Download What can animal studies tell us about drug addiction?

What can animal studies tell
us about drug addiction?
Susan Schenk
Victoria University of Wellington
School of Psychology
The beginning……..
Weeks JR. Science, 138, 143-4 (1962) Experimental morphine addiction: method for automatic intravenous
injections in unrestrained rats.
(1969)
Early studies used Weeks’ design to determine
which drugs were self-administered by laboratory
animals
Thompson T, Schuster CR Psychopharmacologia 5, 87-94 (1964) Morphine Self-Administration,
Food-reinforced, and Avoidance Behaviors in Rhesus Monkeys
Deneau G, Yanagita T, Seevers M. H. lPsychopharmacologia 16, 30-48 (1969) Self-Administration
of Psychoactive Substances by the Monkey A Measure of Psychological Dependence
Schuster, CR, Thompson T Annu. Rev. Pharmacol. 9:483-502 (1969) Self administration of and
behavioral dependence on drugs
Spealman RD, Goldberg SR Ann. Rev. Pharmacol. Toxicol. 18:313-39 (1978) Drug self-administration
by laboratory animals: control by schedules of reinforcement
Collins RJ, Weeks JR, Cooper MM, Good PI, Russell, RR Psychopharmacology, 82, 6-13 (1983)
Prediction of abuse liability of drugs using IV self-administration by rat
Main take-home messages from the early
studies
• All drugs that are abused by humans are self-administered by
laboratory animals (some examples)
• Opiates-morphine, heroin, methadone, meperidine, codeine, pentazocine
• Stimulants- amphetamine, methamphetamine, cocaine, MDMA, nicotine.
methylphenidate
• Cannabinoids- THC, CB1 agonists
• Alcohol
• Sedative hypnotics-barbital, phenobarbital, pentobarbital, diazepam,
chlordiazepoxide
Yanagita T UNODC 1973
What about the new so-called designer
drugs?
• Designer drugs are produced in laboratories, the majority resembling
drugs legally restricted for distribution and possession. They share
one common trait, producing psychoactive effects that can range
from cannabis-like, psychomotor stimulation, dissociative anesthesia
to hallucinogenic.
• Examples include mephedrone, methylone, MDPV, ethylphenidate,
synthetic cannabinoids, 2,5-dimethoxy-4-(n)-propylphenethylamine
(2C-P), N-adamantyl-1-pentylindole-3-carboxamide (2NE1),
methiopropamine, and methoxetamine.
• ALL ARE SELF-ADMNISTERED BY LABORATORY ANIMALS
FDA Assessment of Abuse Potential of drugs:
Guidance for Industry
• “Self-administration tests assess the rewarding properties of a drug.
If animals actively work at a behavioral task to receive a dose of the
drug, it is likely that the drug will be rewarding in humans.”
• “When comparing findings from rat self-administration studies
independently with each clinical indicator of abuse liability, findings
from rat studies were concordant with reports of positive subjectiveeffects in 41 of 54 (75.9%) drug cases and were concordant with
drug scheduling status in 49 of 70 (70%) cases.“ (O’Connor et al.,
Neurosci Biobehav Rev (2011) 35:912-938
So, one thing that animal studies can tell us is
whether drugs have abuse liability
• Important consideration when scheduling new drugs that come onto
the market
• Important consideration when deciding whether drugs pose a
minimal risk of harm
Drugs with high abuse liability also pose the
greatest risk of harm
Nutt King, Saulsbury , Blakemore (2007). Lancet 369 (9566):
1047–53.
How prevalent is drug addiction?
• We have a lot of information on drug use but what about problem
drug use consistent with a substance use disorder?
Data from USA: National Survey on drug use and
health- Drug dependence is a real problem
https://www.drugabuse.gov/publications/drugfacts/nationwide-trends
But…….Not everyone who uses drugs
becomes addicted
Substance Abuse and Mental Health Services Administration,
Office of Applied Studies. (March 27, 2008). The NSDUH
Report: Substance Use and Dependence Following Initiation of
Alcohol or Illicit Drug Use. Rockville, MD.
Is the variability in response to drugs of abuse
related to environmental factors?
Human studies suggest that it is
• Kendler KS et al., Am J Psychiatry 160 (2003):687–695 Specificity of Genetic and Environmental Risk Factors for Use and
Abuse/Dependence of Cannabis, Cocaine, Hallucinogens, Sedatives, Stimulants, and Opiates in Male Twins
• Cadoret RJ et al., Arch Gen Psychiat 43 (1986) 1131-1136. An Adoption Study of Genetic and Environmental Factors in
Drug Abuse
• Lambert NM In Jensen, P . S. & Cooper, J . R. (Eds.). (2002). Attention Deficit Hyperactivity Disorder: State of the Science
; Best Practices . (pp 18-1 to 18-24) Kingston, NJ : Civic Research Institute. Stimulant Treatment as a Risk Factor for
Nicotine Use and Substance Abuse
• Schenk S. in Kandel DB Stages and pathways of drug involvement: Examining the gateway Hypothesis. Sensitization as a
process underlying the progression of drug use via gateway drugs 318-337
Is the variability in response to drugs of abuse
related to genetic factors?
Human studies suggest that it is:
• Plawecki MH et al., Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1:E152-60. Voluntary intravenous self-administration of alcohol
detects an interaction between GABAergic manipulation and GABRG1 polymorphism genotype: a pilot study.
• Pascale et al., Alcohol Alcohol 50 (2015) 259-265 Alcohol dependence and serotonin transporter functional polymorphisms 5HTTLPR and rs25531 in an Italian population.
• Odgerel Z et al., Transl Psychiatr 3(2013) e307 Genotyping serotonin transporter polymorphisms 5-HTTLPR and rs25531 in
European- and African-American subjects from the National Institute of Mental Health's Collaborative Center for Genomic Studies.
• Yang Z et al., Drug Alc Dep 129 (2013) Serotonin transporter and receptor genes significantly impact nicotine dependence through
genetic interactions in both European American and African American smokers.
• London ED et al., Psychiatr Res 174 (2009) 163-170 Effect of the TaqIA polymorphism on ethanol response in the brain.
• Dlugos AM et al., Psychopharmacol 206 (2009) 501-11 Further evidence of association between amphetamine response and
SLC6A2 gene variants.
• Dlugos AM et al., Biol Psychiatr 61 (2007) 1296-305 Norepinephrine transporter gene variation modulates acute response to Damphetamine.
• Lott DC et al., Am J Addict 15 (2006) 327-35 Serotonin transporter genotype and acute subjective response to amphetamine.
What can animal studies tell us about the why
some subjects become addicted and others
appear resistant? Is there a way to alter the
sensitivity to understand environmental and
genetic factors that might impact drugtaking?
Studies from my laboratory have shown that
sensitivity can be increased by certain treatments
• Rats preexposed to nicotine, caffeine, amphetamine,
methylphenidate (Ritalin) all more readily self-administered cocainethe variability in cocaine self-administered was decreased by prior
exposure to other drugs
•
Horger BA et al., Neuroreport. 2(1991):53-6 Caffeine exposure sensitizes rats to the reinforcing effects of cocaine.
•
Schenk S, Izenwasser Pharmacol Biochem Behav 72(2002):651-7. Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine.
•
Horger BA et al., Psychopharm 107(1992):271-6 Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine.
Are these findings relevant to humans?
• Yes!
• Adults who were treated with Ritalin as children were more likely to
abuse cocaine even when a large number of potential confounds
were considered
• Lambert NM, McLeod M, Schenk S. Addiction. 2006 May;101(5):713-25. Subjective responses to initial experience with cocaine: an
exploration of the incentive-sensitization theory of drug abuse.
WHY??
Animal studies can help us to understand why sensitivity to drugs
is altered by preexposure by looking at brain changes that occur
and that can explain the enhanced sensitivity to the positive
reinforcing effects of cocaine
Other questions of interest: Do certain traits
predispose to drug addiction? Impulsivity?
• http://www.impulsivity.org
International Society for Research on Impulsivity
• Barratt Impulsiveness Scale
• BIS11 Translations
• Balloon Analogue Risk Task
• Cued Go No-Go
• Immediate and Delayed Memory Tasks
• Drug addicts are impulsive as indicated by all of these tasks
• Perry, JL and Carroll ME The role of impulsive behavior in drug abuse. Psychopharmacology 2008 Sep;200(1):1-26
But….were they more impulsive to start with or
did drug use make them impulsive----chicken and
egg question
• Grant JE, Chamberlain SR (2014) Impulsive action and impulsive choice across
substance and behavioral addictions: cause or consequence? Addict Behav
39:1632-9
• Studies in Laboratory animals can help to answer this question
Peters et al., TIPS (2013) 20334: 689-95
First, measured impulsivity using 2
different tasks (5-CSRRT and
delayed reward task)
Do a median split to determine high
and low impulsive animals
Measure time to extinction
following acquisition of cocaine selfadministration (a measure of
strength of addiction)
Impulsivity determines extinction of
responding- High impulsive rats
tend to be resistant to extinction of
drug-taking behavioiur
Impulsivity was a good predictor of drug-seeking
following abstinence from MDMA selfadministration in a model of relapse
Bird J, Schenk S. (2013) Addict Biol.
18:654-64.
Is the variability in response to drugs of abuse
related to genetic factors?
Studies in laboratory animals suggest that the answer is “yes” and help to identify specific genetic components:
• Hanrahan JR et al., PLoS One. 9(2014):e85525 GABAA receptors containing ρ1 subunits contribute to in vivo effects of
ethanol in mice.
• Thoimsen M et al., J Neurosci 29 (2009) 1087-92 Dramatically decreased cocaine self-administration in dopamine but not
serotonin transporter knock-out mice.
• Rocha B Eur J Pharmacol 479 (2003) 107-15 Stimulant and reinforcing effects of cocaine in monoamine transporter
knockout mice.
• Caine SB et al., J Neurosci 27 (2007) 13140-50 Lack of self-administration of cocaine in dopamine D1 receptor knock-out
mice.
• Kovacs KM et al./ Alcohol Clin Exp Res 29 (2005) 730-8 Decreased oral self-administration of alcohol in kappa-opioid
receptor knock-out mice.
• And many, many more using knock-out or knock down technologies that interfere with the expression of a specific receptor
gene
A genetic deletion of the Serotonin Transporter
increased MDMA self-administration in rats
Oakley A, Schenk A, Ellenbroek BA Molecular Psychiatry (2013) 19, 534-535;
More information that is available from
animal studies
• Animal studies allow us to determine how the brain has changed as a
result of repeated exposure to drugs of abuse
Drug addiction proceeds as a result of
neuroadaptations resulting from repeated drug
exposure
• Where in the brain?
• What changes?
• Animal studies are well-suited to answer these questions
The mesocorticolimbic dopamine system as target
of addictive drugs
Simple version
More complicated version
Molecular Biology has provided techniques to
study changes in intracellular signalling that occur
with repeated exposure to drugs (eg morphine)
Chao J,. Nestler EJ (2004) Annual Review of Medicine
Vol. 55: 113-132
And new techniques are increasing our ability to
understand relevant changes in brain that occur as
a function of repeated exposure to drugs of abuse
• Optogenetics allows selective activation or inactivation of brain cells
that use a specific neutoransmitter
Channelrhodopsin
•Cation channel
•Activated by blue light (470nm)
•Allows Na+ influx across the membrane and depolarizes the neuron, thus activating it
•Acts as the on switch
Halorhodopsin
Chloride pump
•Activated by yellow light (580 nm)
•Triggers influx of Cl- which hyperpolarizes the cell and inhibits the neuron
Pastrana, E. (2011). Optogenetics: Controlling cell function
with light. Nature Methods, 8(1), 24-25.
•Acts as the Off switch
Holmes D Nature 2015 522:S63
Optogenetics is gaining momentum as a tool to
understand the neurobiology of drug abuse and is
paving the road to novel treatments
• Larson EB et al., (2015) Optogenetic stimulation of accumbens shell
or shell projections to lateral hypothalamus produce differential
effects on the motivation for cocaine. J Neurosci 35:3537-43
• Creed M et al. (2015) Addiction therapy. Refining deep brain
stimulation to emulate optogenetic treatment of synaptic
pathology. Science 347: 659-64
• Luscher C et al., (2015) Optogenetic dissection of neural circuitry:
from synaptic causalities to blue prints for novel treatments of
behavioral diseases. Curr Opin Neurobiol 35:95-100
Summary and Conclusions
• Studies in laboratory animals provide an indication of abuse potential
of drugs
• Studies in laboratory animals allow us to experimentally manipulate
environmental and genetic variables to determine the role of these
variables in the acquisition and maintenance of drug taking
• Animal studies allow us to assess the role of specific prexisting traits
in drug-taking and to determine effects of drug exposure on the
expression of specific traits
• Studies in laboratory animals provide us with the tools to determine
and to manipulate brain mechanisms that are relevant to the
development and maintenance of drug taking