andrew j lawrence - ranzcp.org · drug use is protracted ˝many aging baby boomers &will carry...
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Preclinical assessment ofpotential therapeutic targets
for alcohol & drug abuse
Andrew J Lawrence
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Drug Use Is Prevalent
• Alcohol & Tobacco use (ONS, UK):• more 13-year-olds have drunk alcohol than notthat’s 350,000 13-year-old drinkers in England and Wales alone
• 55% in England 16+ smoked daily, or ex-regular smoker (2001-02)
• Illicit drug use (AIHW):• cannabis: 34% aged 14+ have used in lifetime• opioids (inc. heroin): 2.3%, or 384,800 people• amphetamines: 9.1% (or, 1 in 5 of those aged 20-29)
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Drug Use Is Protracted“many aging baby
boomers…will carrytheir love affair withdrugs into old age”
SciAm, May 08
estimates those aged 50+seeking drug abuse help willrise from 1.7m in 2000/01 to4.4m by 2020
Seattle Hempfest
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Components of the Addicted HumanState
• Relapse – inability to cease drug taking• Underscored by:
– persistent neuroplasticity in motivationalcircuitry
– incubation of craving (drug ‘wanting’) duringabstinence
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Grüsser et al., 2004
Cue-induced activation in theanterior cingulate (BA32) and medialprefrontal cortex (BA10)
Cue-induced activation of the putamen
Imaging substrates for relapse propensity
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Operant responding in rats
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Extinction Reinstatement
Leve
r Pr
esse
s
Cue, stress, prime
Note in the case ofpriming there iscrossover betweenthe ability of one drugto precipitate respondingfor another. In this case,nicotine priming isreinstating extinguishedresponding foralcohol
Le et al., 2003
Cross-sensitization?
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Circuitry Model of Drug-seeking
Kalivas & Volkow 2005
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Kasanetz et al 2010
In rats, cocaine self-administration leads to deficits in NMDA receptor-mediatedcorticoaccumbal LTD.
This recovers in addiction resistant rats, but remains impaired in addictionvulnerable rats.
Suggests transition to addiction related to persistent corticostriatal dysfunction.
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After withdrawal from chronic cocaine administration: GLT1 synaptic GLU & CYS-GLU exchange extrasynaptic GLU.In the postsynaptic neuron, filamentous (F) actin, AMPA receptors and PSD95
During relapse: Release & GLT1 synaptic GLUAMPA receptors & size of spine head
Drug-induced alterations in glutamatergic signalling to basal ganglia
Kalivas 09
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Restoration of Glutamate homeostasis by N-acetylcysteine
Kalivas 09
NAC is deacetylated after administration and dimerizes to cystine, which is transportedinto cells by cystine–glutamate exchange (xc-). Restoration of tone might re-establishthe homeostatic influence of mGluR2/3 on synaptic glutamate release and mGluR5 onsynaptic grading. It is possible that some of the benefits of NAC in treating addictionmight be related to elevating glutathione (balancing redox potential of cells)
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“For the 16 subjects who completed the study, 9 subjects terminated use ofcocaine completely during the medication phase, 5 subjects substantiallydecreased their use, and 2 demonstrated no change in cocaine use.”
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Kalivas 2009
Circuitry for dysregulation of reward-seeking / goal directed behaviour
In the addicted state it is proposedthat the PFC regulation of accumbaloutlfow is diminished
Note differential role of prelimbicvs infralimbic cortex in relapse
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Layer V cells in prelimbic cortex express Orexin1 receptors that arepostsynaptic to OxA input
Li B et al. Cereb. Cortex 2010
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SB334867 Prevents cue-induced reinstatement
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Dayas et al 2007
Orexin-containing neurons are activated duringcue-induced reinstatement to alcohol-seeking
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Leve
r pre
sses
extinction reinstatement
extinction reinstatementabstinence
Will animals reinstate drug-seeking followingextinction & protracted abstinence?
(i) Early reinstatement straight after extinction(ii) Late reinstatement, 5 months withdrawal after extinction
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Active lever Inactive lever
Yes, they do & orexin1 receptorsimplicated at both time points
British Journal of Pharmacology(2011) 162: 880–889
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% change in Fos positive cells due to the effect of protractedabstinence or SB-334867 treatment
Effect of Protracted Abstinence Effect of SB-334867 Treatment
Vehicle Immediate Delayed
PrL +75%* -42%* -26%*
IL +90%* -7% -22%
Piriform +54%* -29% -30%*
OFC +38%* -47%* -34%*
NAc Core +18% -48%* -5%
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Identification of putative loci for orexin1 receptor antagonism to regulatealcohol-seeking
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Prefrontal Cortex in Addiction
• Cortico-accumbal EPSCs are modified following cocainesensitization
• PFC inactivation prevents reinstatement of drug-seeking
• Persistent deficits in corticostriatal LTD in “addicted” rats
• Ascending peptidergic inputs onto PFC may play a role in theintegration of the salience of drug-related cues
Thomas et al 2001
Kalivas & Volkow 2005
Kasanetz et al 2010
Jupp et al 2010
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Acknowledgements
• Bianca Jupp• Elena Krstew• Gabi Dezsi• NHMRC
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Identification of putative loci for orexin1 receptor antagonism to regulatealcohol-seeking