and 2-4 ), that me di ate a fast syn ap tic trans mis sion of the neu ro trans mit ter [29].

Transcription

1 ? C u r r. I s s u e s P h a r m. M e d. S c i. V o l. 2 5, N o. 2, P a g e s C u r r e n t I s s u e s i n P h a r m a c y a n d M e d i c a l S c i e n c e s F o r m e r l y A N N A L E S U N I V E R S I T A T I S M A R I A E C U R I E S K L O D O W S K A, S E C T I O D D D, P H A R M A C I A o n l i n e : w w w. u m l u b. p l / p h a r m a c y T h e r o l eo f a c e t y l c h o i n l i dn re u g a d d i c t i o n K I N G A G A W E Ł, MA Ł G O R Z A T A JE N D A, OJL A N T A H. K O T L I b S K A D e p a r t m e n t o f P h a r m a c o l o g y a n d P h a r m a c o d y n a m i c s, M e d i c a l U n i v e r s i t y, L u b l i n, P o l a n d A B S T R A C T A c e t y l c h o l i n e A C h, i s i n v o l v e d i n m a n y C N S f u n c t i o n s l i k e s e n s o r y a n d me o e p t, o r n o p rc oi c e p s s t i on n g, ms el m o r y, m o o d, s t r e s s r e s p o n s e, a t t e n t i o n, a r o u s a l, m o t i v a t i o n a n d r e w a r d. D u e t o t h e i n t e r ian c etr i go in c w ri e t h w atrh d e sdyo s pta e m m a i n l y i n t h e v e n t r a l t e g m e n t a l a r e a ( V T A ), n u c l e u s a c c u m b e n s ( N A c ) a n d p r e f r o n t a l c o r t e x ( P F C ), ia t C h i s p l ba e y s l ia e v se id g tn hi af ti c a n t r o l e o n t h e i n i t i a t i o n a n d m a i n t e n a n c e o f t h e d r u g a d d i c t i o n. S u b s t a n c e s a f f eyc s t ti en m g bty h e i n c hc o r el ais n ei r n g itc h e s l e v e l s o f A C h, l i k e c h o l i n e s t e r a s e a n d b u t y r y l c h o l i n e s t e r a s e i n h i b i t o r s ( d o n e p e z i l, ri n ve a, s ttaicg r im in ne, e, g ap hl y a sn otsatmiig n me ), r e d u c e d t h e s y m p t o m s o f a d d i c t i o n i n a d r u g i n d u c e td e sc ta P Ps w e l l a s l o c o m o t otr y ac a tu is ve id b y m o r p h i n e, c o c a i hn e r aonid n. U n f o r t u n a t e l y, d o n e p e z i l f a i l e d t o i n h i b i t m e t h a m p h e t a m i n e C P P a s w e l l a s t h e l o c o m o t o r s e n s i t s i zd a r ut g i.fo on r c ca ou m s epd a rbi y s, to hni it h a s b e e n i n d i c a t e d t h a t m i c e l a c k i n g M 5 r e c e p t o r s h o w e d a r e d u c t i o n i n c o c a i n e s e l f a d m i n i s t ria nt di uo cn e d a ncd P P m. o rtp h e i nset i m u l a t i o n o f M 4 r e c e p t o rd e c r e a s e d D A r e l e a s e i n N A c t h ae n da d m i n i s t r a t i o n o f n o n s e l e c t i vt e oaf n mt Aa Cg ho Rns i, s s c o p o l a m di e n e c r e a s e d c o c a i n e i n d u c e d l o c o m o t o r a c it n i v r ai. t sy M o r e o v e r, m e c a m y l a m i n e, a n o n c o m p e t i t v e a n t a g o n i s t o f n A C h R s, p r e v e n tce o d ctahie n e i n c r e a s e i n c o n s u m p t i o n a s w e l l a s b l o c k e d c o c a i n e a n d a m p h e t a m i n e i n d u c e d b e h a v i o rtahl u s s, e n d rs ui gts i azf a ft ei cot n. i n g c h o l i n e r g i c t r a n s d u c t i o n c o u l d b e a p p r o a c h e d a s p o t e n t i a l t h e nr ta s p ef u o r t i pc a at gi e n t s w h o a b u s e d i f f e r e n t p s y c h o a c t. it vh e s se u b i s s ts au ne cs e, sh o w e v e r, r e q u i r e f u r t h e r s t u d i e s. K e y w o r d s : a c e t y l c h o l i n e, a c e t y l c h o l i n e s t e r a s e i n h i bui s t oarcs c, u mnbu ecnl s e, a d d i c t i o n, c o n d i t i o n e d p l a c e p r e f e r e n c e t e s t, r e w a r d s y s t e I N T R O D U C T I O N Acetylcho line (ACh) was the first dis cov ered neu ro trans mit ter that has been found to be in volved in many cen tral and pe riph eral nerv ous sys tem func tions. It is syn the sized from acetyl CoA and cho line by cho line ace tyl trans fe rase (ChAT) and in syn ap tic cleft it is hy dro lyzed by en zymes from cho lin es ter ase group such as: ace tyl (AChE) and bu tyryl cho lin es ter ase (BuChE). In pe riph eral nerv ous sys tem (PNS) ACh is re spon si ble for mus cle con trac tion and func tion ing of the auto nomic nerv ous sys tem [29]. In cen tral nerv ous sys tem (CNS) ACh is in volved in many func tions like sen sory and mo tor proc ess ing, sleep, no cicep tion, mem ory, mood, stress re sponse, at ten tion, arousal, mo ti va tion and re ward [34]. There are two types of ace tyl cho line re cep tors (AChR) that bind ACh and trans mit its sig nal: mus car inic AChRs and nico tinic AChRs, which are named af ter the ago nists mus carine and nico tine, re spec tively. These re cep tors are func tion ally dif fer ent, the mus car inic type be ing G protein cou pled re cep tors (GPCRs) that me di ate a slow meta bolic re sponse via sec ond mes sen ger cas cades, while the nico tinic type are ligand gated ion chan nels, con sisting of pen tamet ric com bi na tions of 12 subunits ( 2 10 C o r r e s p o n d i n g a u t h o r * D e p a r t m e n t o f P h a r m a c o l o g y a n d P h a r m a c o d y n a m i c s, M e d i c a l U n i v e r s i t y, L u b l i n, P o l a n d e m a i l : k i n g a g a w e o 2. p l and 2 4 ), that me di ate a fast syn ap tic trans mis sion of the neu ro trans mit ter [29]. A C E T Y L C H O L I N E, D O P A M I N E A N D A D D I C T I O N D R U G A lot of pub li ca tions also em pha size the sig nifi cant role of ACh on the ini tia tion and main te nance of the drug ad dic tion [18,19] due to the in ter ac tion of the cho liner gic sys tem with the do pa min er gic re ward sys tem mainly in the ven tral teg men tal area (VTA), nu cleus ac cum bens (NAc) and pre fron tal cor tex (PFC). Many years of re search have dem on strated an im por tant role of do pa mine (DA) in the re ward sys tem and in the acute re in forc ing ef fects of the drugs [22]. DA is the prin ci pal neu ro trans mit ter in three ma jor neu ral sys tems in the mid brain : 1) the ni gros tri atal path way which origi nates from do pa minesynthesizing neu rons of the mid brain sub stan tia ni gra com plex and in ner vates the dor sal stria tum (caudate putamen), and whose de gen era tion leads to Park in son s dis ease); 2) the meso lim bic sys tem which origi nates in the mid brain VTA and in ner vates the ven tral stria tum (NAc and ol fac tory tu ber cle) and part of the lim bic sys tem this system in flu ences mo ti vated be havior, in clud ing ac tiv ity re lated to re ward; 3) the VTA also gives rise to the smaller meso cor ti cal path way, which in ner vates part of the fron tal cor tex (FC) and may be in volved in cer tain as pects of learn ing and me moriza tion.

2 T h e r o l e o f a c e t y l c h o l i n e i n d r u g a d d i c t i o n Psy chostimu lants like co caine ele vate ex tra cel lu lar DA level in NAc and this ac tion is re spon si ble for the rewarding ef fect of drug. It was ob served that in tra ve nous co caine ad mini stra tion in creased DA level in NAc. Moreo ver, DA fi ber de struc tion in the meso cor ti co lim bic sys tem caused in hibition of co caine self administration, as well as DA fi ber dam age lim ited to NAc. For com pari son, dur ing with drawal from etha nol, there was a dramatic re duc tion in the level of DA as so ci ated with a sig nifi cant re duction in spon ta ne ous fir ing rates [22]. As men tioned above, ACh is also in volved in the re ward ing ef fects of ad dic tive sub stances. There are two main cho liner gic pro jec tions that in ner vate parts of the re ward sys tem. The first pro jec tion from the fore brain leads to nu cleus ba salis mag no cel lu laris (NMB), which in turn in ner vates cor ti cal and sub cor ti cal struc tures of the HPP and Amy [1]. This path way is mainly as so ci ated with Park in son s and Alz heimer s dis eases, but can also be in volved with learn ing and mem ory as so ci ated with the pro cess of ad dic tion. The sec ond pro jec tion leads from the meso pon tine cell group (Ch 5,6 = ped in cu lo pon tine teg men tal and latero dor sal teg men tal nu clei LDT) di rectly to the VTA, which in turn pro vides pro jec tions to the NAc, which regu lates drug re in force ment [1]. F i g. 1. R e g i o n s o f t h e b r a i n w i t h c h o l i n e r g i c i n f l u e n c e o n d r u g r e w a r d a n d w i t h d r a w a l B [ r 1 o ] k. e n l iens r e p r e s e n t pd ra o j e c t i o n, w h i l e s o l i d l i n e s r e p r e s e n pt r o A Cj he c t i o n s. H P P h i p p o c a m p u s ; N A c n u c l e u s a c c u m b e n s ; F C f r o n t a l c o r t e x ; A m y a m y g d a l a ; V T A v e n t r a l t e g m e n t a l a r e a ; C h 5, 6 p e d i n c u l o p o n t i n e t e g m e n t a l a n d l a t e r o d o r s a l t e g m e n t a l n u c l e i ; N M B n u c l e u s b a s a l i s m a g n o c e l l u l a r i s. The ac tiv ity of neu rons in the NAc is modu lated not only by the DA neu rons, but also by ACh in ter neu rons, which rep re sent less than 1% of all neu rons in this re gion [1, 13]. Moreo ver, cho liner gic in ter neu rons within NAc have large den dritic ar bors and they can modu late DA cell fir ing and meso lim bic DA re lease [17]. DA neu rons and ax ons ter mi nals in NAc are rich in machrs and nachrs, whose stimu la tion re sults in an in creased re lease of DA and re in forced be hav ior [38]. Simi larly in the VTA, stimu la tion of 2 con tain ing nachr leads to an in creased re lease of DA in brain re gions like the NAc and PFC [29]. The ac ti va tion of neu ronal 7 con tain ing nachr on the ter mi nals of the PFC in creases lev els of glu ta mate, which fa cili tates the re lease of DA in the NAc. This mecha nism is criti cal for the re ward ing ac tion of nico tine [29]. The VTA NAc pro jec tion and the cho liner gic neu rons in the PFC may play a role in learn ing and mem ory, which are in volved in ef fects of ad dic tive sub stances such as the de sire to eat sub stances (crav ing), search ing for a sub stance (drugsee king) or re turn to the con sump tion of sub stances of abuse (re lapse). The neu roi mag ing stud ies re vealed de creased ac tiv ity of PFC in drug abus ers, which mani fested poor sus tained at ten tion, re sponse in hi bi tion, and de ci sionmak ing [29]. The ad dic tive sub stances like am pheta mine and co caine in crease ACh re lease in PFC [29]. ACh re lease caused by am pheta mine is ac com pa nied by the de vel op ment of psy cho mo tor sen si ti za tion, which may sug gest that PFC is in volved in the de vel op ment of neu ronal adap tive changes. The cor re la tion be tween ACh re lease and the DA sys tem has been proven by stud ies con ducted on rats. It has been shown that ad mini stra tion of do pa mine D 1 re cep tor ago nist, in creases ACh re lease in the NAc, and the ad mini stra tion of D 2 re cep tor ago nist re duces the level of ACh [5]. The dif fer ence in ac tiv ity is be cause D 1 d op ami ne rgic re cep tor is ex ci ta tory, while D 2 d op ami ne rgic is in hibitory [29]. M A C H R A N D N A C H R A S P O T E N T I A L T A R G E T S I N T R E A T I N G A D D I C T I O N In the syn ap tic cleft, ACh in ter acts with two types of re cep tors: machrs and nachrs. machrs, that are GPCRs are di vided in two main groups based on their G coupling mecha nisms: M 1 (M 1 +M 3 +M 5 ) and M 2 (M 2 +M 4 ). The M 1 machrs are ex pressed mainly in the cere bral cor tex, hip po cam pus and stria tum and are in volved in learn ing and me moriza tion pro cess. These re cep tors can be po ten tial thera peu tic tar get in treat ing Alz heimer dis ease [29]. The M 3 machrs are not well char ac ter ized. The M 5 machrs are widely ex pressed in do pa min er gic neu rons in the sub stan tia ni gra and VTA and ago nists bind ing to these re cep tors cause the re lease of DA in the NAc. Elec tri cal stimu la tion of the latero dor sal teg men tal nu cleus (LDT) in the mice causes ac cum bal DA ef flux in three con secu tive phases. The last strong est ef flux DA in a long third phase is ab sent in M 5 knock out mice [11]. Moreo ver, in mice lack ing M 5 re cep tor in VTA, there was ob served a re duc tion in self administration of low toin ter me di ate doses of co caine [31], re duc tion of morphine induced con di tioned place pref er ence (CPP) [3] and a de crease of morphine induced lo co mo tion by ap proxi mately 4050% [28]. The M 2 and M 4 re cep tors also regu late the neu ro trans mit ter re lease. Block ade of M 2 re cep tor in creases cho liner gic ac tiv ity, while the stimu la tion of M 4 re cep tor de creases DA re lease in NAc. In ter est ingly, the use of mi cro dialy sis showed an in crease of DA level in M 4 knock out mice. In deed, in some brain re gions M 4 re cep tors act as auto re cep tors to ex ert a nega tive feed back of con trol over ACh re lease. In hi bi tion of these re cep tors leads to in crease in the im pact of ex ci ta tory cho liner gic in put to do pa min er gic neu rons, which leads to DA re lease in NAc [32]. V o l. 2 5, 2,

3 K i n g a G a w e ł, M a ł g o r z a t a J e n d a, J o l a n t a H. K o t l i s k a machrs proba bly play a role in re in force ment, since the ad mini stra tion of non se lec tive an tago nist of these re cep tors, sco pola mine, to the me dial pre fron tal cor tex (MPC) en hanced co caine self administration in rats. Moreo ver, intra MPC in jec tions of sco pola mine in creased lo co mo tor ac tiv ity, but de creased cocaine induced lo co mo tor ac tiv ity [21]. In the same ex peri ment, it was showed that in tranac mi cro in jec tions of sco pola mine did not af fect the number of lever presses made and in fu sions de liv ered, what can sug gest, that block ade of machrs in the NAc does not af fect co caine self administration [21]. As it was men tioned above nachrs are ligand gated ion chan nels, con sisting of pen tamet ric com bi na tions of 12 subunits ( 2 10 and 2 4 ), mostly lo cated pre synap ti cally in the CNS, where they modu late the re lease of ACh and DA. They are per me able to so dium, po tas sium, cal cium ions, and most of them con tain 4, 2 or 7 subunits. Those nachrs lo cal ized post synap ti cally on the DA neu rons in VTA, can be criti cal for ad dic tive prop er ties of sub stances. It was ob served that ani mals treated by nico tine showed a sig nifi cant in crease in the number of co caine in fu sions, com pared to sa line group. Moreo ver, dur ing ex tinc tion phase when co caine was un avail able, it was ob served that in jec tions of nico tine caused re in state ment of the lever press be hav ior, what in di cates that nico tine dur ing ac ti va tion of nachr, can fa cili tate co caine re in force ment [4]. Sev eral stud ies have also dem on strated a sig nifi cant role of nachr an ta gonists in re duc ing drug related behav iors. The me cylamine (MEC), a non com peti tive an tago nist all nachr sub types, added to co caine so lu tion pre vented the in crease in co caine con sump tion, but did not elimi nate co caine self administration [17]. The co caine and am phetamine induced be hav ioral sen si ti za tion was blocked by MEC as well [27]. For com pari son, Hi ranita et al. re vealed that nico tine and done pe zil, which is AChE in hibi tors (IA ChE), can at tenu ate the re in state ment of methamphetamineseeking be hav ior. This done pezil s ef fect on meth am phetamine seeking be hav ior was blocked by a nachr an tago nist MEC, but not by machr an tago nist sco pola mine [20]. The ef fect of MEC was also stud ied in cocaine dependent rhesus mon keys. Mon keys were trained to self administer co caine or food by re spond ing on ap pro pri ate lever. Chronic ad min stra tion of vare ni cline, which is se lec tive nachr ago nist, re in forced co caine selfad mini stra tion, while MEC did not have any influence on co caine self administration at doses that main tained foodre in forced re spond ing. Vare ni cline did not have any abuse po tency and did not sub sti tute for co caine in dis crimi na tive sched ule but ad min is tered with MEC or nico tine in creased dis crimi na tive ef fects of co caine. In this model, vare nick line failed to be ef fec tive in treat ing co caine ad dic tion [13]. C H O L I N E S T E R A S E A N D I T S I N H I B I T O R S Sub stances af fect ing the cho liner gic sys tem by in creas ing the lev els of ACh can be used as a po ten tial treat ment tar get of ad dic tion. One group of such drugs is cho lin es ter ase in hibi tors (IChE) widely used for ex am ple in the treat ment of Alz heimer s dis ease and other de men tia dis eases. The level of ACh in the syn apses of the CNS cho liner gic neu rons is mainly re spon si ble for AChE, an en zyme that de grades the neurotrans mit ter [12]. AChE is an en zyme spe cific for the hy droly sis of ACh. There are two types, namely: syn ap tic AChE lo cal ized in the post synap tic mem brane, which di rectly hy dro lyzes ACh af ter nerve im pulse con duc tion, and de prived of the pos si bil ity of a solu ble ACh bind ing to the mem brane re cep tor. Its func tion is non synap tic hy droly sis of ACh, be fore it reaches the post synap tic mem brane. Bu ChE (pseu do cho lin es ter ase) is a non spe cific en zyme, hy dro lyzing not only ACh but also all com pounds hav ing in their struc ture es ter bonds. Bu ChE is lo cated on neu rons, glial cells, en do the lium, and a number of ar eas sup plied by cho liner gic neu rons. The en zyme de com poses the poi sons, es pe cially plant al ka loids, pes ti cides, in sec ti cides. It plays an im por tant role in the me tabo lism of cer tain drugs such as as pi rin or di aze pam [16]. AChE in hibi tors (IA ChE) are di vided into ir re versi ble and re versi ble. Re versi ble AChE in hibi tors are clini cally use ful in the treat ment of Alz heimer s dis ease. This dis ease is char ac ter ized by a sub stan tial loss of cho liner gic in ner va tion in the cere bral cor tex and hip po cam pus, which leads to the loss of neu rons in the ba sal fore brain. The loss of cho liner gic neu rons and the con se quent de crease in cho liner gic neu ro trans mis sion is re spon si ble for the weak en ing of mem ory pro cesses and de men tia [34]. At a later stage of the dis ease when many cho liner gic neu rons rich in AChE die, Bu ChE are be gin ning to play a sig nifi cant role in the regu la tion of cho liner gic sys tem [34]. Stud ies have shown that se lec tive block ing of Bu ChE in the brain cor tex of old rats re sulted in in creased con cen tra tion of ACh in the re gion and im prove ment of cog ni tive func tion, de spite an un changed ac tiv ity of AChE [16]. The first known re versi ble IAChE phy sostig mine and tacrine showed a slight im prove ment in cog ni tive func tion in hu mans. Clini cal stud ies have shown that they are char ac ter ized by low ac tiv ity af ter oral ad mini stra tion, poor brain pene tra tion, low phar ma coki netic pa rame ters, and high he pa to tox ic ity. Be cause of that, tacrine is no longer avail able in the mar ket. A more spe cific and having fewer side ef fects (di ar rhea, nau sea etc.) are the newer cho lin es ter ase in hibi tors, like done pe zil, gal an tamine or ri vas tig mine [34]. C O N D I T I O N E D P L A C E P R E F E R E N C E A N I M A L M O D E L O F D R U G R E W A R D A N D R E L A P S E To as sess the re ward ing ac tions of ad dic tive sub stances and re lapse (even af ter long pe ri ods of ab sti nence), there are used sev eral ani mal mod els e.g. intra cranial elec tric stimu la tion, self administration mod els and con di tioned place pref er ence (CPP), which can as sess con di tioned re sponses re lated to re ward. The ma jor ity of ani mal mod els of re lapse are based on re in state ment mod els, which are a re cov ery of a learned re sponse to hav ing a place where ani mals are ex posed to spe cific stim uli af ter ex tinc tion of such re sponse, C u r r e n t I s s u e s i n P h a r m a c y & M e d i c a l S c i e n c e s

4 T h e r o l e o f a c e t y l c h o l i n e i n d r u g a d d i c t i o n e.g. CPP para digm. This method is based on clas si cal con di tion ing in which the origi nally neu tral en vi ron ment character is tics (tex ture, smell, color) as so ci ated with the sub jec tive ef fects of ad mini stra tion of drugs of abuse, ac quire re ward ing prop er ties (im proved mood, eupho ria). Ad dic tive sub stances cause strong pref er ence of ani mals to a place as so ci ated with their ad mini stra tion [33]. Be ing in this room evokes feel ings com pa ra ble to the ef fects of the re ward [2]. The CPP method con sists of two phases: ac qui si tion and ex pres sion. The first seems to be re lated with re ward and learn ing, while the sec ond one with mo ti va tion and mem ory [25]. I A C H E A S A P O T E N T I A L T A R G E T F O R T H E T R E A T M E N T O F D R U G A D D I C T I O N The lit era ture shows that in ex peri men tal ani mals IA ChE weaken some of the symp toms of ad dic tion to psy choac tive sub stances. Hikida at al. [18, 30] showed that done pe zil in jected be fore co caine or mor phine, in hib ited the CPP caused by these drugs in wild type mice. For com pari son, cho liner gic cell eliminated trans genic mice did not re spond to done pe zil and they showed mor phine CPP com pa ra ble to saline paired mice. Hikida at al. [18] also stud ied the role of ac cum bens ACh in the de vel op ment of co cainei nduced sen sitiza tion. The stud ies showed that in mice, in which choliner gic in ter neu rons were de stroyed by im mu no toxinm ed iated cell tar get ing tech niques, ad mini stra tion of co caine re sulted in a pro gres sive in creas ing of lo co mo tor ac tiv ity much higher com pared to the wildtype lit ter mates [18, 19]. It was also re ported that ad mini stra tion of IA ChE done pe zil, prior to co caine, abol ished the in duc tion of lo co mo tor ac tiv ity caused by co caine in mice. In the same ex peri ment, it was also ex am ined that the other IChE, gal an tamine, also in hib ited cocaine induced hy per lo co mo tion [18]. Gal an tamine also in hib ited nicotine withdrawal symp toms in the form of mem ory im pair ment in mice [35] and in hib ited the dextroamphetamine induced un rest, arousal and stereo typy in cebus mon keys [9]. There was only one study on hu mans, where gal an tamine was ob served to re duce smok ing com pared to pla cebo in 114 alcohol dependent vol un teers [10]. An other group of re search ers led by Taka matsu [30] also ex am ined the im pact of done pe zil on be hav ioral changes in mice caused by ad mini stra tion of co caine and meth am pheta mine. It was found that pre treat ment with done pe zil, abol ished signs of cocaine induced CPP, as well as lo co mo tor sen si ti za tion, but not the de vel op ment of lo co mo tor sen si ti za tion to co caine, which con firmed the re sults of Hikida et al. [18]. Un for tu nately, in the same ex peri ment, they found that pre treat ment with the same dose of done pe zil failed to in hibit methamphetamine CPP as well as the lo co mo tor sen si ti za tion caused by this drug. The dif fer ent ef fect of done pe zil on co caine and metam pheta mine ac tion is proba bly due to a mecha nism of ac tion on vari ous neu ro trans mit ters and mem brane trans port ers. How ever, these re quire fur ther study [30]. In a dif fer ent ex peri ment, IAChE tacrine in hib ited co caine self administration in rats [14]. In one study, 17 hu man vol un teers abus ing co caine were treated with done pe zil. The drug was well tol er ated, but did not change co caineuse be hav ior. Un for tu nately, these re sults should be con firmed by fur ther stud ies, be cause a group of vol un teers was too small for sta tis ti cal evalua tion, and used only one dose of done pe zil [37]. For com pari son, in an other study ri vas tig mine, IA ChE as well as bu tyryl cho lin es ter ase in hibio tor (IBu ChE), did not de crease meth am pheta mine self administration in hu mans ad dicted to this sub stance, but might re duce posi tive ef fects [8]. Grasing et al. confirmed the dif fer ence be tween done pe zil and ri vas tig mine on co caine self administration in rats. It was ob served that both com pounds de creased co caine selfadministration, but in a dif fer ent po tency. Ri vas tig mine de creased co caine self administration in greater po tency com pared to done pe zil. Ri vas tig mine pro duces a greater in crease in ACh level than done pe zil, be cause it in hib its both AChE and BuChE while donepe zil does only IChE [9]. Phy sostig mine, an other IA ChE, given to the hip po cam pal CA1 field, de creased morphine induced CPP in rats [26]. In an other study, cho liner gic en hance ment caused by this drug, dec reased co caine self administration in rhesus mon keys [9]. The role of cho liner gic trans mis sion was con ducted on rats trained to nose poke for intra venous (i.v.) her oin adminis tra tion. It was ob served that phy sostig mine pre treatment re duced the ac qui si tion of heroin administration, and this ef fect can be re versed by pre treat ment of sco pola mine but not MEC [38]. Af ter 14 days of ex tinc tion, the ani mals were sub jected to quench ing ac tion items origi nally as so ci ated with re ward (like house light or the sound of in fu sion pump), but with out an ad dic tive sub stance, to ini ti ate cue dependent re in state ment. It was ob served that phy sostig mine re duced cue induced re in state ment, and only the dose of 0.5mg of the drug was ef fec tive in re duc ing nosepoke re spond ing on the ex tinc tion test [38]. In the same ex peri ment, phy sostig mine was mi cro in jected to NAc or VTA to evalu ate the re gions me di at ing the ef fects of sys temic drug treat ment on re in state ment [38]. It was ob served that mi cro in jec tion of the drug to NAc in hib ited cue induced heroin seeking, with out an in flu ence on ex tinc tion phase. The mi cro in jec tion of the drug to VTA caused in hi bi tion of cue induced her oinsee king as well as ex tinc tion re spond ing. Moreo ver, in ac ti va tion ei ther NAc or VTA by tetro do toxin, in hib ited both ex tinc tion re spond ing and cue induced re in state ment, what con firmed that ACh is in volved in her oinsee king be hav ior [38]. C O N C L U S I O N S Many stud ies have re vealed that ACh plays a sig nifi cant role in the pro cesses un der ly ing drug ad dic tion [6]. Us ing IA ChE such as done pe zil and ri vastyg mine, Hikida et al. [18] in di cated an in hi bi tion of the de vel op ment and per sis tence of be hav ioral ef fects as so ci ated with ad mini stra tion of co caine and mor phine [18]. In ad di tion, done pe zil and the other IA ChE, gal an tamine in hib ited lo co mo tor ac tiv ity in mice caused by co caine [18]. Fur ther more, there are in di ca V o l. 2 5, 2,

5 tions that other IA ChE in hibi tor, tacrine at tenu ated co caine self administration in rats [13], gal an tamine in hib ited nico tine withdrawal symptoms in mice [35], and phy sostig mine de creased mor phinein duced CPP [26] and cue induced heroin seeking in rats [38]. On the other hand, it has been in di cated that mice lack ing M 5 re cep tor in di cated a re duc tion in co caine self administration [31] and re duc tion of morphine induced CPP [3]. The stimu la tion of M 4 re cep tor de creased DA re lease in NAc [32] but the ad mini stra tion of non selective an tago nist of machrs, sco pola mine, to the MPC en hanced co caine self administration in rats, but de creased cocaine induced lo co mo tor ac tiv ity [21]. On the other hand, MEC, a non com pe titve an tago nist of nachrs, added to co caine so lu tion, pre vented the in crease in co caine con sump tion, and blocked co caine and amphetamine induced be hav ioral sen si ti za tion [17]. MEC also blocked done pe zil ef fect on metam pheta mineseeking be hav iors, while sco pola mine failed to block it [20]. In sum mary, IA ChE and sub stances affect ing dif fer ent ACh re cep tors are not only use ful for a bet ter un der stand ing of mecha nisms un der ly ing drug ad dic tion but also pro vide po ten tial thera peu tic tar gets for the treat ment of ad dic tion. R E F E R E N C E S 1. A v e n a N. M., R a d a P. V. : C h o l i n e r g i c m o d u l a t i o n o f f o o d a n d d r u g s a t i e t y a n d w i t h d r a w a l. P h y s i o l. B e h a v., 1 0 6, 3 3 2, B a r d o M. T., B e v i n s R. A. : C o n d i t i o n e d p l a c e p r e f e r e n c e : w h a t d o e s i t a d d t o o u r p r e c l i n i c a l u n d e r s t a n d i n g o f d r u g r e w a r d? P s y c h o p h a r m a c o l o g y, 1 5 3, 3 1, B a s i l e A. S. e t a l. : D e l e t i o n o f t h e M 5 m u s c a r i n i c a c e t y l c h o l i n e r e c e p t o r s a t t e n u a t e s m o r p h i n e r e i n f o r c e m e n t a n d w i t h d r a w a l b u t n o t m o r p h i n e a n a l g e s i a., 9 9, , B e c h t h o l t A. J., M a r k G. P. : E n h a n c e m e n t o f c o c a i n e s e e k i n g b e h a v i o r b e r e p e a t e d n i c o t i n e e x p o s u r e i n r a t s. P s y c h o p h a r m a c o l o g y,1 6 2, 1 7 8, B e r t o r e l l i R., C o n s o l o S. : D 1 a n d D 2 d o p a m i n e r g i c r e g u l a t i o n o f a c e t y l c h o l i n e r e l e a s e f r o m s t r i a t a o f f r e e l y m o v i n g r a t s. J. N e u r o c h e m., 5 4, , B i e k o w s k i P. ( ). U z a l e n i e n i a l e k o w e i s t r a t e g i e f a r m a k o t e r a p i i. I n : F a r m a k o l o g i a. P o d s t a w y f a r m a k o t e r a p i i. K o s t o w s k i W., H e r m a n Z. ( e d i t o r s ). 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K. : S e l e c t i v e b u t y r y l c h o l i t e r a s e i n h i b i t i o n e l e v a t e s b r a i n a c e t y l c h o l i n e, a u g m e n t s i n g a n d l o w e r s A l z h e i m e r b e t a a m y l o i d p e p t i d e i n r o d e n t, 1 0 2, , H a n s e n S. T., M a r k G. P. : T h e n i c o t i n i c a c e t y l c h o l i n e r e c e p a n t a g o n i s t m e c a m y l a m i n e p r e v e n t s e s c a l a t i o n o f c o c a i n e s a d m i n i s t r a t i o n i n r a t s w i t h e x t e n d e d d a i l y a c c e s s. 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6 T h e r o l e o f a c e t y l c h o l i n e i n d r u g a d d i c t i o n 3 3. V e t u l a n i J. : S t a r z e n i e, c h o r o b a A l z h e i my elo rca h o i lbi u n t eys r 3 6. W i n h u s e n T. M. e t a l. : A p l a c e b o c o n t r o l l e d s c r e e n i n g t r i a l t e r a z a P. s y c h o g e r i a t i a, P o l 5, s k1 a, t i a g a b i n e, s e r t r a l i n e a n d d o n e p e z i l a s c o c a i n e d e p e n d 3 4. W i l k i n s o n D. S., G o u l d T. J. : T h e e f f e c t s o f g a l a n t a m i n e tor n e ant i cm o e n t s A. d d i c t i o n 1, 0 0, 6 8, t i n e w i t h d r a w a l i n d u c e d d e in f i c oi n t s t e x t u a l f e a r c o n d i t3i7 o. n Z h o u W. a t a l. : R o l e o f a c e t y l c h o l i n e t r a n s m i s s i o n i n n u c i n g i n C 5 7 B L / 6 m i cbe e. h a v. B r a i n R, e s , 5 3, a c c u m b e n s a n d v e n t r a l t e g m e n t a l a r e a i n h e r o i n s e e k i n g i 3 5. W i l l i a m s M. J., A d i n o f f B. : T h e r o l e o f a c e t y l c h o l i n e di un c ec d o cb ay i nceo n d i t i o n e d cnue eu s r. o s c i e, n c 1e 4 4, , a d d i c t i onn e. u r o p s y c h o p h a r m a c o, l 3o 3 g, y , V o l. 2 5, 2,