introduction
Mesolimbic and mesocortical systems are involved
with reward, planning and salience attribution.
This research demonstrates different activity levels
between controls and detoxified alcoholics in PFC
control, striatal DA activity and subjective pleasure
when challenged with the DAT blocker MP.
This research demonstrates a correlation between
prefrontal regulation of dopaminergic reward circuits
in controls but not alcoholics.
Subjective pleasure for drug liking and high in
alcoholics are substantially reduced
Mesolimbic circuits adapt to long term addiction
including alcoholism.
This research demonstrates profound reductions in DA
receptor availability in detoxified alcoholics.
Addiction theory
• Natural reinforcement:
• Reward for natural reinforcers such as food and water are mediated
through the mesolimbic system.
• Many addictive drugs including alcohol use the same reward system1
• DA changes in VS are correlated with insula metabolism. Insula region
associated with densest DA innervation7 and addiction
• Tolerance:
• Profound reductions in DA activity in VTA is observed on withdrawal from
addictive drugs including chronic alcohol abuse10
• Addiction reduces availability of DA receptors in VS10. Baseline striatal DA
receptor availability associated with PFC metabolism in drug abuse8a,8b.
Genetic risks8c
• Craving:
• Reduced receptors in VS associated with increased craving and greater
incentive attribution and activation of medial PFC and CG11.
• Pleasure vs. reward
• Disruption to OFC, involved in salience attribution11 and/or the CG,
involved with inhibitory control6 considered central to addiction
• The PFC is associated in attribution salience and the addiction process
schematic
INCENTIVE
SALIENCE
PFC/OFC
DA
Loss of
control in
addicts
glut
Striatum
Ventral
striatum
NAc
DA
VTA
reward
Putamen
Caudate
Less DA IN
ADDICTS
method
• Methylphenidate (MP) challenge
• Subjective behavioural effects
• PET: Glucose metabolism in PFC
• (ROI’s OFC, CG, DLPFC)
• PET: Dopamine release in Striatum
• (ROI’s CDT, PUT, VS)
• 20 controls & 20 detoxified alcoholics
• Single blind crossover design
results
D2/D3 receptor
availability in VS
Regression OFC:DA
addictso controls•
7
Subjective liking
and high
6
3.5
5
3
2.5
4
2
3
1.5
addicts
1
control
s
addicts
2
1
0.5
0
PL
MP
0
0
2
4
6
discussion
• Experimental hypotheses: in alcoholics - decreased DA activity;
disrupted regulation of PFC; less subjective pleasure.
• Results show:
• In controls OFC activity negatively correlated with MP induced DA
changes in NAc is consistent3,4 with OFC regulation of NAc via VTA
glutamatergic efferents5
• In alcoholics vs. controls decreased DA release in VS consistent
with other drugs of abuse10
• In alcoholics reduced subjective reward as measured by drug
high(-70%) and liking(-50%) is consistent with drug tolerance
• In alcoholics lower baseline receptor availability is consistent with
adaptive changes to drugs of abuse and to genetic risk factors2,8
• In alcoholics lower receptor availability is associated with activity
in PFC (CG, DLPFC) consistent with other drugs of abuse
Conclusions
• Loss of OFC modulation in mesolimbic systems of
alcoholics and reduced DA increases in VS
consistent with reduced reward systems activation
• Reduced DA cell activity in reward systems
consistent with reduced subjective pleasure in
alcoholics
• Reduced rewards and pleasure could lead to
increased alcohol consumption
• Therapy should address both the profound
reduction in DA activity and loss of PFC modulation
• Exploratory confirmation of correlation between DA
changes in VS and insula metabolism
Future directions: complex theory
Integrated systems
To be integrated
•DA/NAc reward, +ve reinforcement
system1
•Adaptive changes to DA circuits in
addiction2,10
•DA decreases in striatum for
addicts(cocaine, alcohol) 10
•PFC loss of control of VTA in addiction3
•(PFC hypoactive in cocaine addicts9)
•(Genetic factors associated with reduced
DA receptor activity8c)
• Opiods needed for
reinforcement, opiate
receptors sufficient14
• PFC-grey reduction of 10% in
alcoholics12
• Psychosocial stress associated
with D2 reduced receptor
activity and predilection for
addiction13
• Incentive salience11
References
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Student: B0239046 John P Jeffrey
1 Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytia P, Merlo-Pich E, Weiss F (1998) Neurocircuitry targets in ethanol reward and
dependence. Alcohol Clin. Exp Res 22:3–9.
2a) Robbins TW, Everitt BJ (2002) Limbic-striatal memory systems and drug addiction. Neurobiol Learn Mem 78:625– 636.
2b )Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47 [Suppl 1]:24 –32.
3a) White FJ, Hu XT, Zhang XF, Wolf ME (1995) Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in
the mesoaccumbens dopamine system. J Pharmacol Exp Ther 273:445– 454.
3b) Kalivas PW (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4:23–29.
4a) Gariano RF, Groves PM (1988) Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anterior
cingulate cortices. Brain Res 462:194 –198.
4b) Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH (1993) Prefrontal cortex regulates burst firing and transmitter release in rat
mesolimbic dopamine neurons studied in vivo. Neurosci Lett 157:53–56
5 Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413.
6 Volkow ND, Fowler JS, Wang GJ (2003) The addicted human brain: insights from imaging studies. J Clin Invest 111:1444 –1451
7 Gaspar P, Berger B, Febvret A, Vigny A, Henry JP (1989) Catecholamine innervation of the human cerebral cortex as revealed by comparative
immunohistochemistry of tyrosine hydroxylase and dopamine-betahydroxylase. J Comp Neurol 279:249 –271.
8a) Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP (1993b) Decreased dopamine D2 receptor availability is
associated with reduced frontal metabolism in cocaine abusers. Synapse 14:169 –177.
8b) Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, Gifford A, Wong C, Pappas N (2001)
Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J
Psychiatry 158:2015–2021.
8c) Volkow ND, Wang G-J, Begleiter H, Porjesz B, Fowler JS, Telang F, Wong C, Ma Y, Logan J, Goldstein R, Alexoff D, Thanos PK (2006) High levels
of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch Gen Psychiatry 63:999 –1008.
9 Volkow et al.,(1992) cited by Carlson pp. 620
10 Volkow et al.,(2001) cited by Carlson pp.628
11 Heinz A, Siessmeier T, Wrase J, Hermann D, Klein S, Grusser SM, Flor H, raus DF, Buchholz HG, Grunder G et al (2004) Correlation between
dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatry 161:1783–1789.
12 Mathalon et al.,(2003) cited by Carlson pp.621
13 Morgan et al.,(2002) cited by Carlson pp.622
14 Carlson “effects of naloxone” pp.626: Carlson, N. R., (2007), ‘Physiology of Behaviour’, 9th Edition’, Pearson International, USA
Reduced reward in detoxified alcoholics
Loss of control by prefrontal cortex