Janine Gillespie Y2094142 SD805 ECA resubmit

Contents

Abstract.2 Introduction..4 1. Allostasis and drug rewards.5 1.1 Allostasis.5 1.2 Drug reward system10 2. The ndocannabinoid !eC"# system..1$ 2.1 C"1 or hC"1 rece%tors1& 2.2 C"2 or hC"2 rece%tors1' (. The Drugs o) Abuse22 (.1 Cocaine2$ (.2 Alcohol.(4 (.( *%ioids.(4 4. Conclusion.(5 +e)erences..(,

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Abstract

In addiction science- research is being carried out into one o) the most im%ortant systems o) the body. the ndocannabinoid system- it has been argued that it can e/ert an in)luence on the immune system and the gastrointestinal system- howe0er - the in)luence o0er addiction neurobiology and the reward system remains relati0ely under researched.

1owe0er- the theories surrounding the structural bodies related to the reward systems 2 neurochemical sensiti0e areas is 3uite well understood. 4erha%s there was more to this mysterious system o) rece%tors which was 5nown )or its e))ects on the ner0ous system- on both the central and the %eri%heral as%ects. It can %erha%s be best illustrated by the C"2+ system- which is im%aired in multi%le sclerosis and Al6heimer7s disease.

There was a 3uestion whether there would be any in)luence in these rece%tors when a %erson ta5es an illicit substance8 This re0iew ~ ~

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%ro0ides an engaging sna%shot o) the current neuroscience 2 neurochemistry associated with addiction. This re0iew intends to demonstrate that the ndocannabinoid system can and does ha0e a role in the addiction reward system.

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Introduction

+ecreational drugs ha0e been since history began. It has been )ound that addiction has mani)ested when the %erson de0elo%s a need to search )or and administer the drug!s#.

9hen a %erson has an addiction- they o)ten e/hibit negati0e emotional states- the most notable o) which are an/iety- de%ression and irritability- although other signs are mani)ested. Addicts )urther com%ound these emotional states when they are trying to sto% their drug use. Addicts o)ten ha0e a %articular 0ulnerability to days or e0en years o) rela%se relati0e to their drug!s# o) choice.

:euro%harmacological and neuroada%ti0e mechanisms o) addiction are currently being researched in an attem%t to synthesise the mechanisms. This could shed light on the methods o) how the brain beha0es during occasional drug abuse right through to when the addict is ;a sla0e to the chemical<. It is notable that the %ositi0e enhancement %sychological e))ects o) the drug are most o)ten to be )ound in the mesolimbic do%amine system.

Do%amine le0els in the :ucleus Accumbens !:Ac# ha0e been )ound to be increased when all drugs are used- although alcohol- nicotine and some o%ioids are )ound to e/hibit a lesser e))ect than %sychostimulants- which e))ect is strong. =erotonin-

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>A"A !? @ Amino "utyric Acid#- >lutamate and Acetylcholine and other neuro%e%tides are )re3uently interacting in the brain reward systems when obser0ing the addiction %ro)iles o) abused drugs. It should be noted that there are a number o) brain com%onents o) the mesolimbic area o) the brain.

*0er the years- the neural mechanisms o) addiction and %ositi0e reward ha0e been researched- which has lead to a growing interest in the endocannabinoid !eC"# system.

This re0iew will co0er the sections o) allostasis and drug reward systems- the hC"1 and hC"2 systems @ where they are located and what their )unction is- the drugs o) abuse- which are o%ioids- alcohol !ethanol- ethyl alcohol#- cocaine and %sychotro%ic and the conclusion will e/%lain how it all comes together.

1. Allostasis and drug rewards

1.1

Allostasis

The body has an internal standard which is 5nown as homeostasis. The diagram below shows the mechanism o) the system- which is also 5nown as a negati0e

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)eedbac5 mechanism. This indicates that the %arameter can be brought bac5 to the o%timum be)ore the body sustains any damage.
!2#

Aigure 1. ta5en )rom re). !12# 1owe0er- in the mammalian model- there are )aults in the control system.

=lices o) cerebral tissue )rom the brain can )unction )or hours in mediums which are lower than the Bnormal7 body tem%erature- which is ($CC. :euronal sensiti0ity can be increased a%%ro/imately twoD)old )or each 10 degrees- which is similar to biochemical reaction thermal coe))icients.
!(#

1igher tem%eratures increases the neuronal )unctioning o) the cells as they increase the conduction 0elocity- reduce the noise in a/ons !there)ore ma5ing it easier to carry

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out electrogram testing#- the %rocess is carried out by reducing ion o%ening timesthe )inal stage hel%s ion channel 5inetics. Aunctional o0erla% between the di))erent s%i5es can in turn increase the s%i5e e))iciency. The o0erall e))ect o) the combination o) increased energy e))iciency- reduced noise- and increased 0elocity o) conduction can be attributed to endotherm e0olution.
!4#.

=uch an action indicates that the

human brain tem%erature can7t be closely regulated as it would not be o%timal- rather it is a condition which hel%s the o%timal )unctioning o) the neuronal system.

Another reason that homeostatic control may not be the best way to e/%lain holistic body )unctioning is that i) each organ sel) regulated- the body wouldn7t be able to ada%t to wor5 o%timally with the body. ach organ would- in this case- be re3uired to

%osses its own blood and )uel su%%ly- resulting in a much greater strain on the heart !a large heart would be needed#- in addition to a bigger digesti0e ca%acity !to obtain the increased metabolites and nutrients the body re3uires#.
!2#

In reality- organs ha0e a mechanism which allows )or resources to be ;traded<- a short term loan is granted )or other organs to gain access to resources. A good e/am%le o) this is resting s5eletal muscle- it uses E 1.2 litres o) o/ygenated blood %er minute- when in %ea5 e))iciency- the muscle needs E 22 litres %er minute. a substantial increase on the rest o/ygen consum%tion. The resultant cardiac out%ut is increased- howe0er this is not su))icient enough.

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Fuscles store glycogen and )atty acids- but- it does not store much o/ygen- neither can it ha0e a sustained su%%ly o) de D o/ygenated blood as it would re3uire a su%%ly )rom the heart and lungs. There would also be an additional re3uirement )or the digesti0e system to ha0e an increased ca%acity )or the )unctions o) digestionabsor%tion- e/cretion and cooling. It is notable howe0er that this is a resource which cannot be stored- so it is a Bborrowed7 resource.

As we are discussing the brain !as we are tal5ing about how it alters in addiction#the body doesn7t tend to ta5e Bloans7 )rom the brain- so the muscle borrows )rom the brain and the blood su%%ly- so cardiac out%ut shares dro% )rom 20G to 1G.

The )orebrain is a structure which integrates 0arious lower le0el %hysiological signals- which areH =teroidal hormones and %e%tides which are in control o) blood %ressuremineral and energy balance. :eural signals )rom brainstem 0isceral areas- i.e. the nucleus o) the solitary tract and the hy%othalamus. =ignals )rom brainstem ra%he neurons modulate mood and arousal using the neural transmitter serotonin- !5Dhydro/yam%hetamine or 5D1T )or short#.
!,D&#

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In the amygdala- the central nucleus is aroused by cortisol @ which is 5ey in the arousal res%onse mechanism- to release an increased amount o) the hormone C+1 or Corticotro%in +eleasing 1ormone# le0els o) which can correlate with an/iety.
!'#

This is becoming an essential as%ect o) the mechanism o) addiction as an/iety %lays such a large %art in the emotional res%onse o) drug withdrawal- which will be discussed )urther in section (.

1eading bac5 to the discussion- the central nucleus connects reci%rocally with the hi%%ocam%us- !to which the central nucleus# lies beside- to allow e))icient storage and retrie0al o) an/ious or )ear)ul memories. The amygdala re%orts Bconcerns7 to the %re)rontal corte/- which is shown in )igure 2!b# @ the Blimbic7 cascade. The %re)rontal corte/ !4AC# is an area which will be discussed )urther on in the re0iew and is a region concerned with %lanning and deciding. This is a structure which allows signals regarding inci%ent needs and %ast dangers to sha%e %lans. The Bstic57 area o) antici%atory regulation o) the amygdala is o)ten the area used in mo0ement and danger antici%ation. The en0ironment !the drug addiction# in0ol0es a )orm o) )oraging which dictates how the organism decides on the best course o) action. In this as%ect the midbrain reward system underta5es the B)oraging7- which is the reward system- whilst the amygdala Bstic57 is the Bcarrot7.

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Aigure 2. +e%roduced )rom re).

!2#

1.2 Drug +eward =ystem

As we ha0e seen in the %re0ious to%ic- there is an interconnection between the di))erent areas o) the brain- which can be illustrated as in the diagram below with the di))erent neurochemicals.

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Aigure (- ta5en )rom re). !10#

As mentioned and shown in the diagram- there are a number o) di))erent neurotransmitters in0ol0ed in signalling. There are howe0er- certain ones which interact with the ndocannabinoid system !eC"#- these being gamma amino butyric acid !>A"A# and glutamate. "iogenic amines which are seen are do%aminenoradrenaline and serotonin.
!10#

The most 5nown amine associated with addiction is

do%amine and 3uite o)ten it is the D2 rece%tors which are in0ol0ed. As noted- in %articular with cocaine.

The main mechanism o) drug reward system is based around the %ositi0e reward and negati0e reward theory o) ". A. =5inner. This theory shows that drug inta5e

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%ro0ides a B%ositi0e reward7. This means that the drugs are a %ositi0e rein)orcer. The drug is deemed to be a stimulus in the organism7s %leasurable a%%roach. I) this beha0iour occurs- it will be re%eated again and again when the same stimuli occurs.

As in the =5inner bo/- the mechanism can be a5in to the rat obtaining )ood 0ia the le0er- the )ood is the drug and the rat !a)ter )irst accidently bum%ing into the le0er and the recei0ing )ood#- learns the %rocess. It is deemed that there is a need to ha0e the drug- which in turn- switches on a rein)orcement mechanism in the brain @ ;this is a good thing to ha0e- I want some moreI< message being sent to the brain.

There is howe0er- another as%ect to be ta5en into consideration with drugs- and that is the %harmaco5inetics o) the drug. Abused drugs such as heroin and cocaine ! as the two %rime e/am%les#- are smo5ed- inhaled or gi0en intra0enously. The rein)orced as%ect is the action needed to ta5e the drug. so there)ore- it is re%eated and deemed to be the rein)orcement as%ect. It has been shown in 0arious tests on animal subJects that they will 3uic5ly learn that %ressing a le0er %ro0ides sel) medication with the drug o) interest through a %um% or other similar de0ice.

Another im%ortant as%ect o) this theory is the )li%side o) negati0e rein)orcementwhich is when the stimulus concerned needs to be re%eated to sto% it- ta5e )or e/am%le- when the heroin addict is su))ering withdrawal sym%toms- they want to ta5e the drug to sto% them )eeling miserable. There is howe0er another as%ect in drug addiction and that is tolerance. This is when the addict desired more o) a drug to

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obtain a greater e))ect. The resultant conse3uence a nulli)ied e))ect or does not react at all to the drug- so the addict has to obtain more drug to gi0e themsel0es a higher concentration o) the drug to ha0e the same e))ect as be)ore.

Cra0ing and rela%se is the ne/t to%ic )or discussion- which is a mani)estation o) the negati0e rein)orcement mechanism. "elow is a table which is the acti0e sites )or the drug o) addictionH

Drug thanol

=ite o) action :FDA rece%tor !indirect antagonist# >A"AA rece%tor !indirect agonist#

*%iates !heroin- mor%hine and the semi D synthetic analogues# Cocaine

Fu !K# and delta !L# o%iate rece%tor agonist "loc5s reu%ta5e o) do%amine- serotonin and nore%ine%hrine. Also 5nown as a sigma !M# o%iate rece%tor- which is a wea5 rece%tor

Am%hetamine

+eleases do%amine which is initiated by re0erse running the do%amine rece%tors

Table 1H ta5en )rom and edited )rom re).

!11#

As the table abo0e shows- drugs o) abuse react in a %harmacological manner- which normally e/hibits an antagonist or agonist e))ect on the rece%tor and they are de)ined as )ollowsH

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Agonist

;Initiates changes in cell function, producing effects of various types; antagonists bind to receptors without initiating such changes <

There is also a )urther brea5down o) the di))erent ty%es o) agonist.

Aull agonist

Produces maximum effects, have high efficacy; partial agonists (which only produce only submaximal effects) have intermediate efficacy

In0erse agonists

!how selectivity for the resting state of the receptor, this being of significance only in situations where the receptors show constitutive activity

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Aigure 4 ta5en )rom re). !12#

The diagram abo0e shows the twoDstate model which is commonly seen in rece%tor state models which are discussed in addiction %harmacology or rece%tor chemistry.

Antagonism occurs when there is more than one com%ound in the solution which also interru%ts the rece%tor @ e))ector lin5ages- which li5e agonists- ha0e a subset within them.

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4harmaco5inetic antagonism

;"ne drug af)ecting the absor%tion- metabolism or e/cretion o) the other.<

Com%etiti0e antagonism

;#oth drugs binding to the same receptors $he antagonism maybe reversible or irreversible.<

All de)initions in this section are ta5en )rom +ang and Dale7s 4harmacology $ th edition.

The %harmacological de)initions are im%ortant to understanding how the drug beha0es when binding to the rece%tor- or- to understanding how drug rela%se and withdrawal occurs. Drug withdrawal is when the addict e/%eriences the antagonistic e))ects o) ta5ing the drug- )or e/am%le. in a heroin addict @ the withdrawal e))ects are dys%horia- cram%ing- diarrhoea and agitation. This is o%%osite to the e))ects o) the %leasurable as%ects o) the drug which are eu%horia- consti%ation and rela/ationthus %ro0ing that the drug binds strongly to the rece%tors.
!11#

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Drug rela%se occurs when the addict obtains the drug!s# o) choice and the whole reward system is reacti0ated. This gi0es rise to the mechanism o) reinstatement. This is when the addict7s do%amine system is switched bac5 on to res%ond to the signalling )rom the areas o) the brain which res%ond to that %articular drug. A 0ariety o) drugs will be discussed in detail later on in this re0iew.

2. The ndocannabinoid !eC"# system

The ndocannabinoid system is a system o) rece%tors which are named to designate to which the rece%tors res%ond to. In our case- our rece%tors res%ond to the Cannabis sati0a class o) drugs and the )amous substituent o) cannabis- N ' @ Tetrahydracannabinol. !1(# eC"s are li%ids- there)ore they are synthesised ;on demand<.
!14#

"oth the cannabinoid rece%tors re)erred to below- are cou%led to > i and >o %roteins which obser0e a similar transduction system. This %athway acti0es calcium !Ca 2O# channels and can also stimulate correcting %otassium !P O# channels as well as the mitogen @ acti0ated %rotein 5inase %athway- o)ten re)erred to as FA4P.

There ha0e been numerous di))erent ligands and drugs which attach to these rece%tors- and they in turn- hel% to )ormulate the two di))erent subgrou%s o) human cannabinoid rece%tors @ hC"1 and hC"2.

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Aigure 5H ta5en )rom and edited )rom re).

!14#

2.1 C"1 or hC"1 rece%tors

This class o) rece%tor was cloned in 1''0 and is o)ten re)erred to as 2.1H C"DH1HC"1H. This rece%tor has been cloned )rom rat- mouse and human tissue and is )ound in the central ner0ous system- but- has also been )ound in %eri%heral tissue.
!14#

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2.2 C"2 or hC"2 rece%tors

These rece%tors are also termed 2.1HC"DH2HC"2H- 5nown to e/hibit a 4&G homology with C"1 rece%tors. They are located %rimarily in the s%leen- tonsils and thymus glands o) the immune system. +ecent e0idence has shown that there are C" 2 rece%tors located in microglia which ha0e been acti0ated in the C:=- the brain7s immune system- so to s%ea5- and also in neurons in the cerebellum and brainstem.
!14#

The hC"1 rece%tor is the one most o)ten re)erred to in addiction literature as it is mainly located in the C:=. These rece%tors acti0ate %resyna%tic C" 1 rece%tors which then su%%ress the e/citatory neurotransmitters- i.e. glutamate and inhibitory neurotransmitters- i.e. >A"A in a short D term manner or long D term !%lasticity# manner.

The short D term e))ects mediated by eC"s can be described as stemming )rom a %henomenon which is de%olarisation induced su%%ression o) inhibition !D=I# that dam%ens >A"A %resyna%tic release!15- 1,#

and also de%olarisation induced

!1$#

su%%ression o) e/citement !D= # which dam%ens glutamate release. D=I are labelled Bshort term7 as they usually last )or about a minute.

D= and

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The induction o) D= 2 D=I usually occurs when s%eci)ic ty%es o) de%olarising %ostsyna%tic cells occur. This o%ens the Ca2Ochannels !which are 0oltage gated# and also ele0ates cellular Ca2O concentration internally. eC"s are in0ol0ed in this %rocess as obser0ed- by %re0enting D= 2 D=I 0ia the C" 1 rece%tors. As they are located on the %resyna%tic terminals- C"1 agonists and eC" trans%ort inhibitors induce D=I 2 D= .
!1$- 1&- 1,#

2DA>- !2D arachidonyl @ glycerol# is said to be the eC"

most li5ely to be res%onsible )or inducing D=I 2 D= - and A A !Anadamide or : @ arachidonoylethaloamine#- on the other hand- can %roduce e))ects which are a5in to D=I.

Another way in which eC" D mediated short D term %lasticity can be obser0ed is in the %ostsyna%tic metabotro%ic rece%tors that cou%le to > 3 li5e %roteins- m>lu+1- !ty%e 1 metabotro%ic rece%tors# and also the F1 and F( subty%es o) acetylcholine rece%tors- !mACh+1- mACh+(#.
!14#

This system is di))erent because this method o)

rece%tor D dri0en eC" )ormation does not re3uire a raised Ca 2O concentration. 1owe0er- a raised Ca2O concentration within the cells can hel% the %rocess along.

The >3 rece%tors which are directed by eC"s is de%endent on 4QC !%hos%holi%ase C# and DA>Q. This is shown by the short D term %lasticity being inhibited by DA>Qand 4QC on eC" D mediated de%ression in the cerebellar- hi%%ocam%al and RTA neurons. An added e/tra con)irmation is that m>lu+ acti0ation in the hi%%ocam%us or striatum stimulates %re)erred %roduction o) 2 @ A> o0er A A- which suggests that 2 @ A> has an in)luence in this method o) %lasticity. 1owe0er- 4QC @ induced A A-

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is indicati0e o) a )unction in eC" D mediated short @ term de%ression located in certain syna%ses.

It is arguably demonstrated that the eC" induced D=I 2 D= cou%led by > 3 rece%tors ha0e been actually obser0ed in a number o) brain reward mechanisms which are %resent in the RTA- "QA !basolateral amygdala#- dentate gyrus o) the hi%%ocam%usneocorte/ and substantia nigra.
!14#

This system is also thought to induce 0arious

neurotransmitter systems- which are in0ol0ed in addiction- and these beingdo%amine D2 rece%tor inhibition o) striatal glutamate release and short D term su%%ression o) >A"A transmission in the CA1 region o) the hi%%ocam%us. This is thought to in0ol0e C"1 and 5ainate rece%tors interacting with >A"A su%%ression.

Qong D term %lasticity is also termed as QT4 or long @ term %otentiation- which is a sustained increase in the strength o) syna%tic signalling. Qong term de%ression or QTD )or short- is a sustained wea5ening o) syna%tic strength. QT4 and QTD can be %resent )or hours to wee5s and are essential )or some elements o) learning and memory. eC" @ QTD mainly occurs in res%onse to a transient increase in acti0ity with glutaminergic a))erents- ta5ing glutamate to the neurons- which results in %ostsyna%tic m>lu+1s being stimulated and 2 or an increase in Ca 2O concentration within cells- released )rom the %ostsyna%tic cell acti0ation o) C" 1 rece%tors which are located on the original !homosyn%atic eC" @ QTD# a))erents. A))erents are in close %ro/imity !heterosyn%atic eC" @ QTD# to %roduce a sustained decrease in neurotransmission release.

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(. The Drugs o) Abuse

As the %re0ious section has shown- there is short D term and long D term %lasticity. In drug addiction- %lasticity is 5nown to be long D term. There are 5 main areas in which %lasticity occurs. they are the dorsal striatum- nucleus accumbens- amygdalahi%%ocam%us- %re)rontal corte/ and 0entral tegmental areas. I shall go through these areas and )urther on in this section tal5 about the actual drugs o) abuse and the eC" system.

Dorsal striatum

Initial re%orts show )rom in the dorsal striatum studies show that eC" @ QTD comes )rom glutamate release.
!20#

=triatal QTD is in )act bloc5ed by C"1 antagonists and is

!21#

also seen as a 5noc5out !52o# in C"1 mice.

A A has been thought to be in0ol0ed

in the %rocess- which is based on e0idence that %reDsyna%tic loading with A A trans%ort cells inhibitors %re0ents eC" @ QTD. Aurthermore- striatal QTD a%%ears to in0ol0e m>QS+1 ha0ing multi%le signalling %athways- using its antagonists to %re0ent induction o) QTD during high D )re3uency stimulation o) the a))erent glutamatergic syna%ses which are corticostriatal. It occurs due to eC" @ QTD through these a))erent a))erents re3uiring do%amine D2 rece%tors on %ostsyna%tic medium s%iny neurons.
!22#

+ecent studies ha0e shown that eC" @ QTD is actually more sensiti0e
!2(#

to >A"Aeric syna%ses that ha0e been e/%osed to eC" signalling.

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:ucleus accumbens

:Ac C"1 rece%tors %ro0ide inhibitory control o0er immediate glutamate and >A"A release.
!14#

:Ac QTD is bloc5ed by C"1 antagonists and is not seen in C"1 52o mice.

:Ac C"1 eC" @ QTD does howe0er %ossess a distinguishing )actor. it has selecti0e inhibition o) the grou% 1 m>lu+s @ m>lu+ 5 in %articular- but not do%amine D2 rece%tors.
!14#

Although e0idence has shown that eC" @ QTD ta5es %lace at

glutamergic syna%ses- it has not !at time o) writing# been shown that eC"s mediate QTD at >A"Aergic syna%ses within the :Ac.

Amygdala

In this brain structure- stimulation o) a))erent neurons in the "QA induces the QTD o) >A"Aergic neurotransmission that is sto%%ed by C" 1 rece%tor antagonists and not %resent in C"1 rece%tor 52o mice.
!14#

1owe0er- QT4 is signi)icantly im%ro0ed in the

"QA QT4 in wildty%e !wt# mice- thus suggesting a com%ensatory ada%tation )rom between systems in res%onse to li)e D long C" 1 rece%tor absence. +e%orts relati0ely recently %ublished by Che0aleyre in 200$- 1uang in 200( and =hin in 2010 as %art o) their res%ecti0e research grou%s 2 collaborations- ha0e con)irmed eC" @ QTD in the amygdala. This %rocess is also reliant on m>lu+ 1 rece%tor )unction.
!24#

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"QA howe0er- eC" @ QTD is insensiti0e to reduction in Ca 2O- 4QC and DA>Q acti0ities- thus eliminating a %ossible in0ol0ement o) 2 @ A> signalling. eC" @ QTD has shown to be signi)icantly greater in AAA1 52o 0s. wt mice- and also e/hibits sensiti0ity to the inhibition o) adenylate cyclase and 4PC- which suggests that A A is in0ol0ed. It is intriguing to note the e))ects o) acute AAA1 inhibition in wt mice and C"1 rece%tor in0ol0ement in %otentiating eC" @ QTD which is obser0ed in AAA1 52o !D 2 D# mice- has not been e0aluated- which allows )or the %ossibility that a %ortion o) the eC" @ QTD obser0ed in AAA1 inhibition may actually not be mediated by a C" 1 mechanism- but- rather through rece%tors such as the T+4R 1 !Transient +ece%tor 4otential Ranilloid ty%e 1#.
!14#

*bser0ed in addition to those in the "QA- recent

e0idence- clearly highlight that there is a demonstration o) eC" @ mediated D= in the cortical in%uts to lateral and central amygdala.
!25- 2,#

1i%%ocam%us

The glutamatergic %yramidal cells in the CA1 region o) the hi%%ocam%us can be re%eatedly stimulated- to induce heterosyna%tic de%ression at neighbouring >A"Aergic inhibitory syna%ses- is being halted by C" 1 rece%tors and not seen in C"1 52o mice.
!14#

Che0aleyre and Costillo in their 200( %a%er- re%orted that in a

%rocess similar to the amygdala- hi%%ocam%al eC"D QTD is sto%%ed by %harmacological inhibition o) grou% 1 m>lu+s- but- not by the introduction o) a Ca 2O chelator %ostsyna%tically. There is a de)ining as%ect to this structure as o%%osed to the amygdala- and that is that hi%%ocam%al QTD is strengthened by the

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%harmacological inhibition o) DA>Q. This suggests a role )or 2 @ A> in this a%%lication.

There is e0idence which concurs to show that high D )re3uency stimulation o) hi%%ocam%al slices selecti0ely increased 2 @ A> in tissues- although- A A is not seen.
!14#

Sni3ue to the hi%%ocam%us howe0er- are e/%erimental )indings that show

that %ersistent eC" signalling u%regulation at >A"Aergic syna%ses which )acilitates the QT4 o) e/citatory glutamatergic syna%ses which )ollows.
!2$- 2&#

The

Bmeta%lasticity7 which is described re3uires a transient rise in %ostsyna%tic TCa 2OU. !Tcom%oundU is a shorthand way o) describing concentration#. "ut this meta%lasticity does not need concurrent acti0ation o) m>lu+s.
!2'#

4re)rontal corte/ and 0entral tegemental area

In rodent 4AC- C"1 rece%tor acti0ation can su%%ress the e/citatory in%ut to layer 5 %yramidal cells. +e%eated stimulation in 4AC can %roduce QTD o) e/citatory transmission in the region.
!14#

The QTD- which is de%endent on C"1 rece%tors-

re3uires acti0ation o) %ostsyna%tic m>lu+5 and 4QC- which- in turn relies on an increase in %ostsyna%tic TCa2OU. It is )urther enhanced a)ter FA>Q inhibition and attenuated a)ter DA>Q inhibition.
!14#

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Janine Gillespie Y2094142 SD805 ECA resubmit

There is e0idence that the 4AC QTD is not being made im%ure by AAA1 inhibitionand these )indings strongly suggest that that 2 @ A> has a role in this %rocess. The inhibitory %rocess within the 4AC is also regulated by the eC" system. "ut- in contrast to the eC" @ QTD o) these e/citatory syna%ses- the modulation o) inhibitory transmission in the 4AC is triggered by do%amine D 2 rece%tors being acti0ated and is also inde%endent o) %ostsyna%tic ele0ations in TCa 2OU.
!14#

Concerning neurotransmission in the RTA- in regard to do%amine D 2 rece%tors are 5nown to wor5 alongside m>lu+s to )orce eC" @ QTD o) e/citatory and inhibitory transmission o) the syna%se- which is- in a way similar to C" 1 D mediated long term %lasticity in the striatum.
!14#

Acti0ation o) e/citatory 4AC in%uts to RTA do%amine

!(0#

cells shows 2 @ A> D mediated su%%ression o) e/citation- in 0i0o-

thus

decreasing the inhibition o) burst )iring %robability o) do%amine neurons. This B)ine tuning7 o) do%amine transmission which is eC" mediated- connects the limbic and motor systems- and may ha0e a crucial role in the %rocessing o) in)ormation o) reward related stimuli under stress)ul conditions or in drug de%endence.

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Janine Gillespie Y2094142 SD805 ECA resubmit

The basic mechanisms o) the brain structures and %lasticity ha0e been mentioned in the section abo0e and- now the )ocus is on the ( main drugs 2 grou%s o) drugs which are being studiedH

*%ioids Alcohol 2 thyl Alcohol Cocaine

The re0iew will go through these drugs one at a time- starting with Cocaine.

(.1 Cocaine

Cocaine is a drug which is largely snorted or ta5en intra0enously. A recent study has e0idence o) brain C"2 rece%tors modulating Cocaine7s actions in a rodent model.
!(1#

The e/%erimental data suggest that the selecti0e C" 2 agonist V911(( can inhibit

intra0enous cocaine sel) D administration. The )igure below describes the e))ects o) V911(( or another com%ound- >9405&(( !which is another selecti0e C" 2 agonistthe di))erence being in the chemical structure#.

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Janine Gillespie Y2094142 SD805 ECA resubmit

+e%roduced )rom re). !(1#

As seen in the diagram abo0e- it was disco0ered that systematic administration o) V911(( !10- 20 mg %er 5g- intra%eritoneal#- had signi)icantly reduced the %rogressi0e brea5 %oint )or cocaine sel) D administration in wt mice !)igure b#. It is arguable that there was a reduction in the strength o) the cocaine reward and 2 or need )or drug ta5ing beha0iour a)ter V911(( was administered. C" 1 bloc5ade by AF251 had considerably lowered the %rogression brea5 D %oint ratio in rats. It was there)ore included in this e/%eriment and it was )ound that a concentration o) (mg %er 5g- it lowered the brea5 D %oint in rats as seen in the )igure abo0e. This suggests that the data is consistent with the V911(( being able to trigger a reduction in sel) D administration o) cocaine. indicating that the cocaine itsel) had a reduction in reward e))icacy.

Aurther e/%erimentation was underta5en to determine whether V911(( action was brain or %eri%heral C"2 mediated. This was obtained by studying intranasal microinJections o) the com%ound on i.0. administration o) cocaine. This method was

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Janine Gillespie Y2094142 SD805 ECA resubmit

selected because other studies had shown that the blood brain barrier or """ )or short- which o)ten drugs cannot %enetrate- can be administrated instead by the nose and it tra0els to the brain.
!(1#

The results showed that these inJections o)

concentrations o) 50 and 100 Kg %er 10Wl slide- inhibited the cocaine sel) D administration obser0ed- de%ending on the dose. This is illustrated by fig c as shown abo0e. The ne/t ste% in the e/%eriment was to decide whether nasal administration o) V911(( was triggering the drug absor%tion e))ect in nasal 0asculature- then going into the 0enous deli0ery o) drug to the site o) action. =ointra0enous microinJections o) 100 and 200 Wg had no e))ect on the sel) D administration o) cocaine as shown in fig. d. This data suggests that intranasal V911(( was triggering %harmacological e))ects which are mediated by the brainacti0ating C"2 rece%tors as o%%osed to the %eri%heral C"2 rece%tors.

There was a )urther e/%loration by obser0ing the e))ects o) the local administration o) V911(( into the :Ac on cocaine sel) D administration. It was disco0ered that intra D :Ac microinJections o) the V911(( com%ound- which were 0.(- 1 and ( Wg %er slidesigni)icantly inhibited sel) D administration o) cocaine in wt rats in a dose de%endent manner- but- not in C"2 52o mice- in which inhibition was bloc5ed 0ia intra :Ac co @ administration o) AF,(0 at T(Wg %er slideU.

V911(( %ossesses no rein)orcing or a0ersi0e e))ects and this was shown by an e/%eriment which in0ol0ed training mice to learn the sel) D administration o) cocaine and the cocaine was then re%laced by V911(( at T1 mg %er 5g %er in)usionU or

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Janine Gillespie Y2094142 SD805 ECA resubmit

%lacebo 2 0ehicle. It was disco0ered that neither the agonist nor the %lacebo showed stable cocaine sel) D administration in mice which had been taught to administer the cocaine. This is shown by fig. a- illustrated below.

Aigure $ re%roduced )rom re).

!(1#

It was then noted that the beha0iour was gradually diminishing o0er a 5 day %eriod o) substitution testing. This %attern o) e/tinction was essentially the same as when the %lacebo was e/changed )or the cocaine. This altered howe0er when the V911(( or %lacebo was switched )or cocaine- the sel) D administration action returned to the %re0ious le0els o) sel) D administration. Aurthermore- it was obser0ed that the intra%eritoneal cocaine T10 and 20 mg %er 5gU had %roduced a sustained and distinct

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Janine Gillespie Y2094142 SD805 ECA resubmit

robust conditioning- whereas V911(( at the same doses had not %roduced %lace %re)erence or a0ersion in wt mice- fig. b. The )indings a%%ear to argue that the V911(( agonist has no cocaine D li5e rein)orcing beha0iour or a0ersi0e e))ect in a mouse model.

It can inhibit cocaine D enhanced e/tracellular :Ac DA- demonstrated by running a study on whether brain or %eri%heral C"2 rece%tor e))ects were noted. This was done by obser0ing the e))ects o) intranasal or intra D :Ac local administration o) V911(( on e/tracellular DA. It was disco0ered that intranasal administration o) V911((- T100 Wg %er nostrilU- %roduced a strong reduction in e/tracellular :Ac DA in wt and C"1 52o- but not in C"252o mice. ! fig b#

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Janine Gillespie Y2094142 SD805 ECA resubmit

Aigure & re%roduced )rom re).

!(1#

There was a sudden increase in e/tracellular DA in C" 2 52o mice a)ter V911(( was locally administered. The mechanism o) why this occurred is howe0er unclear- it is arguable that V911(( may bind to non D C"2 rece%tors in C"2 mice- which %roduces an increase in e/tracellular DA. Intra D :Ac %er)usion o) AF,(0 T1- 10 and 100 WFU ele0ated e/tracellular DA in a concentration D de%endent manner in both wt and C" 1 52o mice- but not in C"2 52o mice- as shown in fig. c .

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Janine Gillespie Y2094142 SD805 ECA resubmit

This led to a suggestion that the eC"s ionically modulate :Ac DA release through the acti0ation o) brain C"2+. AF,(0 enhanced e/tracellular DA a%%eared stronger in C"1 52o mice than in wt mice. !fig.c# There is arguably a higher eC" baseline acti0ity on the C"2+ in the C"1 52o mouse brain. Qocal intra D :Ac local %er)usion o) AF,(0 also bloc5ed the decrease in e/tracellular :Ac DA that V911(( had %roduced systematically in wt mice and C"1 52o mice as shown in )igures c,d abo0e. This is a suggestion there)ore that the V911(( triggered inhibition o) DA release is mediated by the :Ac C"2+- the microdialysis %robes and microinJection cannulae were seen in the :Ac as shown in the diagram below.

Aigure ' +e%roduced )rom

!(1#

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Janine Gillespie Y2094142 SD805 ECA resubmit

(.2 Alcohol

Chronic and acute e/%osure has been shown to disru%t eC" mediated syna%tic %lasticity. Qow D )re3uency stimulation in short %eriods %roduce a C" 1 D de%endent long D lasting disinhibition !DQQ# o) striatal out%ut neurons as a result o) the syna%tic strength being reduced at inhibitory neurons. =triatal slices which ha0e been acutely e/%osed to moderate alcohol doses clearly reduce the eC" D mediated DQQ in neurons in the dorsolateral striatum.
!14#

DQQ was also reduced signi)icantly in the

dorsolateral striatum o) rats that had consumed %harmacologically rele0ant amounts o) ethanol )or se0eral wee5s 0oluntarily.

(.( *%ioids

*%ioids- which are heroin and mor%hine- ha0e their mu !W# rece%tors in0ol0ed in drug addiction- with both these rece%tors and the C" 1 rece%tors being e/%ressed similarly in a 0ast number o) brain areas in0ol0ed in brain reward %rocesses.
!1#

They also

both ha0e similar signalling cascades. There is growing e0idence to suggest that there is a )unctional interaction between the eC" and o%ioid systems. 9hen each system is acti0ated- it %roduces similar beha0ioural res%onses which include locomotor inhibition or su%%ression- analgesia and reward. The eC" a%%ears to e/hibit a modulatory in)luence on a number o) o%ioid triggered %rocesses.

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Janine Gillespie Y2094142 SD805 ECA resubmit

C"1+ e))icacy is diminished in the striatum o) W D o%ioid rece%tor 52o mice- whilst sel) D administration o) heroin or re%eated administration o) mor%hine leads to increased C"1+ )unctioning in a brain reward system. Deletion o) C" 1+s increases delta !L# and 5a%%a !X# rece%tor e))icacy in caudate %utamen tissue without altering the density o) o%ioid rece%tor e/%ression.

4 Conclusion

This %articular to%ic is an onDgoing a))air- and there is more and more in)ormation )iltering through- in %articular with cocaine and the C" 2 system 2 ndocannabinoid system. *%ioids are a to%ic which is also being researched in addition to the eC" system- as many >4C+s and their or%han rece%tors are being disco0ered. Aor the bene)it o) the re0iew- this is a brie) o0er0iew o) the im%act which the eC" system has as a whole- had on neurochemical signalling. This to%ic will ha0e the %otential to be e/%lored more broadly. At this %oint in time- the e0idence %oints to the eC" system ha0ing a maJor im%act on the understanding o) the neurochemistry o) addiction and how to treat addiction disorders by %harmaceutical means.

+e)erences

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1. =errano A- 4arsons Q1. ndocannabinoid in)luence in drug rein)orcementde%endence and addictionDrelated beha0iors. 4harmacol Ther. 2011 D C 2011.1(2!(#H215D41. 2. =terling 4. AllostasisH A model o) %redicti0e regulation. 4hysiol "eha0. 2012 2012D A%rD12.10,!1#H5D15. (. Dhingra :P- Pao Y1- =terling 4- =mith +>. Contrast threshold o) a bris5Dtransient ganglion cell in 0itro. V :euro%hysiol. 200( FAY 200(.&'!5#H2(,0D'. 4. =engu%ta "- =temmler F- Qaughlin ="- :i0en V . Action %otential energy e))iciency 0aries among neuron ty%es in 0ertebrates and in0ertebrates. 4los Com%utational "iology. 2010 VSQ 2010.,!$#He1000&40D. 5. 9eibel +. =ymmor%hosis H *n )orm and )unction in sha%ing li)e. CambridgeFass.H 1ar0ard Sni0ersity 4ress. 2000. ,. "rombergDFartin =- 1i5osa5a *- :a5amura P. Coding o) tas5 reward 0alue in the dorsal ra%he nucleus. Vournal o) :euroscience. 2010 FAY 5 2010.(0!1&#H,2,2D $2. $. Cools +- :a5amura P- Daw :D. =erotonin and do%amineH Sni)ying a))ecti0eacti0ational- and decision )unctions. :euro%sycho%harmacology. 2011 VA: 2011.(,!1#H'&D11(. &. Fiya6a5i P- Fiya6a5i P9- Doya P. Acti0ation o) dorsal ra%he serotonin neurons underlies waiting )or delayed rewards. Vournal o) :euroscience. 2011 VA: 12 2011.(1!2#H4,'D$'. '. =chul5in V. The neuroendocrine regulation o) beha0ior. CambridgeH Cambridge Sni0ersity 4ress. 1'''. 10. Qo%e6DForeno VA- >on6ale6DCue0as >- Foreno >- :a0arro F. The %harmacology o) the endocannabinoid systemH Aunctional and structural interactions with other neurotransmitter systems and their re%ercussions in beha0ioral addiction. Addict "iol. 200& VS: 200&.1(!2#H1,0D&$. 11. Carlson :+. 4hysiology o) beha0ior. 10th ed. "oston- Fass. . QondonH Allyn Z "acon. 2010. 12. +ang and dale[s %harmacology. $th ed. +ang 14 and Dale FF- editors. dinburghH lse0ier Churchill Qi0ingstone. 2012. 1(. 1owlett AC- "arth A- "onner TI- Cabral >- Casellas 4- De0ane 9A- et al. International union o) %harmacology. \\RII. classi)ication o) cannabinoid rece%tors. 4harmacol +e0. 2002 VS: 2002.54!2#H1,1D202.

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14. =idh%ura :- 4arsons Q1. ndocannabinoidDmediated syna%tic %lasticity and addictionDrelated beha0ior. :euro%harmacology. 2011 D C 2011.,1!$#H10$0D&$. 15. *hnoD=hosa5u T- FaeJima T- Pano F. ndogenous cannabinoids mediate retrograde signals )rom de%olari6ed %ostsyna%tic neurons to %resyna%tic terminals. :euron. 2001 FA+ 2001.2'!(#H$2'D(&. 1,. 9ilson +I- :icoll +A. ndogenous cannabinoids mediate retrograde signalling at hi%%ocam%al syna%ses !0ol 410- %g 5&&- 2001#. :ature. 2001 VS: 21 2001.411!,&40#H'$4D. 1$. Preit6er AC- +egehr 9>. +etrograde inhibition o) %resyna%tic calcium in)lu/ by endogenous cannabinoids at e/citatory syna%ses onto %ur5inJe cells. :euron. 2001 FA+ 2001.2'!(#H$1$D2$. 1&. FaeJima T- 1ashimoto P- Yoshida T- Aiba A- Pano F. 4resyna%tic inhibition caused by retrograde signal )rom metabotro%ic glutamate to cannabinoid rece%tors. :euron. 2001 AS> 1, 2001.(1!(#H4,(D$5. 1'. Qourenco V- Cannich A- Carta F- Coussen A- Fulle C- Farsicano >. =yna%tic acti0ation o) 5ainate rece%tors gates %resyna%tic C"!1# signaling at >A"Aergic syna%ses. :at :eurosci. 2010 A " 2010.1(!2#H1'$DS&1. 20. >erdeman >- Qo0inger DF. C"1 cannabinoid rece%tor inhibits syna%tic release o) glutamate in rat dorsolateral striatum. V :euro%hysiol. 2001 VA: 2001.&5!1#H4,&D $1. 21. >erdeman >Q- +onesi V- Qo0inger DF. 4ostsyna%tic endocannabinoid release is critical to longDterm de%ression in the striatum. :at :eurosci. 2002 FAY 2002.5!5#H44,D51. 22. Preit6er AC- Falen5a +C. Do%amine modulation o) stateDde%endent endocannabinoid release and longDterm de%ression in the striatum. Vournal o) :euroscience. 2005 :*R ' 2005.25!45#H105($D45. 2(. Adermar5 Q- Qo0inger DF. Are3uencyDde%endent in0ersion o) net striatal out%ut by endocannabinoidDde%endent %lasticity at di))erent syna%tic in%uts. Vournal o) :euroscience. 200' A " 4 200'.2'!5#H1($5D&0. 24. A6ad =C- Fonory P- Farsicano >- Cra0att "A- Qut6 "- ]ieglgansberger 9- et al. Circuitry )or associati0e %lasticity in the amygdala in0ol0es endocannabinoid signaling. Vournal o) :euroscience. 2004 :*R ( 2004.24!44#H''5(D,1. 25. Pam%rath P- +omoD4arra 1- 1aering F- >aburro =- Doengi F- Qut6 "- et al. =hortDterm ada%tation o) conditioned )ear res%onses through endocannabinoid signaling in the central amygdala. :euro%sycho%harmacology. 2011 A " 2011.(,!(#H,52D,(.

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2,. Podiro0 =A- Vasiewic6 V- Amirmahani 4- 4syra5is D- "onni P- 9ehrmeister F- et al. ndogenous cannabinoids trigger the de%olari6ationDinduced su%%ression o) e/citation in the lateral amygdala. Qearning Z Femory. 2010 VA: 2010.1$!1#H&(2D&. 2$. Che0aleyre R- Castillo 4 . ndocannabinoidDmediated meta%lasticity in the hi%%ocam%us. :euron. 2004 = 4 1, 2004.4(!,#H&$1D&1. 2&. ]hu 4V- Qo0inger DF. 4ersistent syna%tic acti0ity %roduces longDlasting enhancement o) endocannabinoid modulation and alters longDterm syna%tic %lasticity. V :euro%hysiol. 200$ VS: 200$.'$!,#H4(&,D'. 2'. dwards DA- Pim V- Alger " . Fulti%le mechanisms o) endocannabinoid res%onse initiation in hi%%ocam%us. V :euro%hysiol. 200, VA: 200,.'5!1#H,$D$5. (0. Felis F- 4istis F- 4erra =- Funtoni AQ- 4illolla >- >essa >Q. ndocannabinoids mediate %resyna%tic inhibition o) glutamatergic transmission in rat 0entral tegmental area do%amine neurons through acti0ation o) C"1 rece%tors. Vournal o) :euroscience. 2004 VA: $ 2004.24!1#H5(D,2. (1. \i ]- 4eng \- Qi \- =ong +- ]hang 1- Qiu ^- et al. "rain cannabinoid C"!2# rece%tors modulate cocaine[s actions in mice. :at :eurosci. 2011 = 4 2011.14!'#H11,0DS21,.

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