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Behavioural Pharmacology of Novel Kappa Opioid Compounds

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Behavioural Pharmacology of Novel Kappa Opioid Compounds Behavioural Pharmacology Of Novel Kappa Opioid Compounds By Aashish Sultan Morani A thesis to be submitted to Victoria University of Wellington in fulfilment of the requirements for the degree of Doctor of Philosophy Victoria University of Wellington 2011 CONTENTS Contents ................................................................................................................ 1 Abstract ................................................................................................................. 4 Acknowledgements ............................................................................................... 6 List of figures ....................................................................................................... 8 List of tables ......................................................................................................... 9 List of abbreviations ............................................................................................. 10 Chapter 1.General Introduction .......................................................................... 11 1.1. Current pharmacotherapies for addiction ........................................................ 15 1.2. The addiction cycle ............................................................................................ 18 1.3. Animal models of addiction ............................................................................... 20 1.3.1. Operant conditioning in studying addictive behaviours ........................ 20 1.3.2. Non-operant conditioning in studying aversive behaviours .................. 21 1.4. Cocaine addiction in pre-clinical models ......................................................... 23 1.4.1. Effect of cocaine on dopamine transporter function .............................. 23 1.5. The kappa opioid receptors ............................................................................... 27 1.5.1. Negative feedback loop and dynorphin/ kappa opioid system ................. 29 1.5.2. Kappa opioid receptor agonists ................................................................. 31 1.5.3. Kappa opioid agonists in pre-clinical models of addiction ...................... 33 1.5.3.1. Arylacetamides .................................................................................. 33 1.5.3.2. Benzomorphans ................................................................................ 34 1.5.3.3. Epoxymorphinans ............................................................................. 34 1.5.3.4. Phytochemical KOPr agonists ......................................................... 34 1.5.4. Mechanism of KOPr agonist induced anti-addiction effects ................... 36 1.5.5. Behavioural adverse effects of KOPr agonists ......................................... 38 1.5.5.1. Sedation and psychotomimic effects ................................................ 38 1.5.5.2. Depression and aversion .................................................................. 38 1.5.5.3. Nucleus accumbens and KOPr agonists induced depression and aversion ............................................................................................... 39 1.5.5.4. Central 5HT systems and KOPr activation induced depression and aversion ........................................................................................ 40 1.5.6. Effect of acute vs. chronic kappa opioid receptor activation ................... 42 1.6. Salvinorin A ....................................................................................................... 45 1.6.1. Behavioural pharmacology of Salvinorin A ............................................. 46 1.6.1.1. Sedation, hallucinations and motor suppression ............................ 46 1.6.1.2. Antinociception ................................................................................. 46 1.6.1.3. Drug discrimination ......................................................................... 47 1.6.1.4. Anti-cocaine effects .......................................................................... 47 1.6.1.5. Depression and aversion .................................................................. 48 1.6.1.6. Toxicity studies ................................................................................. 48 1.6.2. C-2 derived Salvinorin A analogues ......................................................... 51 1.7. Mixed opioid compounds as anti-cocaine agents ............................................. 53 1.8. Aims .................................................................................................................... 55 1 | P a g e Chapter 2. Anti-addiction profile of novel kappa opioid receptor agonists ....... 57 2.1. Introduction ....................................................................................................... 58 2.1.1. Cocaine prime induced reinstatement model ........................................... 58 2.1.2. Cocaine induced enhancement in motor activity ..................................... 59 2.1.3. Aims ............................................................................................................ 60 2.2. Methods .............................................................................................................. 61 2.2.1. Subjects ....................................................................................................... 61 2.2.2. Drugs ........................................................................................................... 61 2.2.3. Cocaine prime induced reinstatement test ................................................. 62 2.2.3.1. Surgery ................................................................................................ 62 2.2.3.2. Apparatus ............................................................................................ 62 2.2.3.3. Cocaine self-administration training ................................................. 63 2.2.3.4. Cocaine prime induced reinstatement test ......................................... 63 2.2.3.5. Kappa opioid receptor antagonist reversal experiment ..................... 65 2.2.4. Cocaine induced hyperactivity and behavioural sensitization .................. 67 2.2.4.1. Apparatus ............................................................................................ 67 2.2.4.2. Procedure ............................................................................................ 67 2.2.5. Statistical analysis ...................................................................................... 70 2.3. Results ................................................................................................................ 71 2.3.1. Effect of salvinorin A on cocaine induced reinstatement ......................... 71 2.3.2. Effect of salvinorin A on cocaine induced hyperactivity (drug naive rats) .......................................................................................... 73 2.3.3. Effect of salvinorin A on expression of cocaine sensitization .................. 75 2.3.4. Preliminary study to determine pre-treatment time for DS1 .................... 77 2.3.5. Effect of DS1 on cocaine prime induced reinstatement ............................ 79 2.3.6. Effect of DS1 on cocaine induced hyperactivity (drug naive rats) ........... 81 2.3.7. Effect of DS1 on expression of cocaine sensitization ............................... 83 2.3.8. Effect of MOM Sal B and EOM Sal B on cocaine prime induced reinstatement ............................................................................... 85 2.3.9. Effect of herkinorin on cocaine prime induced reinstatement ................. 87 2.3.10. Effect of nalmefene on cocaine prime induced reinstatement ............... 89 2.4. Summary of results ............................................................................................ 91 2.5. Discussion .......................................................................................................... 92 2.6. Summary and conclusions ................................................................................ 101 Chapter 3. Side effect profile of novel kappa opioid receptor agonists ............. 103 3.1. Introduction ....................................................................................................... 104 3.1.1. Adverse effects of traditional kappa opioid receptor agonists .................. 104 3.1.2. Pre-clinical models to screen side effect profile of KOPr agonists........... 104 3.1.3. KOPr mediated SERT modulation ............................................................. 105 3.1.4. Live cell ASP + uptake accumulation model ............................................... 106 3.1.5. Aims ............................................................................................................. 107 3.2. Methods .............................................................................................................. 108 3.2.1. Subjects ....................................................................................................... 108 3.2.2. Cell culture maintenance for live cell ASP + uptake experiments ............. 111 3.2.3. Drugs ........................................................................................................... 111 3.2.4. Apparatus .................................................................................................... 111 3.2.4.1. Locomotion test ................................................................................... 111 3.2.4.2. Sucrose reinforcement
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