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Progressive Ratio (PR) Intravenous Self-Administration Testing in Rats to Assess the Relative Reinforcing Effects of a Wide Range of Substances of Abuse

Intravenous self-administration (IVSA) in rats on a fixed ratio (FR) schedule provides a “Yes/No” to the question “Is the compound a positive reinforcer?” The European Medicines Agency has advocated the use of break-point determinations from PR self-administration testing of CNS drug-candidates to assess how powerful they are as reinforcers relative to known substances of abuse (EMA, 2006 [EMEA/CHMP/SWP/94227/2004]). We have conducted PR/break-point determinations on a wide range of substances of abuse in rat IVSA studies to evaluate the validity and usefulness of this approach. All experiments were conducted in mildly food-restricted, male, Sprague-Dawley rats that were surgically implanted with intravenous jugular catheters. After establishing operant responding for food rewards, rats were initially allowed to self-administer drugs on a FR schedule (FR2, FR3 or FR5) either directly or by substitution for either low-dose heroin or cocaine after saline extinction. Compounds that served as reinforcers (>6 inj/session) on the FR schedule had their break-points for responding determined on a PR schedule of reinforcement. All break-points were determined across a range of reinforcing drug doses to ensure that the maximum reinforcing effect was identified.  Heroin, remifentanil, oxycodone, cocaine, methylphenidate (all schedule 2 controlled drugs  [C-II] in UK) and nicotine were the most powerful reinforcers with mean break-points ranging between 41-98 lever-presses/infusion. Then came the moderate reinforcers, MDMA (C-I), butorphanol (κ-opioid agonist/µ partial agonist; C-IV), and (-)pentazocine (κ-opioid agonist/µ antagonist; C-IV) with break-points between 25-33 leverpresses/infusion. Finally, there were the weak reinforcers, WIN55,212 (CB1/CB2 agonist; C-I), morphine (C-II), diazepam (C-IV), midazolam (C-IV) and methohexital (C-IV) with mean break-points of 17-22 leverpresses/infusion. The break-point for saline (negative control) was 10.4±0.8 lever-presses/infusion (n=31). The µ-opioid agonists, stimulants and nicotine which are among the most reinforcing drugs in humans supported the highest break-points for self-administration in rats. Although there were some anomalies, eg morphine (C-II), there was a very reasonable association between the break-points for reinforcement in rat IVSA experiments and the controlled drug schedule. The results support the recommendation from EMA that break-point determination provides valuable information on relative reinforcing efficacy.

Key words: intravenous self-administration, progressive ratio, break-point, rats.

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Progressive Ratio (PR) Intravenous Self-Administration Testing in Rats to Assess the Relative Reinforcing Effects of a Wide Range of Substances of Abuse

Experimental

Abuse & Dependence, CNS

Author

SL Smith, SJ Holland, J Slade, M Hallam and DJ Heal