The vicious cyclin of addiction.
The vicious cyclin of addiction.
复制标题
成瘾的恶性循环。
DOI：
10.1038/86480
复制
发表时间：
2001
期刊：
影响因子：
82.9
通讯作者：
Cooper,DC
中科院分区：
文献类型：
--
作者：
White,FJ;Cooper,DC
ety’scostliestdisorders. Addiction canbedefinedasthecompulsiveseekingandtakingofdrugsdespiteserious adverseconsequences. Thelossofcontrol over drug useandtherepetitive natureofintoxication, withdrawaland relapsearehallmarkfeaturesofaddiction. Theviciouscycleofaddictioncan bealife-longprocessfor manyindividuals, withdrugcravingandrelapseoccurringevenafteryearsofabstinence. Such persistenceimpliesthattheactionsofdrugsofabuseinvolvestable adaptationsinneuralfunction. Those whostudytheneurobiologyofaddiction hope that identifying and understanding the responsible neuroadaptationswillpavethewayfordevelopment of effective therapies, whicharecurrently minimal. Inthe15 Marchissueof Nature, Bibbetal. 1 reporttheuseof DNAarrayanalysisof inducible transgenic micetoidentifyacyclin-dependent kinase (Cdk5) that alters striatal dopamine (D1)-receptorsignalingfollowing chronic cocaine exposure. Thesefindingsidentify a new component in the D1-receptorsignaling cascade that might contribute to the neuralandbehavioral plasticity associated with drugaddiction. By blocking the dopaminetransporter on dopamine nerve terminals, cocaine enhances synaptic levelsofthisinfluentialneurotransmitter. Increased dopamine levels enhance activation of the dopamine receptors locatedonthetarget neurons that are postsynaptic to dopamine nerveterminals withinthe striatalcomplex (caudate/putamenand nucleusaccumbens). Thisactivationof dopaminergicsignalinghaslongbeen associated withtherewardingandaddictivepropertiesofcocaine2. Inparticular, D1-receptorstimulationactivates the cAMP-dependent protein kinase (PKA) pathway, leadingtoinductionof transcriptionfactorsandphosphorylation of manysubstrate proteinsinvolvedinneuronalexcitability (Fig. 1). These proteins include ligand-and voltage-gatedionchannels withinthe neuronal membrane. Ligand-gated channelsrespondtofastsynapticinput bybindingneurotransmittersandfluxingNa+, Ca2+orK+ to modulatepostsynapticneuronalexcitability.Voltage-gated channels determine theimpulseoutputoftheneuronsby settingthepassiveandactiveelectrical propertiesoftheneurons, suchasthe action potentialthreshold. Different varieties ofligand and voltage-gated channelshaveinwardoroutwardionic conductancesthatareoften modulated by neurotransmitter-inducedintracellular signalling cascades. Together, thesechannelsdeterminetheresponsivenessofstriatal neuronstoexcitatory, inhibitory and modulatory synapticinputs3–5. Receptor-activated signaling cascades havetremendous potentialfor filteringwhichsynapticinputsgaininfluence over membrane excitability throughoutthevariouscompartments oftheneuron (thatis, withinthevariousdendriticbranchesandthesoma6). Disruptionsinthedynamicbalanceof D1-receptor mediatedphosphorylation and dephosphorylationcascadesindifferentregionsofthe neuron mayleadto impairedintegration of synaptic inputs. Without suchintegration, neurons maybebiasedtorespondtocertaininputs in favor of others, whichcould leadtoaltered neuronal communicationand, ultimately, inappropriatebehavior. Chroniccocaine exposureappearsto disruptthis balance by inducing transcriptionfactorsand their downstream targets for periods lasting muchlonger thanthedurationof the drug exposure7. Thisformofdrug-induced, long-lasting plasticity mayparticipateinthe mechanisms underlying
