Resubmission of my SD805 ECA

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Janine Gillespie Y2094142 SD805 ECA resubmit

Contents

Abstract.2

Introduction..4

1. Allostasis and drug rewards.5

1.1Allostasis.5

1.2Drug reward system10

2. The ndocannabinoid !eC"# system..1$

2.1 C"1or hC"1rece%tors1&

2.2 C"2or hC"2rece%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- howeer - the in)luence oer addiction

neurobiology and the reward system remains relatiely under

researched.

oweer- the theories surrounding the structural bodies related to the

reward systems neurochemical sensitie areas is 3uite well

understood. erha%s there was more to this mysterious system o)

rece%tors which was nown )or its e))ects on the nerous 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 taes an illicit substance8 This reiew

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%roides an engaging sna%shot o) the current neuroscience

neurochemistry associated with addiction. This reiew intends to

demonstrate that the ndocannabinoid system can and does hae a role

in the addiction reward system.

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Introduction

+ecreational drugs hae been since history began. It has been )ound that addiction

has mani)ested when the %erson deelo%s a need to search )or and administer the

drug!s#.

9hen a %erson has an addiction- they o)ten e/hibit negatie 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 hae a %articular ulnerability to days or

een years o) rela%se relatie to their drug!s# o) choice.

:euro%harmacological and neuroada%tie 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 behaes during occasional drug abuse right through

to when the addict is ;a slae to the chemical


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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 obsering

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.

*er the years- the neural mechanisms o) addiction and %ositie reward hae been

researched- which has lead to a growing interest in the endocannabinoid !eC"#

system.

This reiew will coer 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 nown as homeostasis. The diagram

below shows the mechanism o) the system- which is also nown as a negatie

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)eedbac mechanism. This indicates that the %arameter can be brought bac to the

o%timum be)ore the body sustains any damage. !2#

igure 1. taen )rom re). !12#

oweer- 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 ($C. :euronal sensitiity can be

increased a%%ro/imately two)old )or each 10 degrees- which is similar to

biochemical reaction thermal coe))icients. !(#

igher tem%eratures increases the neuronal )unctioning o) the cells as they increase

the conduction elocity- reduce the noise in a/ons !there)ore maing it easier to carry

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out electrogram testing#- the %rocess is carried out by reducing ion o%ening times-

the )inal stage hel%s ion channel inetics. unctional oerla% between the di))erent

s%ies can in turn increase the s%ie e))iciency. The oerall e))ect o) the combination

o) increased energy e))iciency- reduced noise- and increased elocity o) conduction

can be attributed to endotherm eolution. !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 wor 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 digestie ca%acity !to obtain

the increased metabolites and nutrients the body re3uires#. !2#

In reality- organs hae a mechanism which allows )or resources to be ;traded


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Fuscles store glycogen and )atty acids- but- it does not store much o/ygen- neither

can it hae a sustained su%%ly o) de o/ygenated blood as it would re3uire a su%%ly

)rom the heart and lungs. There would also be an additional re3uirement )or the

digestie system to hae an increased ca%acity )or the )unctions o) digestion-

absor%tion- e/cretion and cooling. It is notable howeer that this is a resource which

cannot be stored- so it is a Bborrowed7 resource.

As we are discussing the brain !as we are taling about how it alters in addiction#-

the body doesn7t tend to tae 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 arious lower leel %hysiological

signals- which areH

=teroidal hormones and %e%tides which are in control o) blood %ressure-

mineral and energy balance.

:eural signals )rom brainstem isceral 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- !5hydro/yam%hetamine or 5T )or short#. !,

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In the amygdala- the central nucleus is aroused by cortisol @ which is ey in the

arousal res%onse mechanism- to release an increased amount o) the hormone C+

or Corticotro%in +eleasing ormone# leels 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 (.

eading bac 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 retrieal 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/ !C# is an area which will be discussed )urther on in the reiew 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 Bstic7 area

o) antici%atory regulation o) the amygdala is o)ten the area used in moement and

danger antici%ation. The enironment !the drug addiction# inoles a )orm o)

)oraging which dictates how the organism decides on the best course o) action. In

this as%ect the midbrain reward system undertaes the B)oraging7- which is the

reward system- whilst the amygdala Bstic7 is the Bcarrot7.

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igure 2. +e%roduced )rom re). !2#

1.2 Drug +eward =ystem

As we hae seen in the %reious 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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igure (- taen )rom re). !10#

As mentioned and shown in the diagram- there are a number o) di))erent

neurotransmitters inoled in signalling. There are howeer- 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%amine-

noradrenaline and serotonin.!10#

The most nown amine associated with addiction is

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

%articular with cocaine.

The main mechanism o) drug reward system is based around the %ositie reward

and negatie reward theory o) ". . =inner. This theory shows that drug intae

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%roides a B%ositie reward7. This means that the drugs are a %ositie rein)orcer.

The drug is deemed to be a stimulus in the organism7s %leasurable a%%roach. I) this

behaiour occurs- it will be re%eated again and again when the same stimuli occurs.

As in the =inner bo/- the mechanism can be ain to the rat obtaining )ood ia the

leer- the )ood is the drug and the rat !a)ter )irst accidently bum%ing into the leer

and the receiing )ood#- learns the %rocess. It is deemed that there is a need to hae

the drug- which in turn- switches on a rein)orcement mechanism in the brain @ ;this is

a good thing to hae- I want some more< message being sent to the brain.

There is howeer- another as%ect to be taen into consideration with drugs- and that

is the %harmacoinetics o) the drug. Abused drugs such as heroin and cocaine ! as

the two %rime e/am%les#- are smoed- inhaled or gien intraenously. The

rein)orced as%ect is the action needed to tae the drug so there)ore- it is re%eated

and deemed to be the rein)orcement as%ect. It has been shown in arious tests on

animal subJects that they will 3uicly learn that %ressing a leer %roides sel)

medication with the drug o) interest through a %um% or other similar deice.

Another im%ortant as%ect o) this theory is the )li%side o) negatie rein)orcement-

which is when the stimulus concerned needs to be re%eated to sto% it- tae )or

e/am%le- when the heroin addict is su))ering withdrawal sym%toms- they want to tae

the drug to sto% them )eeling miserable. There is howeer 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 gie themseles a

higher concentration o) the drug to hae the same e))ect as be)ore.

Craing and rela%se is the ne/t to%ic )or discussion- which is a mani)estation o) the

negatie rein)orcement mechanism. "elow is a table which is the actie sites )or the

drug o) addictionH

Drug =ite o) action

thanol :FDA rece%tor !indirect antagonist#

>A"AArece%tor !indirect agonist#

*%iates !heroin- mor%hine and the semi

synthetic analogues#

Fu !K# and delta !L# o%iate rece%tor

agonist

Cocaine "locs reu%tae o) do%amine- serotonin

and nore%ine%hrine.

Also nown as a sigma !M# o%iate

rece%tor- which is a wea rece%tor

Am%hetamine +eleases do%amine which is initiated by

reerse running the do%amine rece%tors

Table 1H taen )rom and edited )rom re). !11#

As the table aboe 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 changeslu+5and QC- which- in turn relies on an

increase in %ostsyna%tic Ca2OU. It is )urther enhanced a)ter FA>Q inhibition and

attenuated a)ter DA>Q inhibition. !14#

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There is eidence that the C QTD is not being made im%ure by AA inhibition-

and these )indings strongly suggest that that 2 @ A> has a role in this %rocess. The

inhibitory %rocess within the C 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 C is triggered by do%amine D2rece%tors being actiated and is

also inde%endent o) %ostsyna%tic eleations in Ca2OU. !14#

Concerning neurotransmission in the RTA- in regard to do%amine D2rece%tors are

nown to wor 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 mediated long term

%lasticity in the striatum. !14# Actiation o) e/citatory C in%uts to RTA do%amine

cells shows 2 @ A> mediated su%%ression o) e/citation- in io- !(0# 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 hae 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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The basic mechanisms o) the brain structures and %lasticity hae been mentioned in

the section aboe and- now the )ocus is on the ( main drugs grou%s o) drugs which

are being studiedH

*%ioids

Alcohol thyl Alcohol

Cocaine

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

(.1 Cocaine

Cocaine is a drug which is largely snorted or taen intraenously. A recent study

has eidence o) brain C"2rece%tors modulating Cocaine7s actions in a rodent model.

!(1#

The e/%erimental data suggest that the selectie C"2agonist V91(( can inhibit

intraenous cocaine sel) administration. The )igure below describes the e))ects o)

V91(( or another com%ound- >9405&(( !which is another selectie C"2agonist-

the di))erence being in the chemical structure#.

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

As seen in the diagram aboe- it was discoered that systematic administration o)

V91(( !10- 20 mg %er g- intra%eritoneal#- had signi)icantly reduced the

%rogressie brea %oint )or cocaine sel) administration in wt mice !)igure b#. It is

arguable that there was a reduction in the strength o) the cocaine reward and or

need )or drug taing behaiour a)ter V91(( was administered. C"1blocade by

AF251 had considerably lowered the %rogression brea %oint ratio in rats. It was

there)ore included in this e/%eriment and it was )ound that a concentration o) (mg

%er g- it lowered the brea %oint in rats as seen in the )igure aboe. This suggests

that the data is consistent with the V91(( being able to trigger a reduction in sel)

administration o) cocaine indicating that the cocaine itsel) had a reduction in reward

e))icacy.

urther e/%erimentation was undertaen to determine whether V91(( action was

brain or %eri%heral C"2mediated. This was obtained by studying intranasal

microinJections o) the com%ound on i.. administration o) cocaine. This method was

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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 traels to the brain. !(1# The results showed that these inJections o)

concentrations o) 50 and 100 Kg %er 10Wl slide- inhibited the cocaine sel)

administration obsered- de%ending on the dose. This is illustrated by fig cas

shown aboe. The ne/t ste% in the e/%eriment was to decide whether nasal

administration o) V91(( was triggering the drug absor%tion e))ect in nasal

asculature- then going into the enous deliery o) drug to the site o) action. =o-

intraenous microinJections o) 100 and 200 Wg had no e))ect on the sel)

administration o) cocaine as shown in fig. d. This data suggests that intranasal

V91(( was triggering %harmacological e))ects which are mediated by the brain-

actiating C"2rece%tors as o%%osed to the %eri%heral C"2rece%tors.

There was a )urther e/%loration by obsering the e))ects o) the local administration o)

V91(( into the :Ac on cocaine sel) administration. It was discoered that intra

:Ac microinJections o) the V91(( com%ound- which were 0.(- 1 and ( Wg %er slide-

signi)icantly inhibited sel) administration o) cocaine in wt rats in a dose de%endent

manner- but- not in C"2 o mice- in which inhibition was bloced ia intra :Ac co @

administration o) AF,(0 at (Wg %er slideU.

V91(( %ossesses no rein)orcing or aersie e))ects and this was shown by an

e/%eriment which inoled training mice to learn the sel) administration o) cocaine

and the cocaine was then re%laced by V91(( at 1 mg %er g %er in)usionU or

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%lacebo ehicle. It was discoered that neither the agonist nor the %lacebo showed

stable cocaine sel) administration in mice which had been taught to administer the

cocaine. This is shown by fig. a- illustrated below.

igure $ re%roduced )rom re). !(1#

It was then noted that the behaiour was gradually diminishing oer 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 howeer when the V91(( or

%lacebo was switched )or cocaine- the sel) administration action returned to the

%reious leels o) sel) administration. urthermore- it was obsered that the

intra%eritoneal cocaine 10 and 20 mg %er gU had %roduced a sustained and distinct

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robust conditioning- whereas V91(( at the same doses had not %roduced %lace

%re)erence or aersion in wt mice- fig. b. The )indings a%%ear to argue that the

V91(( agonist has no cocaine lie rein)orcing behaiour or aersie e))ect in a

mouse model.

It can inhibit cocaine enhanced e/tracellular :Ac DA- demonstrated by running a

study on whether brain or %eri%heral C"2rece%tor e))ects were noted. This was

done by obsering the e))ects o) intranasal or intra :Ac local administration o)

V91(( on e/tracellular DA. It was discoered that intranasal administration o)

V91((- 100 Wg %er nostrilU- %roduced a strong reduction in e/tracellular :Ac DA in

wt and C"1o- but not in C"2o mice. ! fig b#

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igure & re%roduced )rom re). !(1#

There was a sudden increase in e/tracellular DA in C"2o mice a)ter V91(( was

locally administered. The mechanism o) why this occurred is howeer unclear- it is

arguable that V91(( may bind to non C"2rece%tors in C"2mice- which %roduces

an increase in e/tracellular DA. Intra :Ac %er)usion o) AF,(0 1- 10 and 100 WFU

eleated e/tracellular DA in a concentration de%endent manner in both wt and C" 1

o mice- but not in C"2o mice- as shown in fig. c .

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This led to a suggestion that the eC"s ionically modulate :Ac DA release through

the actiation o) brain C"2+. AF,(0 enhanced e/tracellular DA a%%eared stronger

in C"1o mice than in wt mice. !fig.c# There is arguably a higher eC" baseline

actiity on the C"2+ in the C"1o mouse brain. Qocal intra :Ac local %er)usion o)

AF,(0 also bloced the decrease in e/tracellular :Ac DA that V91(( had

%roduced systematically in wt mice and C"1o mice as shown in )igures c,daboe.

This is a suggestion there)ore that the V91(( 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.

igure ' +e%roduced )rom !(1#

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(.2 Alcohol

Chronic and acute e/%osure has been shown to disru%t eC" mediated syna%tic

%lasticity. Qow )re3uency stimulation in short %eriods %roduce a C"1 de%endent

long lasting disinhibition !DQQ# o) striatal out%ut neurons as a result o) the syna%tic

strength being reduced at inhibitory neurons. =triatal slices which hae been acutely

e/%osed to moderate alcohol doses clearly reduce the eC" 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 releant amounts

o) ethanol )or seeral wees oluntarily.

(.( *%ioids

*%ioids- which are heroin and mor%hine- hae their mu !W# rece%tors inoled in drug

addiction- with both these rece%tors and the C"1rece%tors being e/%ressed similarly

in a ast number o) brain areas inoled in brain reward %rocesses. !1# They also

both hae similar signalling cascades. There is growing eidence to suggest that

there is a )unctional interaction between the eC" and o%ioid systems. 9hen each

system is actiated- it %roduces similar behaioural 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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C"1+ e))icacy is diminished in the striatum o) W o%ioid rece%tor o mice- whilst sel)

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 a%%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 ongoing a))air- and there is more and more in)ormation

)iltering through- in %articular with cocaine and the C"2system ndocannabinoid

system. *%ioids are a to%ic which is also being researched in addition to the eC"

system- as many >C+s and their or%han rece%tors are being discoered. or the

bene)it o) the reiew- this is a brie) oeriew o) the im%act which the eC" system has

as a whole- had on neurochemical signalling. This to%ic will hae the %otential to be

e/%lored more broadly. At this %oint in time- the eidence %oints to the eC" system

haing 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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Resubmission of my SD805 ECA

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