Conditioned place preference (CPP) paradigm 성균관약대장춘곤 2010. 09. 07
Drugs of Abuse Dependence ( 의존성 ) Psychological dependence is the compulsion to repeatedly take a drug for personal satisfaction. - craving, drug-seeking behavior - experimental method: conditioned place preference, self- administration Physical dependence is present when withdrawal of the drug produces symptoms and signs that are frequently the opposite of those sought by the user - withdrawal syndrome Tolerance ( 내성 ) Metabolic Tolerance Behavioral Tolerance- compensatory changes for the drug s effects Functional Tolerance- compensatory changes in receptors Reward ( 보상 ) Reinforcement ( 강화 ) Addiction ( 중독 )
Stages of addiction to drugs of abuse Acute Reinforcement / Social Drug-Taking Escalating / Compulsive Use Binge Drinking Genetic variables Environmental factors Stress Conditioning effects Dependence Withdrawal Relapse Protracted Withdrawal Recovery?
Integrative model of brain and behavior of drugs of abuse Drug Reinforcement (Salience Attribution) Reward circuits (ventral tegmental area, nucleus accumbens) Reward circuits (anterior cingulate, prefrontal cortex) Withdrawal ADDICTION Memory (hippocampus) Conditioned response (amygdala) Binging (Loss of Control) Reward circuits (ventral tegmental area, nucleus accumbens) Top-down control (frontal cortex) Craving (Drug Expectation) (cingulate gyrus, prefrontal cortex, orbitofrontal cortex)
Stages of impulse control disorder and compulsive disorder cycles
Introduction 1 The conditioned place preference (CPP) paradigm is a standard preclinical behavioral model used to study the rewarding and aversive effects of drugs. Although a number of different designs and apparatuses are used in this model, the basic characteristics of this task involve the association of a particular environment with drug treatment, followed by the association of a different environment with the absence of the drug (i.e., the drug s vehicle).
Introduction 2 A conditioned place preference (CPP) : The animals spend significantly more time in the drug-paired compartment versus the vehicle-paired compartment. Ex) Drugs of abuse, such as cocaine conditioned place aversion (CPA) : The animals spend significantly more time in the vehicle-paired compartment versus the drug-paired compartment Ex)Drugs elicit aversive effects, such as lithium chloride The behavioral effects of drugs used in the CPP paradigm depend on species, strain, route of administration, time interval of drug administration, dose concentration, and the CPP apparatus used. Many drugs of abuse produce both CPP and CPA, depending on the dose administered.
Introduction 3 Because the CPP paradigm generally provides a reliable indicator for studying the rewarding effects of drugs that require relatively little training compared to self-administration paradigm, the CPP paradigm has been commonly used in conjunction with standard neuroscience techniques to elucidate the subjective effects of drugs
Common Neuroscience Techniques Used in CPP Technique Example References Lesioning - Spyraki C, Fibiger HC, Phillips AG. Cocaine-induced place preference conditioning: Lack of effects of neuroleptics and 6-hydroxydopamine lesions. Brain Res. 1982; 253: 195 203. Knockout mice - Marquez P, Baliram R, Kieffer BL, Lutfy K. The mu opioid receptor is involved in buprenorphineinduced locomotor stimulation and conditioned place preference. Neuropharmacology. 2007; 52: 1336 1341. Microdialysis - Duvauchelle CL, Ikegami A, Asami S, Robens J, Kressin K, Castaneda E. Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration. Brain Res. 2000; 862: 49 58. Microinfusion - van der Kooy D, Mucha RF, O Shaughnessy M, Bucenieks P. Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference. Brain Res. 1982; 243: 107 117. Neurotransmitter depletion - Ventura R, Cabib S, Alcaro A, Orsini C, Puglisi-Allegra S. Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J Neurosci. 2003; 23: 1879 1885. Strain comparisons - Philibin SD, Vann RE, Varvel SA. et al. Differential behavioral responses to nicotine in Lewis and Fischer-344 rats. Pharmacol Biochem Behav. 2005; 80: 87 92.
Research Design and Methodological considerations
CPP Box 1 SPATIAL PLACE PREFERENCE BOX from Panlab Harvard apparatus
CPP Box 2 Standard two- (left) and three-chamber (right) shuttle boxes used to stud conditioned place preference in rodents. From Med-Associates, Inc.,
Conditioned Place Preference (CPP) Paradigm PRE-TESTING PHASE DAY 1 Pre-exposure DAY 2 Pre-test (baseline) (Drug free) CONDITIONING PHASE DAYS 3, 5, 7, 9 Drug injection DAYS 4, 6, 8, 10 Saline injection TESTING PHASE DAY 11 Test (Drug free)
CPP Method 1
CPP Method 2 Date Period Drug Time Remark Day 1 Pre conditioning Nothing 15 min Free assess all boxes Day 2 Pre testing Nothing 15 min Measure the amount of time spent in each chamber (Baseline) Day 3 A group : Drug treat ment 30 min White compartment Day 4 B group: Saline 30 min Black compartment Day 5 B group: Drug treat ment 30 min White compartment Day 6 A group: Saline 30 min Black compartment Conditioning A group: Drug treat Day 7 30 min White compartment ment Day 8 B group: Saline 30 min Black compartment Day 9 B group: Drug treat ment 30 min White compartment Day 10 A group: Saline 30 min Black compartment Measure the amount of
Drug studies using the CPP Paradigm Psychostimulants and opiates reliably produce a CPP - Cocaine, Amphetamine, Nicotine - Morphine, Heroin, Buprenorphine, - CNS depressants Ethanol, diazepam - Cannabinoid receptor agonist delta-9- tetrahydrocannabinal (THC) - Adrenoceptor agonist clonidine. Many of these compounds also produce CPA, depending on the dose administered. -Nicotine produces CPP in rats that are administered doses between 0.4 and 0.8 mg/kg., whereas higher doses are reported to produce CPA. Similar findings have been shown with other drugs, such as morphine and the psychostimulant apomorphine.
In situ hybridization images of NMDAR subunit mrna NR1 NR2A NR2B NR2C
Morphine Conditioned Place Preference 250 Place preference (sec) 200 150 100 50 0 ** # -50 SAL MK 0.1 SAL MK 0.05 MK 0.1 SAL Morphine 5
Cocaine Conditioned Place Preference 300 250 ** Place preference (sec) 200 150 100 50 0 # -50 SAL MK 0.1 SAL MK 0.05 MK 0.1 SAL Cocaine 15
Methamphetamine Conditioned Place Preference Place preference (sec) 300 250 200 150 100 50 0 ** # -50 SAL MK 0.1 SAL MK 0.05 MK 0.1 SAL Methamphetamine 2
Comparison of CPP and Self-Administration
Summary The CPP paradigm is a useful tool for studying the affective properties of drugs, and is routinely used in concert with standard research techniques in neuroscience. Most drugs of abuse elicit a CPP in rats and mice, and the neural substrates of these effects can often be traced to the mesolimbic DA system. Alternative models for assessing the rewarding effects of drugs (e.g., self-administration) do not always produce similar results, and therefore, researchers should be careful when evaluating results based on the behavioral model they are using in their study