RenaSci

Self-administrationIntravenous Self-administration Studies in Rats

 

Self-administration studies measure the reinforcing effects of a drug (ie its ability to produce psychological dependence or craving). Animals will press a lever to self-administer a wide range of drugs that are liked and self-administered by recreational drug users but will not self-administer drugs that humans do not abuse. Self-administration studies therefore play a critical role in abuse liability testing because they provide a direct measure of the motivational or drug-seeking properties of novel drugs in man.

RenaSci offers intravenous self administration testing in rats to evaluate reinforcing properties of novel drugs. The technique involves allowing animals access to low training doses of an abusable drug eg cocaine administered intravenously on a fixed ratio schedule (FR2) until they show reproducible self-injection of the drug and no self-administration of vehicle. Test substances are then substituted for the training drug to determine whether they will maintain self-injection or not on the fixed ratio schedule of reinforcement.

Determination of the Maximum Reinforcing Dose of Methylphenidate using a Fixed Ratio FR2 Schedule of Reinforcement in Cocaine-maintained Rats

 

Comparison of the Most Robustly Reinforcing Dose of Methylphenidate and Two Reinforcing Doses of Cocaine using a FR2 Schedule of Reinforcement

 

The relative efficacy (reinforcing potential) of the novel compound versus suitable comparators (known reinforcers) can also be determined using ascending progressive ratio (PR) schedules. The number of responses needed to acquire an injection is increased following each reinforcement until there is no longer a response. The breaking point determined using progressive ratio schedules measures how hard the rat will work to acquire the drug. Thus, breakpoint analysis (also called survival analysis) quantifies the relative reinforcing efficacy of the test drug compared to known drugs of abuse. In the example given below, survival analysis demonstrated that the breakpoint of methylphenidate 0.1 mg/kg/injection iv was not significantly different from the breakpoint of cocaine 0.32 mg/kg/injection iv but was significantly greater than the breakpoint of cocaine 0.1 mg/kg/injection iv. Furthermore, the breakpoint of the higher dose of cocaine was significantly greater than that of the lower dose. 

Use of Breakpoint Analysis to Compare the Reinforcing Effects of Methylphenidate and Cocaine

Breakpoint Analysis Demonstrates that the Relative Reinforcing Effect of Methylphenidate is Equal to that of a Highly Reinforcing Dose of Cocaine

 

The choice of training drug/positive comparator used in self-administration studies will depend on the pharmacological profile of the test drug. We have recently used both fixed ratio and progressive ratio schedules of reinforcement to evaluate the reinforcing properties of the µ-opioid agonists, heroin (diamorphine), morphine and remifentanil in order to select the best opioid comparator to use to assess the abuse liability of novel opioid-related drugs. Heroin, morphine and remifentanil are used in the clinic for pain relief. Remifentanil is of particular interest as it has a short half-life in the brain and plasma. 

Evaluation of the Reinforcing Effects of Heroin, Morphine and Remifentanil using a FR2 Schedule of Reinforcement

 

All three opioid agonists were positive reinforcers when tested on a FR2 schedule of reinforcement in a rat intravenous self-administration procedure.  

Average Breakpoints of Increasing Doses of Heroin, Morphine and Remifentanil Determined using a PR Schedule of Reinforcement

 

Breakpoint Analysis of Operant Responding for Heroin, Morphine and Remifentanil

 

Comparison of breakpoints, determined using a progressive ratio schedule of reinforcement, indicated that several doses of both remifentanil and heroin were significantly more reinforcing than all of the doses of morphine tested. The relative reinforcing effects of heroin and remifentanil were similar to those of the stimulant, cocaine. 

 

Relative Reinforcing Effects of Heroin, Morphine, Remifentanil and Cocaine

 

These results support the use of heroin as an opioid reference comparator in rat intravenous self-administration studies. Remifentanil may be a useful reference reinforcer when testing novel opioids with short duration of action. 

We have recently validated a nicotine intravenous self-administration model in rats using fixed and progressive ratio schedules of reinforcement. We found that the relative reinforcing effect of nicotine equals that of a highly reinforcing dose of heroin. This model can now be used to assess the abuse liability of novel CNS drugs with nicotinic mechanisms.

 

Nicotine Self-administration in Rats

 

Comparison of the Reinforcing Properties of Nicotine and Heroin

  

Thus, we can use studies in rats trained to self-administer drugs such as cocaine, heroin and nicotine to determine whether novel compounds can substitute for the abusable drug.

All of our self-administration studies are designed and supervised by experts with substantial experience of interactions with the FDA and EMA on abuse liability.

Experiments are customised to meet clients exact requirements. Results can be supplied as fully-audited written reports if required.   

Please contact us for further information about the use of rat intravenous self-administration studies to measure the reinforcing properties of novel drugs.

 

Posters

 

Heal et al. 2013a. Profiles of lisdexamfetamine, methylphenidate and modafinal as positive reinforcers in rats trained to self-administer cocaine. Program No 142.09. Society for Neuroscience Meeting, San Diego, California, USA, 9th-13th November 2013.

 

Heal et al. 2013b. Subjective and reinforcing effects of modafinil in rats. Abstract No 236. Presented at the 75th Annual Scientific Meeting of the College on Problems of Drug Dependence, San Diego, California, USA, 15th-20th June 2013. 

 

Heal et al. 2013c. A progressive ratio determination of the relative reinforcing effect of methylphenidate versus cocaine by intravenous self-administration testing in rats. Abstract No W186. Presented at the 52nd Annual Meeting of the American College of Neuropsychopharmacology (ACNP), Hollywood, Florida, USA, 8th-12th December 2013. Please contact us for a copy of the poster.

 

Heal et al. 2015. Evaluation of remifentanil and morphine as reinforcers in a rat intravenous self-administration procedure.  Abstract No 266. Presented at the 77th Annual Scientific Meeting of the College on Problems of Drug Dependence (CPDD), Phoenix, Arizona, USA, 13th-18th June 2015. 

 

Heal et al. 2016. Investigation of the discriminative and reinforcing properties of the κ-opioid receptor agonist CR845 in rats. Program No. 819.04. Presented at the Society for Neuroscience Meeting, San Diego, California, USA, 12th-16th November 2016.

 

Menzaghi et al. 2016. Preclinical and clinical assessments of the abuse potential of the kappa-opioid receptor agonist CR845 suggest low abuse potential. Poster No 122. Presented at PAINWeek 2016, Las Vegas, Nevada, USA, 6th-10th September 2016. 

 

Oakley et al. 2015. Comparison of the relative reinforcing efficacy of heroin, morphine and remifentanil using fixed and progressive ratio schedules of reinforcement in rat self-administration. Poster No 059P. Presented at Pharmacology 2015 (Annual Meeting of the British Pharmacological Society), London, UK, 15th-17th December 2015. 

 

Schumann et al. 2014. Metadoxine - a novel synaptic transmission modulator with low abuse potential in development for attention-deficit hyperactivity disorder (ADHD). Progam No. 2.30. Presented at the 61st Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), San Diego, California, USA, 20th-25th October 2014.


Smith et al. 2016. Comparison of the reinforcing effects of nicotine versus heroin, remifentanil and cocaine with rat intravenous self-administration. Program No. 549.10. Presented at the Society for Neuroscience Meeting, San Diego, California, USA, 12th-16th November, 2016. 

 

Manuscripts

 

Heal et al. 2013. A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil. Neuropharmacology 73: 348-358. [PubMed]

 

Recommended reading


Silvia Calderon, Alessandra Giarola and David Heal. Chapter 10. Regulatory framework and guidance to the evaluation of the abuse liability of drugs in the United States and Europe. In: Nonclinical Assessment of Abuse Potential for New Pharmaceuticals, 1st Edition. Carrie G Markgraf, Thomas J Hudzik and David J  Compton (Eds). Academic Press, Elsevier, pp 245-268, 2015.