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Mechanisms of Cocaine Addiction

Mechanisms of Cocaine Addiction

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An essay for the 2011 Undergraduate Awards Competition by Carolyn Hayes. Originally submitted for Synaptic Properties at Trinity College, Dublin, with lecturer Dr.Roger Anwyl in the category of Medical Sciences
An essay for the 2011 Undergraduate Awards Competition by Carolyn Hayes. Originally submitted for Synaptic Properties at Trinity College, Dublin, with lecturer Dr.Roger Anwyl in the category of Medical Sciences

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Published by: Undergraduate Awards on Aug 29, 2012
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"Mechanisms of Cocaine Addiction"
Studies of human addicts and behavioural studies in rodent models of addiction indicate that keybehavioural abnormalities associated with drug addiction are extremely long lived. This impliestherefore, that chronic drug exposure causes stable changes in the brain at the molecular andcellular levels that are responsible for these behavioural abnormalities. Drug addiction can bedefined as the loss of control over drug use or the compulsive seeking and taking of drugs despiteadverse consequences (Nestler., 2001). Addiction dramatically alters transmission of glutamatergicsynapses resulting in addicted individuals having a narrowed focus which is directed on obtainingand using the drug. Previous studies on the mechanisms of drug addiction have converged on thehypothesis that addiction represents the pathological usurption of neural processes that normallyfunction in reward based learning (Hyman et al., 2006). Cocaine is a strong central nervous stimulantand a highly addictive drug of abuse. It is believed to work by blocking the dopamine transporter(DAT) and thereby increasing the availability of free dopamine within the brain (Volkow et al., 1997).Dopamine is an excitatory neurotransmitter at glutamatergic synapses and is produced in severalareas of the brain. All addictive drugs cause an increase in levels of dopamine in target structures of the mesocortical limbic pathway
by stimulating its release or blocking it’s reuptake
et al.,
2006). The mesocortical limbic system is the pathway in the brain involved in learning, reward,addiction and also in memory, motivation and emotion. The mesolimbic pathway is shown to beassociated with feelings of reward and desire and this pathway is heavily implicated inneurobiologicaltheories of addiction(R Anwyl). The pathway consists of the ventral tegmentum area (VTA) and the nucleus accumbens (NAc). Theventral tegmental areaconsists of dopaminergic neuronswhich respond toglutamateand are activated when stimuli indicative of a reward are present- the drug (cocaine). The ventral tegmentum supports learning and sensitizationdevelopment and releasesdopamine(DA) into theforebrain.These neurons also project and release dopamine into the nucleus accumbens. Thenucleus accumbens(NAc) consists mainly of medium-spiny projection neurons (MSNs), which areGABAneurons. The NAc is associated with acquiringand eliciting conditioned behaviours and is involved in the increased sensitivity to drugs as addictionprogresses. Virtually all drugs causing drug addiction increase the dopamine release in themesolimbic pathway in addition to their specific effects on plasticity. Synapses respond to activitydependent modifications. An increase in synaptic use stimulates long-term potentiation (LTP), whilea decrease in use stimulates long-term depression (LTD) at glutamatergic synapses, two phenomenathat are commonly thought of as cellular substrates for learning, memory, and developmentalplasticity (Malenka and Bear, 2004). Cocaine use stimulates similar changes in synaptic plasticity onthe ventral tegmental area glutamatergic synapses in the mesolimbic pathway of the brain thatresemble activity dependent long-term potentiation (LTP) in other brain regions. There are manymechanisms of addiction proposed by various studies and all centre around synaptic changes thatoccur in the mesolimbic pathway. The activation of metabotropic glutamate receptors (mGluRs)leads to LTD (mGluR-LTD) and this type of LTD in the ventral tegmental area has been shown toefficiently reverse cocaine-induced strengthening of excitatory inputs onto dopamine neurons(Mameli
et al.,
2007). Animal studies have been fundamental in asserting how this neural pathwayfunctions normally in the brain and how cocaine and other drugs of addiction alter it. To understandthe mechanisms of cocaine addiction we must first understand how long-term potentiation anddepression occur and the receptors responsible for causing these synaptic changes.
 AMPA and NMDA receptors:Both AMPA (
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) and NMDA (N-methly-D-aspartate) are ionotropic glutamate receptors composed of subunits that form a ring-like structurewith an ion-channel at the centre. AMPAR generally mediates fast excitatory transmission in thecentral nervous system (CNS) while NMDAR has a slower transmission speed due to having slowerchannel opening speed. Both ionotropic receptors are ligand gated in that they require glutamatereleased from presynaptic membranes to bind for the channel to open. AMPA receptors areencoded by four genes which generate the four subunits that make up the ion channel; GluR1,GluR2, GluR3 and GluR4. The AMPARs are oligomeric (composed of 2-5 subunits) and also known astransmembrane protein receptors. GluR1/GluR2 heteromers are the predominant subunits in thehippocampus and neocortex with only low levels of GluR3 and GluR4 (80% R1/R2, 20% R2/R3 inCA1). GluR4 is only expressed very early and is lost postnatally within four months of life. The I-Vcurve of 80% of AMPARs (R1/R2) is linear with a very low calcium conductance because of thepresence of GluR2 which prevents Ca
from entering along with an arginine residue (preventschannel block by endogenous polyamines). AMPARs lacking GluR2 are the receptors responsible forLTP and LTD. The I-V curve of AMPARS composed mainly of GluR1/GluR3 shows inward rectificationwhich is a reduced current at positive potentials and is due to endogenous polyamine block. The Ca
influx allows K
channels to open and thereby evoke a hyperpolarisation or depolarisation followingan EPSP that can also induce LTP or LTD.
Figure 1: I-V relationships between a) GluR2-containing and; b) GluR2-lacking AMPARS, R.Anwyl 2010
NMDARs are heteromers composed of 5 subunits (~10 at each syanse vs ~50 AMPAR). They differfrom AMPAR in that they are; both ligand gated and voltage dependent and are highly Ca
 permeable. The receptor is blocked by a magnesium ion (Mg
) and requires sufficient depolarisationto remove this open channel blocker to allow influx of Ca
(Em of -30mV causes Mg
to dissociate).During a single opening typical GluR2 containing AMPAR might only admit ~10 Ca
, GluR1 homomermight admit ~100 Ca
an NMDAR with it’s longer opening time and high Ca
allows entryof ~1000 calcium ions. NMDA mediates fast excitatory transmission like AMPAR but because thechannel is slow to open it can also enter a desensitised state following glutamate binding whichresults in NMDAR excitatory post synaptic potentials having a relatively slow rise time of ~10mscompared to the rapid rise time of AMPARS ~0.1ms. NMDAR block prevents some behaviouralsensitization to drugs of abuse by inhibiting some LTP.
 Metabotropic receptors-mGluRs:The mGluRs perform a variety of functions in the central and peripheral nervous systems: forexample, they are involved inlearning,memory,anxiety,and the perception of pain.Like other metabotropic receptors,mGluRs haveseven transmembrane domainsthat span the cell membrane. Unlikeionotropic receptors,metabotropic glutamate receptors are notion channels.Metabotropic glutamate receptors (mGlus) are a family of G-protein-coupled receptors that activatebiochemicalcascades,leading to the modification of other proteins, as for exampleion channels.This can lead to changes in thesynapse'sexcitability.
Thus far, molecular cloning has revealed eight members of thisfamily, termed metabotropic glutamate receptor 1 (mGluR1) to mGluR8; these have been classifiedinto three subgroups based on their sequence similarity, preferred signal transduction mechanismsand relative pharmacology (Conn and Pin 1997). Group I mGluRs includes mGluR1 and mGluR5 andare selectively activated by 3,5-dihydroxyphenylglycine (3,5-DHPG)- (Ferraguti
et al.,
2006)It is thesegroup 1 mGluRs that have been studied most by researchers and the results of previous studiessuggest that group 1 mGluRs seem to be involved in the reversal of cocaine induced effects. In aprevious study conducted by Bellone and Luscher they found that mGluRs induce LTD in the VTA thatinvolves a switch of the subunit composition of AMPA recepters (Bellone and Luscher. 2005).Synaptic Plasticity:Synaptic plastcity is the basis of many phenomena in the brain as the connectivity between neuronsis a dynamic entity that is constantly changing. It can be defined as an alteration in synaptictransmission induced by a brief period of stimulation that can result in an increase (LTP) or decrease(LTD) in synaptic strength and can be short-term, lasting a few minutes, or long-term, lasting hours,days or weeks.Both AMPAR and NMDAR function are required to induce LTP and LTD and to ensuretheir expression. Postsynaptic depolarisation alone does not induce either as pairing of both apresynaptic action potential with post synaptic depolarisation is required (R.Anwyl). LTP ishomosynaptic and is induced by high frequency stimulation at a synapse (approximately <1sec atfrequencies <20Hz aka theta bursts). High frequency stimulation results in the summation of AMPARmediated EPSPs causing a large depolarisation which results in activation of NMDAR as Mg
channelblock is removed. The activation of NMDAR allows a postsynaptic rise in Ca
to occur which isessential for LTP induction as the increase in intracellular Ca
triggers activation kinases- CaMKII.The expression of LTP is due to an increase in the number of AMPARS in the post synapticmembrane which occurs via trafficking from intracellular stores (synthesis occurs in the endoplasmicreticulum). The increased expression of AMPARs is due to NMDAR activation of protein kinases; onekinase acts on AMPAR (sodium channel) making it more sensitive to glutamate while a secondtriggers production of a paracrine that causes the presynaptic cell to release produce moreglutamate. The net effect of more glutamate acting on a more sensitive postsynaptic cell is aprolonged depolarisation resulting in LTP. LTD is the reversal of LTP and caused by low frequencystimulation of a synapse which causes a reduction in the number of AMPAR. Metabotropicglutamate-dependent LTD is dependent on activation of group 1 mGluRs and is NMDARindependent. mGluR-dependent LTD also involves kinases. Previous evidence suggests that synapticplasticity in reward circuits is hijacked by addictive drugs to produce the pathological behaviors thatcharacterize addiction (Hyman et al., 2006). Results from a study conducted by Kourrich et al.

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