NeuIOSCience 1 76 (201 1) 328-335

GABAPENTiN BLOCKS METHAMPHETAMINE-INDUCED SENSiTIZATiON

AND CONDITIONED PLACE PREFERENCE VIA INHIBITloN oF α218-1

SUBUNITS OF THE VOLTAGE-GATED CALCIUM CHANNELS

K. KURoKAWA, M. SHiBASAKl, K, MIZUNo ANDS. OHKUMA*

Department of Phamacology, Kawasaki Medical School, MatsushI'ma

577, Ku伯Sh妬Okayama 701-0192, Japan

Abstract-一〇ur previous investigation demonstrated that re-

peated administration of morphine Sign胴cantly enhanced

a218･1 Subunit expression in the frontal colteX and limbic

torebrain of mice as well as mcrphine･jnduced place prefer-

ence. lloweyer, little is known about regulatory mechanisms

of a2I8-1 Subunit expressiorl in ccnditicned place preference

by methamphetamine (METH). in the present study, we inves-

tigated the mie of α2I8-1 subuhit of voitage一gated ca一cium

channe一s (VGCcs) in the mouse brain under repeated t輪at･

meれt with METH, The level of α2I8-1 subunit increased sign昨

icantly in the limbic forebrain including the nucleus accumbens

and the fmnぬI c°hex of mice showing METH-induced sehSitL

zaticn. Under these conditions, the development of behavioral

sensitization induced by the interm肌ent administration of

METH was sign胴cahtiy supp記SSed by the co･administ輪tion

of gabapentin (G且p) With binding activity to an exofacial

epitcpe of a218-1 subunit. Furthemcre, GBP administered

i.c.V. caused a dose･dependent inhibition of the METH･in-

duced p一ace preference, Chronic G且p treatment at the dose

alleviatirlg SenSitization and place preference significantly

reduced the e一evation of α2I6-1 subunit of VGCc induced by

the repeated administ輪tion of METH in the iimbic b晦b輪in

and什ontai co競ex, whereas there were no changes in the

increase of a2/8･1 subunit mFWA･ These findings indicate

that a216･1 Subunit plays a critical role in the development cf

METH･induced place preference follcwlng neurOnal plastic･

itv, and that G且p, which sign櫛cantiy suppressed METH-

induced place preference by its possible inhibitcry action cf

a218 subunit tc neuronal membrane, may possibly be used as

an a一ternative dmg to treat or prevent dmg dependence.

⑥ 2011 Pub一ished by Eisevier Ltd on beha一f of iBRo,

Key words: gabapentjn, methamphetamine, a2/6-1 subunit of

high voltage･gated calcium channels, place preference, traf･

傭cking.

The abuse of psychostimuiants such as methamphet-

amine (METH) and coca活e 一eads to the deve一opment of

psychotic symptoms that resemb一e those of paranoid

schizophrenia. in rodents, repeated adm面stration of psy-

chostimuiants resu一ts in a progressive and persistent eie-

*Conesp°rding author. Tel: +81 -086462-1 1 1 1 ; fax: +81-086462-1 199.

E-mai一 address. sohkuma@bcc kawasakトm.aCJP (S. Ohkuma).

AbbreviatI'ons.'CaMKll. Ca2+/calmodulln-mediated kinase I I ; GBP, ga-

bape楠∩; METH, methampheねmine; PKC, protein kinase C; VGCCs,

Voltage一gated ca一cium channe一s.

vation in the motor-stimu一ant e惰ed e一icited by subsequent

drug chaIIenge, which js calied behavio輪i sensitization

(Vanderschuren and Kaiivas, 2000). The p一ace-Condition-

ing procedure is used to eva一uate motjvatjonai prope軸es

such as the reward活g and aversive e的cts of METH活

anima一s (Nahta et aI･, 2001), it has been wide一y accepted

that the p一ace preference and behaviora一 sensitization

caused by METH are charaderistics of drug dependence

and addiction (Vanderschuren and Kalivas, 2000).

A growing body of evidence suggests that the me-

solimbic dopamine system, which originates in the ventrai

tegmentaI area and ma剛y prqleCtS tO the nuc一eus accum-

bens and the media一 prefrontai cohex, p一ays an impohant

ro一e in the deve一opment of dependence on psychostimu-

Iants (Robinson and Berridge, 1993; Nestler, 2005). There-

fore, it is worthwhile to identify the factors that can increase

dopamine re一ease as weli as enhance the responsiveness

of postsynaptic receptor-mediated intrace剛ar signai

transduction pathways活the fronta一 cohex and the limbic

forebrain area during the development of behaviora一 sen-

sitizatjon to METH (Nar船et ai., 2002, 2004, 2005: Miyat-

ake et aL 2005). Recent investigations have repoHed that

α216 subunit was wide一y distributed in brain, especiaIIy in

fronta一 cohex and iimbicわrebrain (Tayior and Garrido,

2008)･ ln addition, our previous investigation demonstrated

that interm批ent adm面stration of morphine produced sen-

sitization and conditioned p一ace preねrence高association

with up-regu一ated expression of α218-1 subunit (Shibasaki

et aI･, 2009)･ However, I圃e is known about the ro一e of α218

subunit on psychoiogICai dependence on METH.

VO胎ge『ated Ca2+ channe一s NGCCs) a晦heteromeric

∞mpIexes consisted of α1, α2, 6, β and γsubunits. The CaV1

and Cav2 subfamilies are made up of pore-forming subunits

and a晦aSSOCiated with membrane-anchored, predominant一y

ex廿acelluiar, α2伶1 subunits (Davies et aI., 2007). Gabapen-

tin (GBP), an a南ep胎ptic dmg mat is clinicaiiy usedめr the

treatment of pain and anxiety disorders (Welty et al., 1993;

Beydoun et ail, 1995; Na鵬el aI., 2007) bmds with high

a仰nity to the α218 subunit (Gee et aI., 1996; Marais et ai.,

2001 )- Severa一 studies found that GBP is an inhibkor of α2/6-1

subunit t語仰ciking (Davies et ai., 2007; Bauer et a上2009;

Tran-Van-M活h and Do一phin, 2010), A一though mese resu一ts

suggest that α2伶1 subunit may be c舶cai for the functiona一

assemb一y of VGCCs, which may be a key p一ayer in drug

abuse, little is known about the role of a2/6-1 subunit on

psychologiCai dependence on METH,in the p記Sent Study, we examined whemer α2I8-1 sub-

unit modulated the properties of functional VGCCs and at-

thbuted to exp一ain the e情∞α of GBP against dmg abuse by

03064522111 8 - see Front matter@ 2011 Published by EIsevier Ltd on behalf ot IBROdoi:1 0.1 01 6lj.neuroscience.201 0. 1 1.062

328

K〟 Kurokawa et aI. I Neuroscjence 176 (2011) 328-335

c一arifying the invo一vement of α2伶1 subunit jn the fronta一 coト

tex and iimbicねrebrain in the deve一opment of the METH-

induced p一ace preference and sensitization to METH-induced

hyperlocomotion. We report here for the first time the critical

ro一e of α2I8-1 subunit in the METH-induced p一ace preference

and sensitization to METH-induced hypes iocomo簡on in ad-

dition to an活crease in α2伶1 subunit mRNAand its protein in

the五〇ntai cohex and iimbic forebram in mice that exhibited

METHJnduced behaviora一 changes.

EXPERIMENTAL PROCEDURES

Anima一s

The present study used ma一e ddY mice (Japan SLC, inc.,

Hamamatsu, Japan), which were housed活a room maintained at

22±1 oC, 55±0.5% with a 12 h iighUdark cyc一e (lighton 8:00 AM tO

8:00 pM). Food and water were ava鴫bie ad 〟bitum. Tota一 number

of mice used in this study was 290,

Aii expehments presented而this paper were approved by the

Anima一 Research Comm肘ee of Kawasaki Medica一 Schoo一 and

conducted accord活g to仙e "Guide for Care and Use of Laboratoγ

Anima一s" of Kawasaki Medica一 Schoo一 that is based on the Na-

tiona一 Institute of Hea一th Guideわr the Care and Use of Laboratory

Anima一s (NiH Pub一ications N0- 80-23) revised 1996. Eveγ e備Oh

was made to minimize the numbers and any suffering ot animals

used in the foliowing experiment.

Locomotor assay

The locomotor activity of mice was measured by an anima一-move-

ment analysis system (Actim0-100 system, Shintechno Ltd, Fu-

kuoka, Japan), which consists of a rectangu一ar enc一osure (30×20

cm2) With a side wali equipped with photo sensors at 2-cm mter-

vals as deschbed previous一y (Shibasaki et aL 2009). Each pair of

photo sensors scanned anima一 movement at 0 5-S活teNais Total

activity counts in each lO一mjn segment were automaticaliy re一

ccrded for30 min pnorto the injection of and for 180 min a備erthe

administration of METH.

The repeated両ection was ca南ed out as described previ-

ous一y (Kuhbara and Uchihashi, 1993; Shibasaki etaL 2009). Mice

were s,C. injeded METH (2 mglkg, eveγ 96 h, ¶ve times) to

induce sensitization to METH-induced hyperlocomotion. Tota一 ac-

tivity was counted for 3 h a偶er each treatment.

To investigate the imp一ication of α218 subunit in the deveiop一

meれt of sensitization to METH-induced hyperiocom°tion, mice

30　0　　約　60　90　120 150180

両Ii巾

329

2　　　　　3

(seSsio巾

4　　　　　5

Fig. 2. B一ockade of the deve一opment of sensitization to METH-in-

duced hyperlocomotIOn by GBP. MICe Were glVen five Injections of

METH (2 mg/kg･ S･C･: once every 96 h) foIIowng pretreatment wm

vehicle or GBP (30 nmol/mouse日.C.V.) 30 mln before each METH injec-

tion. Tota一 activity was counted tor 180 mln a償er each METH treatment

The data represent the meanfSEM obtained from 10 mICe. ''* P<0.001

vs. the let drug admlnlStratl0n (Dunnett's test), a p<0.05, #p<0 001 vs.

vehICIe-METH group ln each session (Bonferroni's test).

were p'etreated with vehic一e o'GBP (30 nmoilmouse言･C･V･) 30

剛in prior tO METH treatment

P一ace conditionlng

The piece-Conditioning procedure was carried out according to the

method repohed previous一y (Shibasaki et a1., 2009). P一ace condi-

tioning Studies were conducted using an apparatus COnSisting of a

sh皿e box (15.5×35×17 cm3; widthxiengthxheight), which was

made of acryIIC resin board and divided mto two equaLsized

compahments. One companment was white with a textured 鯛oor

and another was b一ack with a smooth [oor to create equaiiy

inviting compahments. The conditioning P一ace preference sched-

u一e consisted of three phases (preconditioning test, conditioning,

and postconditioning test).

The preconditioning test Was pe巾ormed as foliows: the pa舶-

tiOn Separating the two compahments was raised to 7 cm above

揮Vehlci e　　　3　　　10　　　　30

GsP　くれmollmouse言.C.V.)

MBTNQmgj'*9. 8.C.)

Fig･ 1･ Acute effect of GBP on total activity of METH一両uced hyperiocomotiOn･ (A) T-me-coTrSe and (B) total activity of the METH-induced

hypeTIocomotion in mice that had been pretreated with GBP (3, 10 and 30 nmoI/mouse). Mce were I.C.V. Pretreated with vehlCle or GBP prior to METH

injection Each point or coiumn晦PreSentS the mean±SEM of iocomotor adivity counts obtained from 1 0 mice.

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