T h e re is s tro n g evidence to suggest th a t the m e s o lim b ic do p a m in e rg ic system th a t projects fro m the V T A to the N A c c , the C P u and the p re fro n ta l co rte x (PFC) is the m a jo r substrate fo r natu ra l rewards and re in fo rce rs, as w e ll as add ictive drugs (O lds 1956; O ld s & M iln e r 1954; W ise 1998). T h e N A c c is in v o lv e d in o rch e stra tin g b e h a vio u ra l responses to m o tiv a tio n a l s tim u li, acting as a site o f convergence o f co rtic a l and su b co rtica l in fo rm a tio n , and c o n tro llin g b e h a vio u r th ro u g h its o u tp u ts to the b ra in stem via the v e n tra l p a llid u m (M ogenson
et al.
1980), whereas the C P u seems to be m o re im p o rta n t fo r ‘h a b it’ learning and executing learned sequences o f behaviours (G ra yb ie l 1998; W h ite 1997). U n d e r n o rm a l circum stances, this pathw ay is in v o lv e d in c o n tro llin g responses to s tim u li associated w ith survival, such as fo o d and o p p o rtu n itie s fo r re p ro d u c tio n . H o w e v e r, m o st add ictive drugs also b rin g about increases in these neurones’ a c tiv ity and dop a m in e release in the N A c c , especially in its m e dial ‘shell’ re g io n ( D i C hiara & Im p e ra to 1988; H e m b yet al
1995; H u rd
et a l
1989; Im p e ra toet a l
1986; K iy a tk inet al
1993; P e ttit & Justice 1989; P o th o set a l
1991; W iseet al
1995; W ise 1998). O p io id s achieve th is b y in h ib itin g the G A B A e rg ic neurones th a t n o rm a lly in h ib it the d o p a m in e rg ic cells in th e V T A (D e vin eet al
1993; Jo h n so n & N o r th 1992; Leoneet al
1991), whereas p sychostim ulan ts seem to cause lo c a l increases in the release o f dopam ine, p rim a rily b y p re v e n tin g its reuptake in to nerve term inals (G o ldet al
1989).Lesions o f the N A c c , o r p harm acolo gical blockade o f dop a m in e receptors here p re ve n t the e xecution o f rew a rd and re in fo rce m e n t-re la te d behaviours. T h u s, rats wiU self-adm inister am phetam ine in to the N A c c (H o e b e l
et al
1983), b u t 6 - O H D A lesions o f this system p re v e n t the se lf-a d rn in istra tio n o f am phetam ine and cocaine (G e rrits & V a n Ree 1996; Lynesset a l
1979; P e ttitet al
1984; R oberts & K o o b 1982). F u rth e rm o re , actions th a tChapter one Introduction
increase dopa m in e release in this b ra in re g io n tend to be repeated: indeed, the u p re g u la tio n o f this pathw ay is postulate d to u nderlie the sensitisation observed w ith repeated drug exposure (see C h apter 4). W ith d ra w a l fro m a several drugs o f abuse, in c lu d in g alcohol, n ico tin e , opiates and psychostim ulants, reduces the extracellular co ncentratio ns o f do pam ine in the N A c c (Im p e ra to
et al
1992; Parsonset a l
1991; P aulsonet a l
1991; P othoset a l
1991; R o b e rtso net al
1991; R ossettiet al
1992), T h e central ro le o f d o pam ine is fu rth e r su p p o rte d b y w o r k w ith m ice th a t lack d o pam ine D 2 receptors. These m ice consum e less a lc o h o l than th e ir w ild type htterm ates (PhiUipset a l
1998), and also fa il to d em onstrate a CPP to m o rp h in e , alth o u g h they e x h ib it n o rm a l physical signs o f w ith d ra w a l (M a ld o n a d oet al
1997). Sim ilarly, m ice la ckin g the d o pam ine tra n sp o rte r, one o f the p u ta tive targets o f cocaine, show reduced s e lf-a d m in istra tio n o f the d ru g (Rochaet al
1998). P aradoxically, how ever, the physical signs o f opiate w ith d ra w a l are reduced fo llo w in g lo ca l in fu s io n o f a d o pam ine D2 re ce p to r agonist in to the N A c c (H arris & A ston-Jones 1994). T h e net e ffe c t o f dopam ine release, as w e ll as the d ire c t actions o f a ddictive drugs such as PC P and cannabinoids w ith in the N A c c is to b rin g a b o u t an in h ib itio n o f the m e d iu m spiny neurones (H e m a n d e z-L o p e zet a l
2000; Y a s u m o toet al
2 0 0 2) — h o w e ve r the w ay in w h ic h this actually leads to re in fo rc e m e n t is n o t clear.H o w e v e r, d o pam ine release in the fo re b ra in is p ro b a b ly n o t e q uivale nt to ‘pleasure’ . U npleasant n o xio u s s tim u li also cause release o f d o pam ine in this b ra in re g io n , as do s tim u li w ith n o o b vio u s h e d o n ic co m p o n e n t. W o rk b y Schultz and colleagues has dem onstrate d th a t the m e so lim b ic d opam ine rgic neurones m ay in fa ct serve as a learning o r ‘e rro r’ signal, and thereby play a ro le in learning a b o u t the m o tiv a tio n a l significance o f a stim ulus (see Schultz 1998, 2000). I n m onkeys, these neurones fire in response to an u n a n ticip a te d rew ard. H o w e v e r, as the m o n ke y leams to associate a p a rtic u la r cue w ith th a t rew ard, the dopam in e rg ic neurones begin to fire in response to the cue, w h ile the response to the rew a rd its e lf habituates. I f a p re d icte d rew ard is o m itte d , h ow ever, the baseline firin g o f these neurones is suppressed. These neurones th e re fo re m ay act as a rew ard ‘e rro r signal’, in d ic a tin g h o w the perceived re w a rd in g e ffe c t o f a stim u lu s compares to th a t expected. T h e general arousing e ffe ct o f increased dop a m in e e fflu x in the fo re b ra in , co m b in e d w ith m o re detailed in fo rm a tio n a b o u t the c o n te x t and nature o f the stim ulus fr o m areas such as the h ippoca m p us and amygdala, is th e re fo re b elieved to drive the processes in v o lv e d w ith le a rn in g a b o u t the value o f a stim ulus. Since the strength and
Chapter one Introduction
persistence w ith w h ic h drugs o f abuse activate this pathw ay is p ro b a b ly greater than th a t o bserved w ith n a tu ra l re in fo rce rs, i t is p ostulate d th a t they stim ulate an exaggerated le a rn in g signal, w h ic h m ay d rive the fo rm a tio n o f changes in b ra in stru ctu re and fu n c tio n u n d e rp in n in g the d e ve lo p m e n t o f a d d ic tio n (Berke & H y m a n 2000).
T h e N A c c has been intensively studied as a locus in w h ic h m olecular, cellular and synaptic changes o c c u r in response to d ru g a drninistratio n. Changes in gene expression are p o stu la te d to be central to the d e ve lo p m e n t o f a d d ic tio n , b y a lte rin g th e m olecular c o m p o s itio n o f neurones th a t are affected b y d ru g a d m in is tra tio n and shaping fu tu re responses (Terw iU iger
et al.
1991). F o r example, c h ro n ic exposure to opiates, cocaine o r a lc o h o l reduces the levels o f in h ib ito ry G -p ro te in s (M cL e m a net al.
2000; N e s tle ret al
1990; S trip h n & Kahvas 1993), and in a c tiv a tio n o f G; and G^ p ro te in s w ith in tra - accum bens in fu s io n s o f pertussis to x in reduces the re w a rd in g effects o f intravenous cocaine and h e ro in (S elfet al
1994). S im ilarly, c h ro n ic m o rp h in e , cocaine, am phetam ine o r a lc o h o l a d m in is tra tio n increases the levels and a c tiv ity o f C R E B in a n u m b e r o f brain regions in c lu d in g the N A c c and V T A (Coleet al.
1995; T u rg e o net al
1997). C R E B activates tra n s c rip tio n w h e n p h o sp h o ryla te d and has been sh o w n to be in v o lv e d in tolerance, physical dependence and possibly the c o n d itio n e d aspects o f a d d ictio n . Indeed, o verexpressio n o f C R E B in the N A c c decreases the re w a rd in g effects o f opiates and cocaine, w h ile a dom in a n t-n e g a tive m u ta n t fo rm o f C R E B has the o p p o site e ffe ct (C arlezonet a l
1998). Changes in the expression o f the im m e d ia te early genes (lE G s )z-fos
andc-Jun
o c c u r w ith d ru g a d rn in istra tio n (see C hapter 5), and the expression o f related p ro te in s , such as A F o sB is beheved to be o f im p o rta n c e in m e d ia tin g the lo n g -te rm b e h a v io u ra l changes characteristic o f the sw itch to an addicted state (H o p eet a l
1994; K e lzet a l
1999; M orataUaet al
1996). Changes in synaptic strength also o ccu r in response to d ru g a d m in is tra tio n . B o th lo n g -te rm p o te n tia tio n (L T P ) and lo n g -te rm depression (L T D ) have been observed in the N A c c and V T A , and m ay be related to the effects o f repeated d ru g exposure o n b ra in fu n c tio n (Joneset a l
2000; T h o m a set al
2000). Indeed , L T D in the V T A is d isru p te d b y am phetam ine a d m in is tra tio n and in the CPu, whose cyto a rc h ite c tu re is sim ila r to th a t o f the N A c c , L T P and L T D are k n o w n to o ccu r in a d o p a m in e re ce p to r-d e p e n d e n t m anner (Joneset al
2000; T h o m a set a l
2000). L T P betw een glutam aterg ic term inals and the d o pam ine rgic cells o f the V T A has also been observed in response to a single a d rn in istra tio n o f cocaine (Unglesset al
2001).Chapter one Introduction
F u rth e rm o re , lo n g lasting changes in the size and n u m b e r o f d e n d ritic spines have been observed o n do p a m in e rg ic neurones w ith in the N A c c and P F C fo llo w in g c h ro n ic cocaine o r am phetam in e a d m in istra tio n , whereas c h ro n ic opiate a d m in is tra tio n decreases th e ir size (R o b in so n & K o lb 1997; R o b in s o n & K o lb 1999; S k la ir-T a v ro n
et a l
1996). S im ilar changes to these have been observed in anim al m odels o f le a rn in g and m em ory, h ig h lig h tin g the sim ila rity in the neural processes u n d e rly in g these tw o fo rm s o f b e h a vio u ra l change, and in th e ir persistence (D eisserothet a l
1995; L iis c h e ret al
2000; M a rtin & K a n d e l 1996; Silva & M u rp h y 1999; Y in & TuUy 1996).W h ils t the N A c c is k n o w n to be im p o rta n t in m e d ia tin g the re w a rd o f p s y c h o m o to r stim u la n t drugs via d o p a m ine -dependent m echanism s, the ro le o f th is nucleus in opiate rew ard is less clear. A lth o u g h rats w ü l self-adm inister opiates in to the V T A (B ozarth & W ise 1981; D e v in e & W ise 1994; P h illip s & Lepiane 1980), and this b rin g s a b o u t increases in accum bal d o pam ine transm ission (D e vin e