What can animal studies tell us about drug addiction?

Susan Schenk

Victoria University of Wellington

School of Psychology

Weeks JR. Science, 138, 143-4 (1962) Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats.(1969)

The beginning……..

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-administrationby 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

Early studies used Weeks’ design to determine which drugs were self-administered by laboratory animals

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 anesthesiato 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 subjective-effects 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

Nutt King, Saulsbury , Blakemore (2007). Lancet 369 (9566): 1047–53.

Drugs with high abuse liability also pose the greatest risk of harm

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

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.

But…….Not everyone who uses drugs becomes addicted

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 5-HTTLPR 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 D-amphetamine.

• 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 drug-taking?

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 cocaine-the 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.

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

WHY??

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 Behav39:1632-9

• 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 self-administration (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 self-

administration 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

Oakley A, Schenk A, Ellenbroek BA Molecular Psychiatry (2013) 19, 534-535;

A genetic deletion of the Serotonin Transporter increased MDMA self-administration in rats

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 MedicineVol. 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 neutoransmitterChannelrhodopsin

•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

•Acts as the Off switchPastrana, E. (2011). Optogenetics: Controlling cell function with light. Nature Methods, 8(1), 24-25.

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