Behavioral Pharmacology: What it was, is, and might be.

1. Behavioral Pharmacology: What it was, is, and might be. Marc N. Branch University of Florida

2. One of the enduring problems in drug therapeutics is variation in drug response. • Both within and across subjects • Especially prominent in psychiatry – “Try this” • Promise of pharmacogenomics – genetically tailored treatment. • Behavioral pharm may also provide useful information

3. Origins • Chlorpromazine in the 1950’s • Beginnings of Psychopharmacology • Early results • Behavior -specific drug effects (e.g., CPZ avoid/escape)

4. Syllogism • Major premise: Different behavior affected differently by drug • Minor premise: Different behavior results from different experience • Conclusion: Different experience can produce different drug effects

5. Study that founded B. Pharm. • Dews, 1955 • Pigeons – trained to peck key by having key pecks result in food presentation • Two behavioral conditions • 1. Every 50th peck resulted in food presentation • 2. First peck every 15 min resulted in food presentation • Test various doses of sodium pentobarbital

7. Characteristics of pharmacology that made EAB attractive

8. Isolated-organ preparations

10. Compatibility of EAB and Pharmacology • Isolated organ – isolated behavior • Highly controlled environments • Baseline, permits ABA design (B = drug) • Easy replication • Easy dose-response analysis • Automatic real-time measurement

12. Early important contributions • Schedule vs. Motivational Effects • Rate-dependency • Behavioral Tolerance

13. Kelleher and Morse (classic) • Squirrel Monkeys • Lever press • Multiple FR30 FI10-min • SR = food or escape from shock-stimulus complex

14. Baseline performance

15. Drug effects

16. What is it about schedules? • It’s not what the behavior is • It’s not what the schedule delivers • Schedules do produce different rates and temporal patterns. • First option is rates of responding. • Feat of experimental economy with a single FI schedule • Get 10 rates from one schedule!

17. Voila!

18. Give drug to animal responding under an FI schedule • Amazingly orderly result.

19. Lots of interest in this phenomenon • Under FI, many drugs, from many classes, produced this effect. • Too many different drugs? • Dews’ seminal experiment went the other way – high FR rates up while lower FI rates down. • What about those FI (supposed) rates?

21. New interpretation • Drug disrupts temporal organization. • More evident when re-plotted as rate against rate

22. As rate-dependency’s reach was seen as ever more restricted, a void developed. If response-rate is not the “cause” of drug effects, what is? Because there were no obvious answers, the field moved in other directions.

23. One direction, which was consistent with the original emphasis on the role of behavioral factors in drug effects, was the study of tolerance to behavioral effects of drugs.

24. Seminal experiment here was by Schuster, Dockens, and Woods • Rats under mult FI 30-s DRL 30-s • Amphetamine daily for 30 sessions

25. Main result

26. Led to a general technique • B-A procedure • Usually between group • One group gets drug repeatedly before sessions • Other gets same dose after sessions (equates drug exposure) • Group A, then gets drug before session • Logic is that if drug-behavior interaction is necessary for tolerance, groups should differ. Only B got it.

27. Example: Carlton & Wolgin

28. Followed by other analyses, e.g. Smith

29. The other research directions, however, emphasized stimulus functions of drugs, specifically reinforcing and discriminative. A great deal of work focused on drug self-administration (drugs as reinforcers) and drug discrimination (drugs as SDs).

31. Drug discrimination – basic procedure • Two manipulanda • One is “hot” (usually FR sched of SR), other is not (EXT) • Which is hot in a given session depends on whether drug or vehicle was given before session. • Basically a 2-response multiple schedule with components alternating between sessions.

32. Miraculous Effects Emerge • Not so miraculous – train with one dose, others show generalization

34. More miraculous- Train with one drug, and others known to interact at same receptor (determined in vitro) generalize!

35. What is miraculous? • Drugs known to bind to different receptors are not generalized to! Animal responds like it’s vehicle! • Why is that amazing? • Complexity of neurophysiology • Downstream effects • Organization of systems

36. Can do “real” pharmacology

38. Why the downturn over the past decade? • It really is as complicated as it seems it ought to be. • Example: * % rats showing ≥ 80% choice of EtOH Lever

39. Self-administration

40. Much continuing research • Face Validity • Drugs can serve as reinforcers • Abuse-liability assessment • Model of drug abuse – examine factors that influence SA • Alternative reinforcers • Punishment (interestingly, not much work here) • Measure reinforcing effectiveness: choice, PR, demand

41. What happened to research on behavioral factors that influence drug action?

42. What BP might be • Renewed focus on behavioral factors • How can that be done in apparent absence of theoretical base? • SA continues on face validity • DD has pharmacology and receptor theory guiding it • One possibility, suggested long ago (Thompson and Schuster, 1968) is to focus on “Behavioral Mechanisms of Action”

43. Definition “By behavioral mechanism of drug action, we refer to a description of a drug's effect on a given behavioral system expressed in terms of some more general set of environmental principles regulating behavior.” (Thompson, 1981)

44. Clarifying(?) analogy • Drug affects blood presssure • What factors NORMALLY control blood pressure? • Heart rate • Stroke volume • Peripheral resistance • Baroreceptor reflexes • Fluid balance

45. Suppose drug just decreases stroke volume. If so, it’s mechanism of action in reducing blood pressure would be that it reduces stroke volume. • Suppose it just decreased peripheral resistance; then the lowering of pressure would be by decreasing peripheral resistance. • In either case, as the “justs” show, need to measure drug’s interaction with each of the known possible contributors.

46. As in all cases in natural science, can go more microscopic (until you hit the basic physics). For example, what are mechanisms involved reducing stroke volume? That would/could involve understanding heart-muscle mechanics.

47. For BP, consider the following

48. Behavior is usually complexly determined. • We know of many, as previous slide indicates, possible influences. • They all have to be tested for as complete a characterization as possible. • It will be time consuming, but there is no way around it. • Regrettably, even the most basic of findings has yet to be subjected to such an examination (e.g., Dews, 1955)

49. Two advantages of making the effort • May well provide an improved understanding of the origins of variation in drug response (original problem). • Is likely to improve our “list” of possible controlling variables (i.e., BP research can inform behavioral research)

50. Some brief examples of the latter • Is punishment a unitary process?