Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

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Mechanisms of Action and Persistent
Neuroplasticity by Drugs of Abuse
Article in Pharmacological reviews · September 2015
DOI: 10.1124/pr.115.010967
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1521-0081/67/4/872–1004$25.00 http://dx.doi.org/10.1124/pr.115.010967
PHARMACOLOGICALREVIEWS PharmacolRev67:872–1004,October2015
Copyright©2015byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics
ASSOCIATEEDITOR:MARKKUKOULU
Mechanisms of Action and Persistent Neuroplasticity
by Drugs of Abuse
EsaR.Korpi,BjørnardenHollander,UsmanFarooq,ElenaVashchinkina,RamamoorthyRajkumar,DavidJ.Nutt,PetriHyytiä,
andGavinS.Dawe
DepartmentofPharmacology,FacultyofMedicine,UniversityofHelsinki,Finland(E.R.K.,B.d.H.,E.V.,P.H.);Departmentof
Pharmacology,YongLooLinSchoolofMedicine,NationalUniversityHealthSystem,NeurobiologyandAgeingProgramme,LifeSciences
Institute,NationalUniversityofSingapore,Singapore,andSINAPSE,SingaporeInstituteforNeurotechnology,Singapore(E.R.K.,R.R.,
G.S.D.);InterdepartmentalNeuroscienceProgram,YaleUniversity,NewHaven,Connecticut(U.F.);andCentrefor D
Neuropsychopharmacology,DivisionofBrainSciences,BurlingtonDanesBuilding,ImperialCollegeLondon,London. ow
UnitedKingdom(D.J.N.) nlo
a
d
e
d
Abstract.....................................................................................875 fro
m
I. Introduction.................................................................................875 p
h
A. Different Forms of Neuroplasticity.......................................................876 arm
B. Short-term Neuroplasticity ..............................................................878 re
v
C. Main Forms of Long-term Neuroplasticity: Long-term Potentiation and Long-term .a
s
Depression ..............................................................................879 pe
1. Presynaptic Forms of Long-term Plasticity...........................................880 tjou
2. Postsynaptic Forms of Long-term Plasticity. .........................................880 rna
ls
3. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate .o
Receptor Phosphorylation............................................................880 arg
4. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate t U
n
Receptor Trafficking.................................................................881 iv
o
D. Forms of Long-term Plasticity at Inhibitory Synapses ....................................881 f H
E. Developmental Maturation of the Brain in Rodents and Humans.........................882 els
F. Developmental Neuroplasticity: Critical Periods, Reopening of Plasticity in Adults........883 ink
G. Neurotrophins as Regulators of Neuroplasticity: Brain-Derived Neurotrophic i V
iik
Factor as an Example ...................................................................885 k
i S
H. Animal Models of Drug Reinforcement and Addiction.....................................885 c
ie
II. Actions and Persistent Effects of Specific Drugs of Abuse.....................................886 n
c
e
A. Cocaine, a Stimulant and Local Anesthetic...............................................886 L
ib
1. Persistent Ventral Tegmental Area Neuroplasticity after a Single Dose...............887 o
n
2. Changes in the Nucleus Accumbens Mediate Cocaine Addiction and Relapse..........890 S
e
3. Altered Gene Expression in the Nucleus Accumbens in Cocaine Seeking and Relapse. 893 p
te
4. Progressive Involvement of the Dorsal Striatum......................................895 m
b
5. Changes in Lateral Habenula and Rostromedial Tegmental Nucleus Contribute e
r 2
to Aversive Symptoms of Cocaine Withdrawal........................................895 8
6. Complex Alterations in the PFC. ....................................................896 , 20
1
7. Hippocampal Functional Changes....................................................897 5
8. Bed Nucleus of Stria Terminalis and Amygdala are Involved in
Stress-Induced Reinstatement of Cocaine Seeking....................................897
9. Effects of Adolescent Cocaine Exposure. .............................................898
10. Human Imaging Studies.............................................................898
11. Limited Evidence of Cocaine Neurotoxicity...........................................899
ThisprojectwaspartiallyfundedbytheAcademyofFinland,theSigridJuseliusfoundation,theFinnishFoundationforAlcoholStudies,
theJaneandAatosErkkoFoundation,theFoundations’Professorpool,andtheOrionResearchFoundation.
Address correspondence to: Dr. Esa R. Korpi, Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, POB 63
(Haartmaninkatu8),FI-00014UniversityofHelsinki,[email protected],DepartmentofPharmacology,
YongLooLinSchoolofMedicine,BuildingMD3,#04-01Y,16MedicalDrive,Singapore117600.Email:[email protected].
dx.doi.org/10.1124/pr.115.010967
872
Drug-InducedNeuroplasticity 873
12. Potential Mechanisms in Cocaine Neurotoxicity and Neuroprotection.................900
13. Methylphenidate and Novel Psychoactive Substances.................................900
14. Conclusions. ........................................................................900
B. Amphetamine-type Psychostimulants ....................................................900
1. Many Stimulant Amphetamines for Abuse and Therapy..............................902
2. Molecular Targets and Mechanisms of Action of Amphetamines. .....................902
3. Comparison of the Mechanisms of Action of Amphetamine versus Methamphetamine. 902
4. Effects of Amphetamine at Plasmalemmal Dopamine Transporter....................903
5. Regulation of Dopamine Efflux Via the Dopamine Transporter by Protein Kinase
C and Ca2+/Calmodulin Kinase II Phosphorylation, and by Reactive Oxygen Species..904
6. Effects on Secretory Vesicles.........................................................904
7. Other Amphetamine Targets: Monoamine Oxidase, Tyrosine Hydroxylase, other Mono-
amine Transporters, Trace Amine-Associated Receptor 1, and Sigma Receptors. ......905
8. Action of Substituted Amphetamines and Cathinones. ...............................905
9. Action of Stimulants Common in Clinical Use........................................906
10. Efficacy and Addiction Liability of Amphetamines in Clinical Use. ...................906
11. Neuroplasticity Related to Sensitization and Addiction to Amphetamines.............907
12. Glutamate andAmphetamine/Methamphetamine Reinforcement/Extinction/Reinstatement..908
13. Long-term Neuroadaptation/Neurotoxicity after Exposure to High Doses of
Psychostimulants....................................................................909
a. Effects on brain structure. .......................................................909
b. Effects on neurochemistry........................................................910
c. Effects on behavior...............................................................910
14. Limited Evidence for Long-term Effects of Substituted Cathinones in Rodent
Models..............................................................................911
15. Mechanisms Involved in Long-term Adaptation and Neurotoxicity....................911
a. Oxidative stress: DA oxidation and drug metabolites as sources of reactive species.911
b. Mitochondrial dysfunction: ATP deficit, superoxide leakage, and apoptosis.........912
ABBREVIATIONS: AC, adenylyl cyclase; ADHD, attention deficit hyperactivity disorder; 2-AG, 2-arachidonoylglycerol; ALDH,
aldehyde dehydrogenase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPH, amphetamine; BDNF, brain-derived
neurotrophic factor; BLA, basolateral complex of the amygdala; BNST, bed nucleus of stria terminalis; BOLD, blood oxygen level
dependent;BZ,benzodiazepine;CAM,celladhesionmolecule;CaMKII,Ca2+/calmodulinkinaseII;CCK,cholecystokinin;CeA,central
nucleus of the amygdala; CNS, central nervous system; CPP, conditioned place preference; CREB, cAMP response element-binding
protein;CRF,corticotropin-releasingfactor;D R,dopamine-1receptor;D R,dopamine-2receptor;DA,dopamine;DARPP-32,DA-and
1 2
cAMP-regulated phosphoprotein; DAT, dopamine transporter; DBI, diazepem binding inhibitor; DGL, diacylglycerol lipase; DOI,
2,5-dimethoxy-4-iodoamphetamine;DSE,depolarization-inducedsuppressionofexcitation;DSI,depolarization-inducedsuppressionof
inhibition;eCB,endocannabinoid;ECM,extracellularmatrix;EEG,electroencephalography;EPSC,excitatorypostsynapticcurrents;
ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ETC, electron transport chain; FC, frontal cortex; fMRI,
functional magnetic resonance imaging; G9a, lysine dimethyltransferase G9a; GABA, g-aminobutyric acid; GHB, gamma-
hydroxybutyrate;GPCR,Gprotein-coupledreceptor;HC,hippocampus;HDAC,histonedeacetylase;HFS,high-frequencystimulation;
HPPD,hallucinogenpersistingperceptiondisorder;5-HT,5-hydroxytryptamine,serotonin;ICSS,intracranialself-stimulation;iGluR,
iontropic glutamate receptor; IL, infralimbic cortical region; IP inositol 1, 4,5-trisphosphate; IPN, interpeduncular nucleus; IPSC,
3,
inhibitorypostsynapticcurrents;IPSP,inhibitorypostsynapticpotential;JNK,c-JunN-terminalkinases;Kal-7,postsynapticdensity-
localizedkalirin-7;KCC,potassium-chloridecotransporter;KO,knockout;LA,lateralnucleusofamygdala;LC,locusceruleus;LDTg,
laterodorsal tegmental nucleus; LDX, lisdexamfetamine; LFS, low-frequency stimulation; LHb, lateral habenula; LSD, lysergic acid
diethylamide;LTD,long-termdepression; LTP,long-termpotentiation; MAO, monoamineoxidase;MAPK, mitogen-activatedprotein
kinase;MDMA,3,4-methylenedioxymethamphetamine(ecstasy);MDMC,methylone;METH, methamphetamine;mGlu, metabotropic
glutamate receptor; MHb, medial habenula; MK-801, dizocilpine; 4-MMC, mephedrone; MPH, methylphenidate; MRI, magnetic
resonanceimaging;MSN,mediumspinyneuron;mTOR,mammaliantargetofrapamycin;NAc,nucleusaccumbens;nAChR,nicotinic
acetylcholine receptors; NE, norepinephrine; NET, norepinephrine transporter; NFkB, nuclear factor kappa-B; NMDA, N-methyl-D-
aspartate;NO,nitricoxide;NOP,nociceptinreceptor;N/OFQ,nociceptin/orphaninFQ;NPY,neuropeptideY;OFC,orbitofrontalcortex;
OR, odds ratio; OX, orexin; P, postnatal day; PAG, periaqueductal gray area; PBR, peripheral benzodiazepine receptor; PCP,
phencyclidine;PET,positronemissiontomography;PFC,prefrontalcortex;PI3K,phosphatidylinositide3-kinase;PKA,proteinkinase
A;PKC,proteinkinaseC;PKMzeta,atypicalPKC;PLC,phospholipaseC;PNN,perineuronalnets;PrL,prelimbiccorticalregion;PSA-
NCAM,polysialylatedneuronalcelladhesionmolecule;PSD,postsynapticdensity;Pv,parvalbumin;R,receptor;RGS,regulatorofG
protein signaling; rmTg, rostromedial tegmental nucleus; ROS, reactive oxygen species; SA, self-administration; SERT, serotonin
transporter; SN, substantia nigra; TA , trace amine-associated receptor 1; TH, tyrosine hydroxylase; THC, tetrahydrocannabinol;
1
TLR4, toll-like receptor 4; TPH, tryptophan hydroxylase; TrkB, tropomyosin receptor kinase B; TSPO, mitochondrial translocator
protein;VGCC,voltage-gatedcalciumchannel;vHC,ventralhippocampus;VMAT-2,vesicularmonoaminetransporter2;VTA,ventral
tegmentalarea.
874 Korpietal.
c. Excitotoxicity: glutamate receptor involvement and intracellular excitotoxic
processes.........................................................................913
d. Hyperthermia: a catalyst of other toxic processes. ................................913
e. Other factors: inflammation, blood-brain barrier disruption, protective
preconditioning. .................................................................914
16. Evidence of Long-term Plasticity and Cognitive Effects after Stimulant Use in
Humans.............................................................................914
a. Cognitive behaviors. .............................................................914
b. Brain imaging of receptors, transporters and activity/metabolism..................915
c. Magnetic resonance imaging studies..............................................915
d. Magnetic resonance spectroscopy and analysis of postmortem tissue...............916
e. Prospective and experimental studies.............................................916
17. Conclusions. ........................................................................917
C. Nicotine.................................................................................917
1. Nicotinic Acetylcholine Receptors. ...................................................917
2. Upregulation of Nicotinic Receptors..................................................918
3. Nicotine-priming Effects and Upregulation of Catecholamine Synthesis...............919
4. Nicotine and Neuroplasticity within the Ventral Tegmental Area.....................920
5. Nicotine and Neuroplasticity in the Lateral Hypothalamic Orexin System. ...........921
6. Nicotine and Glutamatergic Neuroplasticity..........................................921
7. Nicotine and the Habenula. .........................................................922
8. Long-term Sequelae of Adolescent Exposure to Nicotine..............................923
9. Conclusions. ........................................................................924
D. Neural Adaptations Induced by Ethanol .................................................925
1. Cell Membrane Ion Channels as Primary Targets of Ethanol.........................925
2. Ethanol-Induced Changes in Glutamatergic Transmission............................928
3. Ethanol-Induced Changes in g-Aminobutyric Acidergic Transmission. ................929
4. Ethanol-Induced Changes in Neuropeptide Mechanisms..............................931
5. Role of Acetaldehyde in Ethanol’s Reinforcing Actions................................933
6. Structural Plasticity in Alcohol Dependence..........................................933
7. Conclusions. ........................................................................934
E. Benzodiazepines and Other GABAergic Drugs............................................934
1. Molecular Targets for Benzodiazepines...............................................935
2. Neuroplasticity Induced by Benzodiazepines and Related Compounds. ...............936
3. Behavioral After-effects of g-Aminobutyric Acid A Drugs. ............................939
4. Effects of Flumazenil on Benzodiazepine and Alcohol Tolerance. .....................939
5. Treatment of Addictions by g-Aminobutyric Acid B Receptor Agonists. ...............940
6. g-Hydroxybutyrate as a Drug of Abuse and a Therapeutic Compound.................941
7. Anesthetics and Neuroplasticity. ....................................................942
8. Conclusions. ........................................................................943
F. N-methyl-D-aspartate Receptor Antagonists ..............................................943
1. Ketamine: a Dissociative Anesthetic with Rapid Antidepressant Effects in Patients...944
2. Phencyclidine. ......................................................................946
3. Dizocilpine, a Prototypic Noncompetitive N-methyl-D-aspartate Receptor Antagonist. .948
4. Conclusions. ........................................................................949
G. Opioid-Induced Neural Adaptations......................................................949
1. Desensitization and Internalization in Opioid Tolerance and Dependence.............950
2. Cellular Signaling in Opioid Tolerance and Dependence..............................950
3. Novel Mechanisms in Between-systems Adaptations. ................................951
4. Opioid-Induced Changes in Excitatory and Inhibitory Synaptic Plasticity. ............952
5. Chronic Opioids and Synaptic Plasticity..............................................953
6. Conclusions. ........................................................................955
H. Cannabinoids: Multiple Mechanisms and Possible Indications ............................955
1. Endocannabinoid System as an Endogenous Lipid Messenger System.................956
2. Short-term Plasticity Involving Retrograde Endocannabinoid Signaling...............957
3. Long-term Plasticity and CB Receptors. ............................................958
1
4. Cannabinoid Effects on Brain Development. .........................................958
Drug-InducedNeuroplasticity 875
5. Cannabinoid-Induced Cognitive Impairment. ........................................959
6. Rewarding and Aversive Behaviors, Specific Actions on VTA DA Neurons. ...........960
7. Cannabinoids during Adolescence: Increased Risk for Schizophrenia?.................961
8. Conclusions. ........................................................................962
I. Hallucinogens...........................................................................962
1. Effects of Serotonergic Hallucinogens Are Mediated by the 5-HT Receptor. .........962
2A
2. Hallucinogen Action—A Perturbation of Sensory Gating or Desynchronization
of Cortical Rhythms?.................................................................963
3. Behavioral Effects and Addiction Potential...........................................964
4. Long-term Residual Effects of Serotonergic Hallucinogens: the Role of
Neuroplasticity......................................................................964
a. Sensory processing...............................................................964
b. Mood and anxiety................................................................965
5. Scopolamine: Another Hallucinogen Revisited for Depression.........................966
6. Conclusions. ........................................................................966
III. General Discussion..........................................................................966
A. Novel Methods for Future Studies .......................................................967
References ..................................................................................969
Abstract——Adaptation of the nervous system to conditioned drugs effects, such as cue- or stress-
differentchemicalandphysiologicconditionsisimpor- induced reinstatement of drug seeking. In rodents,
tant for the homeostasis of brain processes and for adolescent drug exposure often causes significantly
learning and remembering appropriate responses to more behavioral changes later in adulthood than
challenges. Although processes such as tolerance and a corresponding exposure in adults. Clinically the
dependencetovariousdrugsofabusehavebeenknown most impairing and devastating effects on the brain
for a long time, it was recently discovered that even are produced by alcohol during fetal development. In
a single pharmacologically relevant dose of various adultrecreationaldrugusersorinmedicatedpatients,
drugs of abuse induces neuroplasticity in selected it has been difficult to find persistent functional or
neuronal populations, such as the dopamine neurons behavioralchanges,suggestingthatheavyexposureto
oftheventraltegmentalarea,whichpersistlongafter drugs of abuse is needed for neurotoxicity and for
thedrughasbeenexcreted.Prolonged(self-)adminis- persistent emotional and cognitive alterations. This
tration of drugs induces gene expression, neurochem- review describes recent advances in this important
ical, neurophysiological, and structural changes in areaofresearch,whichharborstheaimoftranslating
many brain cell populations. These region-specific thisknowledgetobettertreatmentsforaddictionsand
changes correlate with addiction, drug intake, and relatedneuropsychiatricillnesses.
I. Introduction and ethnic groups studied in the United States. Indi-
vidualswithalcoholorillicitdrugabuseordependence
Braindiseasesareassociatedwithanenormouscost
inthepastyearconstituted5%oftheadolescentsaged
toaffectedindividuals,theirfamilies,andthesociety.In
between12and17andmorethan8%ofallindividuals
Europe,ithasbeenestimatedthatthetotalyearlycost
aged12orolder(SAMSHA,2014a).Oftheracial/ethnic
ofbrain diseases in 2010 was close to 800 billion euros
groups studied among those aged 12 and older, Asians
(Olesenetal.,2012),ofwhichaddictionsareresponsible
hadthelowestproportionofbingealcoholdrinkersand
for as much as anxiety disorders, with only dementia
past-month illicit drug users, likely partly due to
and mood illnesses costing more (DiLuca and Olesen,
societal/cultural traditions. These findings on rather
2014). Drug abuse produces both direct and indirect
widespread drug and alcohol exposures at young ages
coststothesociety,althoughmanyofthedrugsarealso
are very alarming, because brain development contin-
clinically used to treat various patient groups. The
purpose of this review is to present up-to-date knowl- ues well past the age of 17 years and because the
edge of the mechanisms of action of the main drugs of exposuretoseveraldifferentdrugs,suchasillicitdrugs,
abuseandtorevealthepossiblelong-termalterationsin cigarettes, and alcohol, appears to concentrate on the
thenervoussystemassociatedwiththeuseandabuseof same individuals (SAMSHA, 2014b). Therefore, it is
variousdrugsactingonthebrain,alsopayingattention possible that harmful effects from early drug use will
tothetrajectoryofbraindevelopment. prevail later in life, because drugs of abuse induce
Addictionisacomplexphenomenon,whichisnotonly different modulations in brain circuitries (adaptation,
dependent on pharmacological mechanisms, but also plasticity,learning,andmemory)duetotheirpharma-
has a societal/cultural dimension. This is reflected in cological actions and due to behavioral/social effects
the proportion of drug addiction among different age associated with their use and settings. Thus, we will
876 Korpietal.
explore the data on different drugs and how they and adaptations. The focus in this review will be more
persistently affect brain functions if the drugexposure ontheneuroplasticityoftheglutamatesynapsesonDA
occursduringadolescence. neurons.
Thereviewfirstgivesageneralbasicintroductionto Pharmacological actions of drugs are mediated by
neuroplasticity.Thensectionsondifferentdrugsfollow specific receptors.On theotherhand, theeffectsofthe
and they have different focuses, because the various drugs of abuse are often modulated by experimental
drugs do not invoke exactly similar mechanisms or settings and expectancies in both preclinical studies
adaptationsinthenervoussystem.Thereviewwillend and human experiments. Drug intake in rodents is
withashortgeneralsummary. dependent, for example, on cage conditions, with the
Certain mechanisms seem to be common for many effectsdifferingbetweenopioidsandstimulants(Badiani
drugs, for example, activation of the extracellular et al., 2011). Voluntary self-administration (SA) (self-
signal-regulatedkinase(ERK)pathwayinspecificbrain stimulation or cocaine) induces different brain regional
structures is necessary for effects of and tolerance to activations (Porrino et al., 1984), or more prolonged
cocaine, nicotine, MDMA, phencyclidine, alcohol, and synaptic molecular adaptations, than experimenter-
cannabinoidsafterbothacuteandchronictreatmentsin given stimulation or drug injections (Chen et al., 2008).
rodents (Kyosseva et al., 2001; Salzmann et al., 2003; Placebo/noceboeffectsarerealinhumanstudies,andthe
Valjent et al., 2004; Rubino et al., 2005; Tonini et al., expectancyofstrongoruncertaindrugeffectsareknown
2006; Schroeder et al., 2008). One human postmortem to affect human brain imaging results in response to
brain study suggested that cocaine, cannabis, and/or acute drugs (Volkow et al., 2010). For example, in
phencyclidine abuse all decrease transcription of smokers,positiveandnegativebeliefsonnicotinecontent
calmodulin-related genes and increase transcription of of cigarettes influenced functional magnetic resonance
genesrelatedtolipid/cholesterolandGolgi/endoplasmic imaging (fMRI)-scanned striatal responses to value and
reticulum(ER)functionintheanteriorprefrontalcortex rewardpredictionerrorsduringaninvestmenttask(Gu
(PFC),whichmayunderliechangesinsynapticfunction et al., 2015), indicating that beliefs can affect cognitive
and plasticity (Lehrmann et al., 2006). However, post- performancealsounderthedrug-associatedstates.These
mortem brain regional gene expression profiling in issuesindicatethat,inadditiontodirectpharmacological
alcohol-dependentpatientshasindicatedwidelydiffer- actions,abuseddrugsmayalsochangebasiclearningand
ing sets of affected genes between different brain memory processes, for example, by conditioning and
regions (Flatscher-Bader et al., 2005, 2006), with alco- environmentalfactors.
holics nevertheless being easily separable from non-
A. Different Forms of Neuroplasticity
alcoholic controls and smokers (Flatscher-Bader et al.,
2010).Thesamesituationwasfoundforotherdrugsof The ability of the brain to remodel its connections
abuse (Albertson et al., 2004, 2006). Significant alter- functionally and structurally in response to individual
ations in glutamate and GABA receptor mRNAs were experiencehasbeendescribed bytheconceptofneuro-
found in postmortem brains of alcohol-dependent sub- plasticity. Neuroplasticity occurs on a variety of levels
jects,butthechangesdifferedfromonebrainregionto ranging from molecular changes in synapses to large-
another (Jin et al., 2011, 2014a,b; Bhandage et al., scale changes involved in neurocircuitry remapping.
2014). For these obvious reasons, we reviewed the Synaptic plasticity refers to adaptive changes in the
literature for each drug according to the specific brain strengthofsynapticconnections.Onthebasisofitstime
regions where alterations have been observed most frame, synaptic plasticity has been classified as short-
commonlyinpreclinicalexperiments.Thesebrainareas term (acts on a timescale of milliseconds to minutes)
and pathways, which serve for positive and negative and long-term (hours to days) plasticity. Short-term
reinforcing behavioral and emotional effects and for plasticity is achieved through transient changes, such
goal-directedandhabitualdrugseeking,areillustrated as facilitation or depression of a synaptic connection,
inFig.1.However,itwillbenecessaryinthefutureto which then quickly return to their initial state. How-
study the plasticity and mechanisms more precisely ever, repeated stimulation causes a persistent change
at the level of different neuronal populations and intheconnectiontoachievelong-termplasticity.
subpopulations. Hebbian or activity-dependent plasticity is the most
Asisusualinaddiction-relatedreviewsandresearch, studied form of long-term plasticity. It occurs when
the dopamine (DA) mechanisms are center stage. The presynaptic stimulation coincides with postsynaptic
reader is referred to recent reviews on various aspects depolarization (Hebb, 1949; Bi and Poo, 2001). The
of DA as a neurotransmitter and a regulator of motor, best-knownexampleofHebbianplasticityisN-methyl-
cognitive,andmotivatedbehavior(BjorklundandDunnett, D-aspartatereceptor(NMDAR)-mediatedlong-termpo-
2007; Beaulieu and Gainetdinov, 2011; Salamone and tentiation (LTP). Importantly, this form of LTP occurs
Correa, 2012). DA is important for a wide number of only in synapses that actively contribute to the in-
brain functions, and it will be impossible to cover each ductionprocess,soitisinputandsynapsespecific.The
andeveryaspectoftheDAmechanismsindrugactions term “anti-Hebbian” plasticity currently describes
Drug-InducedNeuroplasticity 877
Fig.1. Brainregionsofmajorimportancefortheacuteandchronicaddictiveeffectsofdrugsofabuse.Thetopdrawingshowsmanypathwaysthat
participateinrewarding/drug-seekingbehavior.Themiddledrawingdepictsseveralpathways/brainregionsthatareparticularlyrelatedtoaddiction-
relatedaversivebehaviors(wideconnectionsofthelocusceruleustootherbrainareasarenotshown).Thebottomdrawingillustratestheroleofmidbrain-
striatal-corticalloopsingoal-directedandhabitualdrugtaking.SeeFig.10foradditionalpathwaysinvolvedinnicotineneurotoxicity.Amy,amygdala;
BNST,bednucleusofstriaterminalis;CeA,centralnucleusofamygdala;DLS,dorsolateralstriatum;DMS,dorsomedialstriatum;HC,hippocampus;LC,
locusceruleus;LDTg,laterodorsaltegmentalnucleus;LH,lateralhypothalamus;LHb,lateralhabenula;mPFC,medialprefrontalcortex;NAc,nucleus
accumbens;OFC,orbitofrontalcortex;rmTg,rostromedullarytegmentalnucleus;SN,substantianigra;VTA,ventraltegmentalarea.
eitherlong-termdepression(LTD)(Nelson,2004)orLTP effectsofdevelopmentalandlearningprocesses.Other-
that occurs when presynaptic activation coincides with wise, activity-dependentforms ofplasticity could drive
postsynapticinactivity(KullmannandLamsa,2007). neural activity toward runaway excitation or quies-
Inrodents,theneuronalorganizationremainsimma- cence (Miller, 1996; Turrigiano, 1999; Turrigiano and
ture at birth (see below). The process that describes Nelson,2004).
changes in neuronal organization during develop- Metaplasticity refers to “plasticity of synaptic plas-
ment as a result of environmental interactions and ticity,”whichdescribeschangesintheabilitytoinduce
experience/learning-induced neural changes is known further synaptic plasticity (Abraham and Bear, 1996).
as developmental plasticity. To maintain the balance For example, prolonged exposure to cocaine induces
between neuronal excitation and inhibition, homeo- a population of silent glutamatergic synapses in the
staticplasticityregulatestheoverallactivityofcomplex nucleus accumbens (NAc) that form sites for future
circuits by specifically regulating the destabilizing plasticity(reviewedinLeeandDong,2011).
878 Korpietal.
To help appreciate the effects of abused drugs on Ca2+channelactivityandincreasesintheprobabilityof
synapticplasticity,inthefollowingparagraphswewill Ca2+ influx, altered vesicle pool properties, local de-
briefly introduce mechanisms of the most common pletionofCa2+buffers,andincreasesinquantalsizeof
presynaptic and postsynaptic forms of synaptic neurotransmitter release contribute to short-term fa-
plasticity. cilitation (Fioravante and Regehr, 2011). On the other
hand, vesicle depletion, inactivation of neurotransmit-
B. Short-term Neuroplasticity terreleasesites,andCa2+channelscontributetoshort-
termsynapticdepression(NeherandSakaba,2008).In
Short-termplasticitycanappearasatransientfacil-
addition, glial-neuronal interactions impact on short-
itation, depression, or augmentation and posttetanic
term synaptic plasticity by controlling the speed and
potentiation in synaptic strength that lasts for up to
extentofneurotransmitterclearancefromthesynaptic
a few minutes (reviewed in Fioravante and Regehr,
cleft(Berglesetal.,1999)aswellasbyastroglialrelease
2011). Despite the variety in synaptic neurotransmit-
ters, all forms of short-term plasticity are primarily of substances that can affect synaptic efficacy (Araque
governed by presynaptic mechanisms associated with et al., 2001). Most importantly, there is retrograde
fluctuationsofpresynapticresidualCa2+,whichactson communication between post- and presynaptic termi-
oneormoremoleculartargets,resultinginthechanges nals: both endocannabinoids (reviewed in Wilson
in neurotransmitter release (Fig. 2). Enhancement of and Nicoll, 2002; Kano et al., 2009) and nitric oxide
Fig.2. Typicalinductionprotocolsandmainfactorsregulatingmechanismsofshort-termplasticity.(A)Briefpaired-pulse(PP)stimulationinduces
short-termfacilitationofneurotransmissionbytransientlyincreasingtheCa2+-dependentreadilyreleasablepool(RRP)ofsynapticvesicles.(B)Short-
termdepressionofneurotransmissioncanbeinducedbyfrequenttetanicstimulation,whichtransientlydepletessynapticvesicles.(C).Depolarization-
inducedsuppressionofinhibition(DSI)orsimilarlythatofexcitation(DSE;notshown)isalocallyinducedtransientdepressionofneurotransmission
that is dependent on retrograde eCB signaling. Depolarization-induced suppression of inhibition/excitation begins with stimulation of excitatory
neuronalconnectionsinducingeCBsynthesis,and2-AGinparticularthenmovestoactivatepresynapticCB receptorsonsurroundingneurons.This
1
induceslocal,transientdepressionofinhibitoryorexcitatory(notshown)neurotransmission.
Drug-InducedNeuroplasticity 879
(NO)-guanylyl cyclase signaling (Sammut et al., 2010) and DSI), which was found to be dependent on retro-
contribute in a general transient “local” process that gradeencocannabinoid(eCB)signaling(seesectionII.H
tunesneurotransmitterreleaseanddifferentaspectsof oncannabinoids).
synaptic dynamics both in inhibitory and excitatory
C. Main Forms of Long-term Neuroplasticity:
synapses(discussedinmoredetailinsectionsII.Gand
Long-term Potentiation and Long-term Depression
II.H). Short depolarization of a neuron may cause
a transient suppression of excitation or inhibition of Long-termformsofsynapticplasticitycanappearas
that and neighboring neurons, called depolarization- potentiation (long-term potentiation, LTP) or depres-
induced suppression of excitation or inhibition (DSE sion (long-term depression, LTD) in synaptic strength
Fig. 3. Main factors regulating pre- and postsynaptic plasticity mechanisms, such as LTP and LTD, after most typical induction protocols. (A)
PresynapticLTPisoftenmeasuredusingpaired-pulse(PP)stimulatione.g.,at50-msinterstimulusintervals(ISI).ThisleadstopresynapticCa2+
influx via VGCCs, activation of adenylate cyclase (AC) and phosphorylation of synaptic vesicular proteins, such as Rab3a and RIM1a, leading to
increasedtransmitterrelease.(B)Duringlow-frequencystimulation(LFS;oftenusedforLTDinduction)weakpresynapticdepolarizationtriggersonly
a modest Ca2+ influx that activates phosphatases (calcineurin, protein phosphatase 1, and protein phosphatase 2) in the postsynaptic cell. These
phosphatases dephosphorylate AMPA and NMDA receptors, thus promoting receptor removal from the membrane. (C) During high-frequency
stimulation(HFS;oftenusedforLTPinduction)strongpresynapticdepolarizationtriggersrobustglutamatereleasepromotingCa2+influxviaAMPA
andNMDAreceptorsintothepostsynapticcell.ThisCa2+influxactivatesproteinkinases(FYN,PKA,PKC,PKMz,andCaMKII)thatphosphorylate
receptorsandpromotestabilizationofreceptorsatthemembrane.Thesekinasesalsoactivatelocalproteinsynthesis,whichleadstoinsertionofnew
receptorsinthemembrane.(D)ByinducingrobustglutamatereleasewithHFSupto300Hz,activationofpostsynapticgroupImGlureceptorsleads
toAMPAreceptorinternalization.(E)TheLTPthatisdependentonretrogradeendocannabinoid(eCB)signalingconsistspostsynapticactivationthat
induceseCBsynthesis,especiallyincreasing2-AG,whichthenactspresynapticallyonCB receptorslimitingtransmitterrelease(formoredetails,see
1
Fig.12).Thisformofplasticitycanbeexperimentallyevoked,e.g.,inthestriatalneuronsby100-HzHFS.
880 Korpietal.
that last for hours to weeks. In contrast to short-term Ininvitroexperimentsonacutebrainslices,LTPand
plasticity, the nature of long-term forms of plasticity LTD can be induced by distinct patterns of activity
involvesbothpre-andpostsynapticalterations(Fig.3). (reviewed in Holscher, 1999; Luscher and Malenka,
1. Presynaptic Forms of Long-term Plasticity. 2012) (Fig. 3). High-frequency stimulation (HFS) of the
PresynapticLTPhasbeenbeststudiedathippocampal presynaptic cell (tetanic pulses at 50–100 Hz) is com-
CA3mossyfibersynapses(Weisskopfetal.,1994;Nicoll monly used to induce LTP. This stimulation protocol
andSchmitz,2005),butsimilarformsofLTPhavebeen causesastrongpostsynapticdepolarizationthatremoves
foundinmultiplebrainareas(Salinetal.,1996;Castro- theMg2+blockofNMDARs,allowingtimedCa2+influx.
Alamancos and Calcagnotto, 1999; Lopez de Armentia This triggers the downstream molecular cascades in-
and Sah, 2007). This presynaptic LTP appears at both ducingLTP.Incontrast,low-frequencystimulation(LFS,
at0.1–5Hz)ofteninducesLTD.Typically,itcausesonly
excitatoryandinhibitorysynapsesanddoesnotrequire
aweakpostsynapticdepolarizationthatresultsinamod-
postsynaptic NMDARs (but see Yeckel et al., 1999).
estbutprolongedCa2+influxtriggeringthedownstream
Instead, presynaptic LTP appears to be induced by an
molecularcascadesdrivingtoLTD.
activity-dependentriseofpresynapticresidualcalcium
SincetheoriginaldiscoveryofLTPinthehippocam-
thatresultsinariseincAMPandsubsequentactivation
pus (HC) (Bliss and Lomo, 1973), LTP and LTD have
of protein kinase A (PKA). This, in turn, modifies the
been observed in a variety of other brain regions
functions of proteins that act to coordinate synaptic
including the ventral tegmental area (VTA), NAc,
vesicle interactions with the presynaptic active zone,
PFC, and amygdala ex vivo (Luscher and Malenka,
leading to a long-lasting increase in neurotransmitter
2011) and in vivo (Canals et al., 2009; Zhang et al.,
release(Castillo,2012).
2015b).Differentbrainregionsappeartoexhibitdiffer-
Endocannabinoid-mediated long-term depression
ent forms of LTP and LTD, and therefore, synapses
(eCB-LTD) is a widely expressed form of long-term
recruitdifferentsignalingpathwaystoaccomplishtheir
plasticity at both excitatory and inhibitory synapses.
functions.Themoststudiedformsofneuroplasticityare
Briefrobustneuronalstimulationtriggersthesynthesis
NMDAR-dependent LTP and LTD, with the NMDARs
of eCBs, lipophilic molecules that travel retrogradely providing the major pathway for Ca2+ influx (Huang
across the synapse to activate the presynaptic CB
1 andKandel,1996).ThereisalsoNMDAR-independent
cannabinoid receptors (see section II.H), which sup-
LTP and LTD, in which VGCC (Kato et al., 2009) or
presses neurotransmitter release via a wide range of
GluA2 subunit-lacking AMPARs (Lamsa et al., 2007)
effector molecules, including voltage-dependent cal- providetheCa2+influxtriggeringinduction.
cium channels (VGCC), potassium channels, PKA, p38 In the early phases of LTP, elevated Ca2+ triggers
mitogen-activated protein kinase (MAPK), and c-Jun
persistentactivationofproteinkinasesincludingPKA,
N-terminal kinases (JNK) (reviewed in Howlett et al., Ca2+/calmodulin kinase II (CaMKII), and protein ki-
2002). Importantly, CB receptors activation per se is
1 nase C (PKC). A striking feature of CaMKIIa is its
not sufficient for eCB-LTD induction. Rather, the pre-
capacity for autophosphorylation at threonine residue
synapticterminalintegratesmultiplesignalstogener-
Thr286, which keeps this kinase activated even in the
ateeCB-LTD(HeifetsandCastillo,2009).CB1receptors absence of Ca2+ (Giese et al., 1998). During this stage,
alsomediateshort-termplasticityofDSIandDSE(Fig.
atypical protein kinase C (PKMz) may also become
2). Interestingly, some hippocampal inhibitory synap-
autonomously active (Ling et al., 2006; Sacktor, 2008).
sescanundergobothshort-andlong-termformsofeCB-
Autonomously active and other protein kinases use
mediatedplasticity,wherethetimeframeofdepression
phosphorylationtocarryoutthetwomajormechanisms
(short-term versus long-term manner) depends on the
underlyingtheexpressionofLTP:first,theyphosphor-
downstream signaling pathways (Heifets and Castillo,
ylateexistingAMPARsandNMDARstoincreasetheir
2009). Particularly, cAMP/PKA-dependent signaling
activity,andsecond,theymediatetheinsertionofnew
has been shown to be necessary only for eCB-LTD but
receptorsintothepostsynapticmembrane(seebelowfor
notforDSI(ChevaleyreandCastillo,2003).
moredetaileddescription).
2. Postsynaptic Forms of Long-term Plasticity.
3. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
NMDAR-dependent LTP and LTD are the best un-
acidandN-methyl-D-aspartateReceptorPhosphorylation.
derstoodformsoflong-lastingsynapticplasticity(Bliss
Huganir and coworkers made detailed experiments
andLomo,1973;Hayashi etal., 2000). Early phases of
on the regulation of AMPAR trafficking and function
LTPand LTD aremediatedbya redistributionofboth by phosphorylation during LTP/LTD (reviewed in
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Shepherd and Huganir, 2007). During LTP, PKA and
receptors (AMPAR) and NMDARs at the postsynaptic CaMKIIarerecruitedtophosphorylateserineresidues
membrane and/or by changes in presynaptic transmit- intheGluA1subunitatSer831(Mammenetal.,1997)
terrelease.Withtime,suchchangesareconsolidatedby andSer845(Rocheetal.,1996)andtheGluA2subunit
structural alterations, which require synthesis of new at Ser880 (Chung et al., 2000), promoting receptor
proteins(Kasaietal.,2010). insertionandsynapticpotentiation(MalenkaandBear,