rapidly degraded by reuptake (both by neurons and by glial cells) and subsequent hydrolysis.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Endocannabinoids act on specific cannabinoid receptors, especially types 1 and 2 (CB<span class="elsevierStyleInf">1</span> and CB<span class="elsevierStyleInf">2</span>). The first cannabinoid receptor described in the brain, in 1988,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> was CB<span class="elsevierStyleInf">1</span>; it was molecularly cloned in humans,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and identified as a member of the superfamily of receptors of G-protein-coupled neurotransmitters. A second cannabinoid receptor, CB<span class="elsevierStyleInf">2</span>, also belonging to the family of G-protein-coupled membrane receptors, was identified at the peripheral level.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> CB<span class="elsevierStyleInf">2</span> receptors share an overall homology of 44% with CB<span class="elsevierStyleInf">1</span> receptors (68% in transmembrane regions); they are abundantly expressed in lymphocytes, which suggests that this subtype of receptor mediates the immunomodulatory action of cannabinoids. Although the CB<span class="elsevierStyleInf">2</span> receptor has been identified in glial cells in the brain,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> CB<span class="elsevierStyleInf">1</span> is the main cerebral cannabinoid receptor in neurons. In the mammal brain, CB<span class="elsevierStyleInf">1</span> proteins are preferentially expressed in neuronal populations closely related to addiction and reward systems. A high density of CB<span class="elsevierStyleInf">1</span> receptors is found in the neurons of the nucleus accumbens, dorsal striatum, and cerebellum, which also explains the effects of acute stimulation (ataxia, dysmetria, and hypokinesia); the receptor is also found in the neurons of the hippocampus and amygdala. The remaining areas, such as the neocortex, superior colliculus, and habenula, show a moderate presence of these receptors. As previously mentioned, drugs of abuse alter both short- and long-term endocannabinoids-mediated synaptic neuroplasticity. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the SUD-related synaptic plasticity phenomena involving endocannabinoids.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Endocannabinoids and short-term neuroplasticity</span><p id="par0025" class="elsevierStylePara elsevierViewall">Endocannabinoids mediate short-term plasticity. Short-term plasticity phenomena may be either inhibitory or disinhibitory. Among inhibitory endocannabinoid-mediated phenomena, particularly important processes are depolarisation-induced suppression of inhibition (DSI) and depolarisation-induced suppression of excitation (DSE); these phenomena reduce the synaptic release of glutamate, GABA, or glycine.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20–22</span></a> Both processes are based on the fact that release of endocannabinoids after synaptic activity inhibits the subsequent presynaptic calcium influx and the release of the (excitatory or inhibitory) neurotransmitter, as has been shown in the cerebellum,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> hippocampus,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> or brainstem nuclei.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Endocannabinoids induce DSI and DSE through CB<span class="elsevierStyleInf">1</span> receptors: CB<span class="elsevierStyleInf">1</span> antagonists and agonists block and stimulate those synaptic phenomena, respectively.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,23</span></a> DSI phenomena are associated with dependence; for example, caffeine provokes a considerable alteration of DSI mediated by GABA.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Among disinhibitory endocannabinoid-mediated phenomena, we should highlight the disinhibition of neuronal activity, especially endocannabinoid-mediated disinhibition in the striatum (long-lasting disinhibition; DLL), and the suppression of GABA release in the hippocampus.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Both processes are mediated by CB receptors.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In the case of the suppression of GABA release in the hippocampus, glutamate release activates kainate receptors, which in turn stimulate the production of endocannabinoids that suppress synaptic GABA release (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Short-term changes seem to be mediated mainly by 2-AG.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Short-term synaptic changes last only minutes, but modify synaptic transmission and may underlie acute hedonic and motor changes caused by drugs. For example, alcohol blocks DLL phenomena induced by endocannabinoids in the dorsal striatum, which is associated with abnormal motor response.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Alcohol alters the delicate balance of excitation and inhibition in the striatum, mediated by endocannabinoids.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Drugs alter DSI and DSE phenomena in several regions associated with addiction, such as the VTA, amygdala, striatum, hippocampus, and neocortex.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29–32</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Endocannabinoids and long-term neuroplasticity</span><p id="par0040" class="elsevierStylePara elsevierViewall">Endocannabinoids also participate in long-term plasticity phenomena, which are longer-lasting and more stable in the brain engram; these phenomena include long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are important in memory and learning consolidation; drugs modify the normal neurophysiology of these processes, promoting the consolidation of addiction.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Endocannabinoids mainly participate in LTD phenomena. Endocannabinoid-mediated LTD occurs after a transient increase in glutamate levels, triggering increased postsynaptic endocannabinoid production, which in turn causes a long-term decrease in glutamate release, as is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This phenomenon has been detected in several structures associated with addiction, such as the nucleus accumbens, dorsal striatum, prefrontal cortex, amygdala, hippocampus, and VTA. The main LTD-mediating endocannabinoids is AEA,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> except in the hippocampus, where it seems to be 2-AG.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Such drugs as δ9-THC and cocaine block endocannabinoid-induced LTD in the nucleus accumbens, at least in animal models.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36,37</span></a> Alcohol also blocks endocannabinoid-induced LTD phenomena, in this case in the dorsal striatum.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Amphetamines block LTD in the amygdala through their action on endocannabinoids.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Another important plasticity phenomenon caused by drugs is hypofrontality: in the prefrontal cortex, interaction between dopamine (through D2 receptors), endocannabinoids, and several drugs of abuse may provoke prefrontal dopaminergic hypoactivity.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The importance of this process in the development of addiction is increasingly recognised, and it constitutes the basis of hypofrontality.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> There is mounting evidence suggesting that frontal areas, and especially the prefrontal area, prepare the subject to adequately respond to acute stress and show resilience to future stress. Endocannabinoids are key mediators in frontal activity, and endocannabinoid alterations due to drug abuse significantly modify the subject’s response and resilience to stress.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Another significant plasticity phenomenon in the development of addiction is sensitisation to addiction, although the role of endocannabinoids in these cases is not so relevant.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Acute administration of several drugs increases dopamine release in the main areas of the mesolimbic circuit, ie, the VTA and nucleus accumbens. This dopamine release is reinforced by the chronic consumption of the drug, in a process called dopaminergic sensitisation.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,43,44</span></a> This represents a crucial aspect differentiating addictive drugs from natural reinforcers (food, water, and sex), which do not present dopaminergic sensitisation.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Sensitisation is related to LTP, and several drugs including psychostimulants, opiates, ethanol, and nicotine are known to induce the LTP phenomenon in the VTA.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45–47</span></a> However, from a biochemical perspective, sensitisation is mainly mediated by an increase in glutamatergic transmission, NMDA and D1 dopamine receptor upregulation, and hyperactivity of the cAMP/protein kinase A pathway.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Therefore, endocannabinoids do not play a relevant role; they are only known to play a clear role in sensitisation to opiates.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In fact, endocannabinoids act on CB<span class="elsevierStyleInf">1</span> receptors located on dopaminergic neurons in the VTA, and mediate sensitisation to opiates. Sensitisation to cocaine has also recently been associated with CB<span class="elsevierStyleInf">1</span> receptors and, possibly, with endocannabinoids.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49,50</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Lastly, endocannabinoids and CB<span class="elsevierStyleInf">1</span> receptors are important in incentive sensitisation phenomena, which is the potentiation over time of the reinforcing role of spatial cues associated with the consumption of the drug; this type of conditioning is also essential in the development of drug addiction. For example, endocannabinoids facilitate behavioural association to spatial cues caused by cocaine,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> nicotine,<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> and alcohol.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="par0065" class="elsevierStylePara elsevierViewall">Drug abuse disrupts the synaptic plasticity of cerebral circuits involved in the development of the addiction and plays an important role in the alteration of the normal endocannabinoid activity. Endocannabinoid alteration facilitates anomalous changes in the brain and the development of the addictive behaviours that characterise SUD. Without doubt, good understanding of these phenomena will facilitate the development of treatments based on the modulation of endocannabinoids in the brain, with the aim of minimising the devastating effects of SUD.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1740769" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1535295" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1740770" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1535296" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Endocannabinoids" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Endocannabinoids and short-term neuroplasticity" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Endocannabinoids and long-term neuroplasticity" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack614931" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-08-29" "fechaAceptado" => "2018-12-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1535295" "palabras" => array:5 [ 0 => "neuroplasticity" 1 => "drug of abuse" 2 => "endocannabinoid" 3 => "addiction" 4 => "dependence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1535296" "palabras" => array:5 [ 0 => "neuroplasticidad" 1 => "droga" 2 => "endocannabinoide" 3 => "adicción" 4 => "dependencia." ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Drugs impact brain reward circuits, causing dependence and addiction, in a condition currently described as substance use disorders. Mechanisms of synaptic plasticity in these circuits are crucial in the development of addictive behaviour, and endocannabinoids, particularly anandamide and 2-arachidonyl-glycerol, participate in normal neuroplasticity. Substance use disorders are known to be associated with disruption of endocannabinoid-mediated synaptic plasticity, among other phenomena. Endocannabinoids mediate neuroplasticity in the short and the long term. In the short term, we may stress “inhibitory” phenomena, such as depolarisation-induced suppression of inhibition and depolarisation-induced suppression of excitation, and such “disinhibitory” phenomena as long-lasting disinhibition of neuronal activity, particularly in the striatum, and suppression of hippocampal GABA release. Drugs of abuse can also disrupt normal endocannabinoid-mediated long-term potentiation and long-term depression. Endocannabinoids are also involved in the development of drug-induced hypofrontality and sensitisation. In summary, substance abuse causes a disruption in the synaptic plasticity of the brain circuits involved in addiction, with the alteration of normal endocannabinoid activity playing a prominent role. This facilitates abnormal changes in the brain and the development of the addictive behaviours that characterise substance use disorders.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Las drogas impactan en los circuitos de recompensa cerebrales y originan dependencia y adicción, lo que se define actualmente como trastornos por consumo de drogas. Los mecanismos de plasticidad sináptica en dichos circuitos son cruciales en el desarrollo de la conducta adictiva, y los endocannabinoides, entre los que destacan la anandamida y el 2-araquidonil-glicerol, participan en la normal neuroplasticidad. Se sabe que los trastornos por consumo de drogas se asocian, entre otros fenómenos, a disrupción de la plasticidad sináptica mediada por endocannabinoides. Estas moléculas median neuroplasticidad de corta duración y perdurable. Respecto a la de corta duración, destacan fenómenos de carácter «inhibidor», como la supresión de la inhibición inducida por despolarización y la supresión de la excitación inducida por despolarización; y otros «desinhibidores», como la desinhibición de la actividad neuronal, sobre todo en el núcleo estriado, y la supresión de la liberación GABA en el hipocampo. Por otra parte, las drogas pueden alterar la normal potenciación perdurable y la depresión perdurable mediadas por endocannabinoides. Los endocannabinoides también influyen en el desarrollo de hipofrontalismo y sensibilización causados por las drogas. En fin, el abuso de drogas origina una disrupción en la plasticidad sináptica de circuitos cerebrales involucrados en la adicción y en ello juega un destacado papel la alteración de la normal actividad endocannabinoide. Ello facilita los cambios anómalos cerebrales y el desarrollo de conductas adictivas que caracterizan a los trastornos por consumo de drogas.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Fernández-Espejo E, Núñez-Domínguez L. La plasticidad sináptica mediada por endocannabinoides y «trastornos por consumo de drogas». Neurología. 2022;37:459–465.</p>" ] ] "multimedia" => array:5 [ 0 => array:9 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: modified from Licciardi and Manfredi.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1386 "Ancho" => 1674 "Tamanyo" => 267372 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Distribution of endocannabinoids in the human brain. Darker tone indicates higher density of endocannabinoid receptors.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1184 "Ancho" => 1674 "Tamanyo" => 112492 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Biochemical phenomena occurring during endocannabinoid-mediated suppression of GABA release in the hippocampus. Glutamate release activates postsynaptic kainate receptors, which induce sodium influx and production of endocannabinoids. Endocannabinoids are released into the synaptic space and act on G protein–coupled CB1 receptors on terminals that release GABA. This induces a decrease in presynaptic calcium influx and a decrease in GABA release.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">++</span>: calcium; CB<span class="elsevierStyleInf">1</span>R: CB<span class="elsevierStyleInf">1</span> receptor; eCB: endocannabinoid; G: G protein; GABAR: GABA receptor; Na<span class="elsevierStyleSup">+</span>: sodium.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1320 "Ancho" => 1674 "Tamanyo" => 119597 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Biochemical phenomena occurring during endocannabinoid-mediated long-term depression. Glutamate release activates postsynaptic ionotropic receptors and type 5 metabotropic glutamate receptors. The latter induce the production of endocannabinoids through Homer proteins and ryanodine receptors in calcium-storing vesicles and the endoplasmic reticulum. Endocannabinoids are released into the synaptic space and act on G protein–coupled CB<span class="elsevierStyleInf">1</span> receptors on terminals that release glutamate. This induces a decrease in presynaptic glutamate release.</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">++</span>: calcium; CB<span class="elsevierStyleInf">1</span>R: CB<span class="elsevierStyleInf">1</span> receptor; eCB: endocannabinoid; G: G protein; iGluR: ionotropic glutamate receptors; mGluR5: type 5 metabotropic glutamate receptors; RyR: ryanodine receptor.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">These criteria are based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-V).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">1.</span> Taking the substance in larger amounts or for longer than you’re meant to. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">2.</span> Wanting to cut down or stop using the substance but not managing to. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">3.</span> Spending a lot of time getting, using, or recovering from use of the substance. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">4.</span> Cravings and urges to use the substance. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">5.</span> Not managing to do what you should at work, home, or school because of substance use. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">6.</span> Continuing to use, even when it causes problems in relationships. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">7.</span> Giving up important social, occupational, or recreational activities because of substance use. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">8.</span> Using substances again and again, even when it puts you in danger. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">9.</span> Continuing to use, even when you know you have a physical or psychological problem that could have been caused or made worse by the substance. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">10.</span> Needing more of the substance to get the effect you want (tolerance). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">11.</span> Development of withdrawal symptoms, which can be relieved by taking more of the substance. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Criteria for the diagnosis of substance use disorders.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:2 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Short-term plasticity \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Depolarisation-induced suppression of inhibition \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Depolarisation-induced suppression of excitation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Long-lasting disinhibition of neuronal activity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suppression of GABAergic release in the hippocampus \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] 1 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Long term plasticity \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Long term depression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Long term potentiation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypofrontality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sensitisation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Synaptic plasticity phenomena associated with substance use and involving the participation of endocannabinoids.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "titulo" => "The ICD-10 classification of mental and behavioral disorders: clinical descriptions and diagnostic guidelines" "fecha" => "1992" "editorial" => "Organización Mundial de la Salud" "editorialLocalizacion" => "Ginebra" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neurobiology of addiction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. 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