The Demonstration of the Rewarding Effects of Opiates on Rats
In order to examine if an opiate drug of abuse is actually rewarding to an animal, it is necessary to demonstrate that the drug will be self-administered through intracranial administration. In order to find the structure in the brain that acts as the reward producer, cannulae can be implanted into different areas of the brain and when self-administration is observed, one can assume that they have found the reward center. Post-mortem analysis of the brain tissue will allow the experimenter to determine where the site was. An alternative to self-administration is the place preference paradigm which will also help determine where the reward producing site is.
For intracranial self-administration, several effects must be demonstrated. The rat must demonstrate that he is pushing the lever for drug injections and isn’t just pushing the lever as a function of nonspecific behavioral arousal. It must also be established that the effects of drug injection are dependent on the same receptor mechanisms that mediate systemic drug reward. And finally, it must be determined whether intracranial self-administration of a drug is localized to restricted brain regions or is an effect seen in all regions of the brain. When the cannula is implanted in the ventral tegmental area, it has been demonstrated that the rats learn the lever-pressing response very quickly. Naloxone, a competitive antagonist of the opioid receptors, demonstrates a stop to self-administration (3). This shows that the reward sensation was due to opiate-receptor mechanisms rather than some other type of change in the brain. To make sure that the results are accurate, the rat should be compared to a control group that is injected with a saline solution when the lever is pressed. The single unit activity can also be taken into account to determine location of action. For example, injection of morphine into the ventral temental area causes an increase in single unit activity. The same type of experiments can be conducted with the cannula implanted in other areas of the brain to see if similar behaviors are evoked. It is also important to take into account the dose of opiate injected. For example, if a large dose of opiate is injected into the lateral hypothalamic area, self-administration may occur because of diffusion of the drug to the VTA. However, there is a much greater response rate when the cannula is close to the reward producing area than when it is farther away or in a different area. It is also important to experiment on a rat that has never been exposed to lever pressing before because previously trained rats may maintain their learned response and produce a rewarding affect even when the cannula is placed elsewhere in the brain, but perhaps not as strong.
A second experiment to demonstrate the action of drug reward is the place preference paradigm. In this experiment, a rat is placed in a cage that has wood floor on one side and a wire mesh floor on the other side. Over the next couple of days, the preferred side of the rat is determined. Once this has been determined, the drug is administered on the nonpreferred side and is later observed which side it will go to when no longer on the drug. It has been shown that the rat will go to the side associated with the morphine injections (1).
1) http://wings.buffalo.edu/aru/CPDD82.html; Localization of the Reward-Relevant Opiate Receptors from Bozarth, M.A., & Wise, R.A. (1982)
2) http://www.acnp.org/G4/GN401000072/CH072.html; Animal Models of Drug Addiction by George F. Koob (2000)
3) http://jpet.aspetjournals.org/cgi/content/full/281/1/188; Intracranial Self-Stimulation in Rats: Sensitization to an Opioid Antagonist Following Acute or Chronic Treatment with Mu Opioid Agonists by Keith W. Easterling and Stephen G. Holtzman (1997)