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Review article
Endocannabinoid-mediated synaptic plasticity and substance use disorders
La plasticidad sináptica mediada por endocannabinoides y «trastornos por consumo de drogas»
E. Fernández-Espejoa,
Corresponding author
efespejo@us.es

Corresponding author.
, L. Núñez-Domínguezb
a Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
b Centro Médico Diagnóstico, Pamplona, Spain
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    "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&#44; &#8220;addictive&#8221; is a difficult word to define&#46; Several terms have been used to define the psychobiological effect caused by drugs of abuse&#59; these include addiction&#44; dependence&#44; abuse &#40;Diagnostic and Statistical Manual of Mental Disorders-IV &#91;DSM-IV&#93;&#41;&#44; and harmful use &#40;International Classification of Diseases&#44; 10th revision &#91;ICD-10&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Addiction is defined as a chronic and recurrent disease of the brain&#44; characterised by searching for and compulsively consuming drugs&#44; despite their harmful consequences&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Dependence would be a broader term than addiction&#44; encompassing mild &#40;for example&#44; dependence on caffeine&#41; to compulsive needs &#40;an established addiction&#41;&#44; according to 6 criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Abuse &#40;DSM-IV terminology&#41;&#44; or harmful use &#40;ICD-10 terminology&#41;&#44; is based on a list of somatic and psychological effects of drug use&#46; Today&#44; the DSM-V<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> no longer uses these terms&#59; instead&#44; it includes &#8220;substance use disorders&#8221; &#40;SUD&#41;&#44; defined according to 11 criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and ranging from mild &#40;presence of fewer than 3 criteria&#41; to severe &#40;more than 6 criteria&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">From a neurobiological viewpoint&#44; drugs or addictive substances have an impact on the brain&#8217;s reward circuits&#44; originating in the ventral tegmental area &#40;VTA&#41;&#44; as well as on limbic and memory-related regions including the amygdala and the hippocampus&#46; Brain reinforcement mechanisms and synaptic plasticity in these circuits are essential in the development of addiction and addictive behaviour&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4&#8211;6</span></a> Basic neuroplasticity events occur in mesolimbic reward circuits&#44; which include the nucleus accumbens and ventral striate&#44; the prefrontal cortex&#44; and the VTA in the midbrain&#44; as mentioned previously&#46; These limbic structures consolidate the abnormal behaviour&#44; associating numerous internal and external events with drug-related reward &#40;conditioning&#41;&#46; These conditioned effects are critical in the development of addiction&#44; both in the active consumption phase and in the abstinence phase&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In terms of neurobiological effects&#44; the neurotransmitters dopamine&#44; GABA&#44; and glutamate are key factors in mesolimbic neuroplasticity&#59; the increasing relevance of such other neuromessengers as endocannabinoids is also worth mentioning&#46; Endocannabinoids are known to cause retrograde modulation of synaptic signals&#44; especially in glutamatergic and GABAergic synapses&#44; and play a crucial role in synaptic neuroplasticity phenomena&#46; SUDs are associated with a disruption of endocannabinoid-mediated plasticity&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the distribution of endocannabinoids in the human brain&#46;</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 &#40;N-arachidonoylethanolamine&#44; AEA&#41;&#44; followed by 2-arachidonoylglycerol &#40;2-AG&#41; 2 years later&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Other cannabinoid molecules have subsequently been identified&#44; including 2-arachidonoylglycerol ether&#44; N-arachidonoyl dopamine&#44; virodhamine&#44; N-homo-gamma-linolenoylethanolamine&#44; and N-docosatetra-7&#44;10&#44;13&#44;16-enoylethanolamine&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;13</span></a> Because endocannabinoids are lipidic compounds&#44; synaptic vesicular storage is impossible due to their high liposolubility&#46; Therefore&#44; they are synthesised on demand by membrane precursors&#46; After acting&#44; endocannabinoids are rapidly degraded by reuptake &#40;both by neurons and by glial cells&#41; and subsequent hydrolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Endocannabinoids act on specific cannabinoid receptors&#44; especially types 1 and 2 &#40;CB<span class="elsevierStyleInf">1</span> and CB<span class="elsevierStyleInf">2</span>&#41;&#46; The first cannabinoid receptor described in the brain&#44; in 1988&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> was CB<span class="elsevierStyleInf">1</span>&#59; it was molecularly cloned in humans&#44;<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&#46; A second cannabinoid receptor&#44; CB<span class="elsevierStyleInf">2</span>&#44; also belonging to the family of G-protein-coupled membrane receptors&#44; was identified at the peripheral level&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> CB<span class="elsevierStyleInf">2</span> receptors share an overall homology of 44&#37; with CB<span class="elsevierStyleInf">1</span> receptors &#40;68&#37; in transmembrane regions&#41;&#59; they are abundantly expressed in lymphocytes&#44; which suggests that this subtype of receptor mediates the immunomodulatory action of cannabinoids&#46; Although the CB<span class="elsevierStyleInf">2</span> receptor has been identified in glial cells in the brain&#44;<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&#46; In the mammal brain&#44; CB<span class="elsevierStyleInf">1</span> proteins are preferentially expressed in neuronal populations closely related to addiction and reward systems&#46; A high density of CB<span class="elsevierStyleInf">1</span> receptors is found in the neurons of the nucleus accumbens&#44; dorsal striatum&#44; and cerebellum&#44; which also explains the effects of acute stimulation &#40;ataxia&#44; dysmetria&#44; and hypokinesia&#41;&#59; the receptor is also found in the neurons of the hippocampus and amygdala&#46; The remaining areas&#44; such as the neocortex&#44; superior colliculus&#44; and habenula&#44; show a moderate presence of these receptors&#46; As previously mentioned&#44; drugs of abuse alter both short- and long-term endocannabinoids-mediated synaptic neuroplasticity&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the SUD-related synaptic plasticity phenomena involving endocannabinoids&#46;</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&#46; Short-term plasticity phenomena may be either inhibitory or disinhibitory&#46; Among inhibitory endocannabinoid-mediated phenomena&#44; particularly important processes are depolarisation-induced suppression of inhibition &#40;DSI&#41; and depolarisation-induced suppression of excitation &#40;DSE&#41;&#59; these phenomena reduce the synaptic release of glutamate&#44; GABA&#44; or glycine&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#8211;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 &#40;excitatory or inhibitory&#41; neurotransmitter&#44; as has been shown in the cerebellum&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> hippocampus&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> or brainstem nuclei&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Endocannabinoids induce DSI and DSE through CB<span class="elsevierStyleInf">1</span> receptors&#58; CB<span class="elsevierStyleInf">1</span> antagonists and agonists block and stimulate those synaptic phenomena&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;23</span></a> DSI phenomena are associated with dependence&#59; for example&#44; caffeine provokes a considerable alteration of DSI mediated by GABA&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Among disinhibitory endocannabinoid-mediated phenomena&#44; we should highlight the disinhibition of neuronal activity&#44; especially endocannabinoid-mediated disinhibition in the striatum &#40;long-lasting disinhibition&#59; DLL&#41;&#44; and the suppression of GABA release in the hippocampus&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Both processes are mediated by CB receptors&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In the case of the suppression of GABA release in the hippocampus&#44; glutamate release activates kainate receptors&#44; which in turn stimulate the production of endocannabinoids that suppress synaptic GABA release &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Short-term synaptic changes last only minutes&#44; but modify synaptic transmission and may underlie acute hedonic and motor changes caused by drugs&#46; For example&#44; alcohol blocks DLL phenomena induced by endocannabinoids in the dorsal striatum&#44; which is associated with abnormal motor response&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Alcohol alters the delicate balance of excitation and inhibition in the striatum&#44; mediated by endocannabinoids&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Drugs alter DSI and DSE phenomena in several regions associated with addiction&#44; such as the VTA&#44; amygdala&#44; striatum&#44; hippocampus&#44; and neocortex&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#8211;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&#44; which are longer-lasting and more stable in the brain engram&#59; these phenomena include long-term potentiation &#40;LTP&#41; and long-term depression &#40;LTD&#41;&#46; LTP and LTD are important in memory and learning consolidation&#59; drugs modify the normal neurophysiology of these processes&#44; promoting the consolidation of addiction&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Endocannabinoids mainly participate in LTD phenomena&#46; Endocannabinoid-mediated LTD occurs after a transient increase in glutamate levels&#44; triggering increased postsynaptic endocannabinoid production&#44; which in turn causes a long-term decrease in glutamate release&#44; as is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This phenomenon has been detected in several structures associated with addiction&#44; such as the nucleus accumbens&#44; dorsal striatum&#44; prefrontal cortex&#44; amygdala&#44; hippocampus&#44; and VTA&#46; The main LTD-mediating endocannabinoids is AEA&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> except in the hippocampus&#44; where it seems to be 2-AG&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Such drugs as &#948;9-THC and cocaine block endocannabinoid-induced LTD in the nucleus accumbens&#44; at least in animal models&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> Alcohol also blocks endocannabinoid-induced LTD phenomena&#44; in this case in the dorsal striatum&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Amphetamines block LTD in the amygdala through their action on endocannabinoids&#46;<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&#58; in the prefrontal cortex&#44; interaction between dopamine &#40;through D2 receptors&#41;&#44; endocannabinoids&#44; and several drugs of abuse may provoke prefrontal dopaminergic hypoactivity&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The importance of this process in the development of addiction is increasingly recognised&#44; and it constitutes the basis of hypofrontality&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> There is mounting evidence suggesting that frontal areas&#44; and especially the prefrontal area&#44; prepare the subject to adequately respond to acute stress and show resilience to future stress&#46; Endocannabinoids are key mediators in frontal activity&#44; and endocannabinoid alterations due to drug abuse significantly modify the subject&#8217;s response and resilience to stress&#46;<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&#44; although the role of endocannabinoids in these cases is not so relevant&#46;<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&#44; ie&#44; the VTA and nucleus accumbens&#46; This dopamine release is reinforced by the chronic consumption of the drug&#44; in a process called dopaminergic sensitisation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;43&#44;44</span></a> This represents a crucial aspect differentiating addictive drugs from natural reinforcers &#40;food&#44; water&#44; and sex&#41;&#44; which do not present dopaminergic sensitisation&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Sensitisation is related to LTP&#44; and several drugs including psychostimulants&#44; opiates&#44; ethanol&#44; and nicotine are known to induce the LTP phenomenon in the VTA&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#8211;47</span></a> However&#44; from a biochemical perspective&#44; sensitisation is mainly mediated by an increase in glutamatergic transmission&#44; NMDA and D1 dopamine receptor upregulation&#44; and hyperactivity of the cAMP&#47;protein kinase A pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Therefore&#44; endocannabinoids do not play a relevant role&#59; they are only known to play a clear role in sensitisation to opiates&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In fact&#44; endocannabinoids act on CB<span class="elsevierStyleInf">1</span> receptors located on dopaminergic neurons in the VTA&#44; and mediate sensitisation to opiates&#46; Sensitisation to cocaine has also recently been associated with CB<span class="elsevierStyleInf">1</span> receptors and&#44; possibly&#44; with endocannabinoids&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Lastly&#44; endocannabinoids and CB<span class="elsevierStyleInf">1</span> receptors are important in incentive sensitisation phenomena&#44; which is the potentiation over time of the reinforcing role of spatial cues associated with the consumption of the drug&#59; this type of conditioning is also essential in the development of drug addiction&#46; For example&#44; endocannabinoids facilitate behavioural association to spatial cues caused by cocaine&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> nicotine&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> and alcohol&#46;<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&#46; Endocannabinoid alteration facilitates anomalous changes in the brain and the development of the addictive behaviours that characterise SUD&#46; Without doubt&#44; good understanding of these phenomena will facilitate the development of treatments based on the modulation of endocannabinoids in the brain&#44; with the aim of minimising the devastating effects of SUD&#46;</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&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Endocannabinoids"
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          "titulo" => "Endocannabinoids and short-term neuroplasticity"
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          "titulo" => "Endocannabinoids and long-term neuroplasticity"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "Acknowledgements"
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            0 => "neuroplasticity"
            1 => "drug of abuse"
            2 => "endocannabinoid"
            3 => "addiction"
            4 => "dependence"
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            0 => "neuroplasticidad"
            1 => "droga"
            2 => "endocannabinoide"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Drugs impact brain reward circuits&#44; causing dependence and addiction&#44; in a condition currently described as substance use disorders&#46; Mechanisms of synaptic plasticity in these circuits are crucial in the development of addictive behaviour&#44; and endocannabinoids&#44; particularly anandamide and 2-arachidonyl-glycerol&#44; participate in normal neuroplasticity&#46; Substance use disorders are known to be associated with disruption of endocannabinoid-mediated synaptic plasticity&#44; among other phenomena&#46; Endocannabinoids mediate neuroplasticity in the short and the long term&#46; In the short term&#44; we may stress &#8220;inhibitory&#8221; phenomena&#44; such as depolarisation-induced suppression of inhibition and depolarisation-induced suppression of excitation&#44; and such &#8220;disinhibitory&#8221; phenomena as long-lasting disinhibition of neuronal activity&#44; particularly in the striatum&#44; and suppression of hippocampal GABA release&#46; Drugs of abuse can also disrupt normal endocannabinoid-mediated long-term potentiation and long-term depression&#46; Endocannabinoids are also involved in the development of drug-induced hypofrontality and sensitisation&#46; In summary&#44; substance abuse causes a disruption in the synaptic plasticity of the brain circuits involved in addiction&#44; with the alteration of normal endocannabinoid activity playing a prominent role&#46; This facilitates abnormal changes in the brain and the development of the addictive behaviours that characterise substance use disorders&#46;</p></span>"
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        "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 adicci&#243;n&#44; lo que se define actualmente como trastornos por consumo de drogas&#46; Los mecanismos de plasticidad sin&#225;ptica en dichos circuitos son cruciales en el desarrollo de la conducta adictiva&#44; y los endocannabinoides&#44; entre los que destacan la anandamida y el 2-araquidonil-glicerol&#44; participan en la normal neuroplasticidad&#46; Se sabe que los trastornos por consumo de drogas se asocian&#44; entre otros fen&#243;menos&#44; a disrupci&#243;n de la plasticidad sin&#225;ptica mediada por endocannabinoides&#46; Estas mol&#233;culas median neuroplasticidad de corta duraci&#243;n y perdurable&#46; Respecto a la de corta duraci&#243;n&#44; destacan fen&#243;menos de car&#225;cter &#171;inhibidor&#187;&#44; como la supresi&#243;n de la inhibici&#243;n inducida por despolarizaci&#243;n y la supresi&#243;n de la excitaci&#243;n inducida por despolarizaci&#243;n&#59; y otros &#171;desinhibidores&#187;&#44; como la desinhibici&#243;n de la actividad neuronal&#44; sobre todo en el n&#250;cleo estriado&#44; y la supresi&#243;n de la liberaci&#243;n GABA en el hipocampo&#46; Por otra parte&#44; las drogas pueden alterar la normal potenciaci&#243;n perdurable y la depresi&#243;n perdurable mediadas por endocannabinoides&#46; Los endocannabinoides tambi&#233;n influyen en el desarrollo de hipofrontalismo y sensibilizaci&#243;n causados por las drogas&#46; En fin&#44; el abuso de drogas origina una disrupci&#243;n en la plasticidad sin&#225;ptica de circuitos cerebrales involucrados en la adicci&#243;n y en ello juega un destacado papel la alteraci&#243;n de la normal actividad endocannabinoide&#46; Ello facilita los cambios an&#243;malos cerebrales y el desarrollo de conductas adictivas que caracterizan a los trastornos por consumo de drogas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Fern&#225;ndez-Espejo E&#44; N&#250;&#241;ez-Dom&#237;nguez L&#46; La plasticidad sin&#225;ptica mediada por endocannabinoides y &#171;trastornos por consumo de drogas&#187;&#46; Neurolog&#237;a&#46; 2022&#59;37&#58;459&#8211;465&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Biochemical phenomena occurring during endocannabinoid-mediated suppression of GABA release in the hippocampus&#46; Glutamate release activates postsynaptic kainate receptors&#44; which induce sodium influx and production of endocannabinoids&#46; Endocannabinoids are released into the synaptic space and act on G protein&#8211;coupled CB1 receptors on terminals that release GABA&#46; This induces a decrease in presynaptic calcium influx and a decrease in GABA release&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">&#43;&#43;</span>&#58; calcium&#59; CB<span class="elsevierStyleInf">1</span>R&#58; CB<span class="elsevierStyleInf">1</span> receptor&#59; eCB&#58; endocannabinoid&#59; G&#58; G protein&#59; GABAR&#58; GABA receptor&#59; Na<span class="elsevierStyleSup">&#43;</span>&#58; sodium&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Biochemical phenomena occurring during endocannabinoid-mediated long-term depression&#46; Glutamate release activates postsynaptic ionotropic receptors and type 5 metabotropic glutamate receptors&#46; The latter induce the production of endocannabinoids through Homer proteins and ryanodine receptors in calcium-storing vesicles and the endoplasmic reticulum&#46; Endocannabinoids are released into the synaptic space and act on G protein&#8211;coupled CB<span class="elsevierStyleInf">1</span> receptors on terminals that release glutamate&#46; This induces a decrease in presynaptic glutamate release&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Ca<span class="elsevierStyleSup">&#43;&#43;</span>&#58; calcium&#59; CB<span class="elsevierStyleInf">1</span>R&#58; CB<span class="elsevierStyleInf">1</span> receptor&#59; eCB&#58; endocannabinoid&#59; G&#58; G protein&#59; iGluR&#58; ionotropic glutamate receptors&#59; mGluR5&#58; type 5 metabotropic glutamate receptors&#59; RyR&#58; ryanodine receptor&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">These criteria are based on the Diagnostic and Statistical Manual of Mental Disorders &#40;DSM-V&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">3&#46;</span> Spending a lot of time getting&#44; using&#44; or recovering from use of the substance&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">4&#46;</span> Cravings and urges to use the substance&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">5&#46;</span> Not managing to do what you should at work&#44; home&#44; or school because of substance use&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">6&#46;</span> Continuing to use&#44; even when it causes problems in relationships&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">9&#46;</span> Continuing to use&#44; even when you know you have a physical or psychological problem that could have been caused or made worse by the substance&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">11&#46;</span> Development of withdrawal symptoms&#44; which can be relieved by taking more of the substance&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Depolarisation-induced suppression of excitation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Long-lasting disinhibition of neuronal activity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Suppression of GABAergic release in the hippocampus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Long term plasticity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Long term depression&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Long term potentiation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Hypofrontality&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Sensitisation&nbsp;\t\t\t\t\t\t\n
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                    0 => array:1 [
                      "Libro" => array:4 [
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              "identificador" => "bib0010"
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                      "titulo" => "Neurobiology of addiction"
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                          "etal" => false
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                  ]
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                    0 => array:1 [
                      "Libro" => array:4 [
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                        "edicion" => "5&#170; edici&#243;n"
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                        0 => array:2 [
                          "etal" => false
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                            2 => "E&#46;J&#46; Nestler"
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                    0 => array:2 [
                      "doi" => "10.1146/annurev.neuro.29.051605.113009"
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                  "contribucion" => array:1 [
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                      "titulo" => "Drug-evoked synaptic plasticity in addiction&#58; from molecular changes to circuit remodeling"
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                            0 => "C&#46; L&#252;scher"
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                      "doi" => "10.1016/j.neuron.2011.01.017"
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                      "titulo" => "Bases neurobiol&#243;gicas de la drogadicci&#243;n"
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ISSN: 21735808
Original language: English
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