Within-Subject and Between-Subjects Evaluation of the Effects Of

Western Michigan University ScholarWorks at WMU

Dissertations Graduate College

12-1990

Within-Subject and Between-Subjects Evaluation of the Effects of Hallucinogenic Drugs in Pigeons Responding Under Two Variations of a Fixed-Consecutive-Number Schedule

Rodney D. Clark Western Michigan University

Follow this and additional works at: https://scholarworks.wmich.edu/dissertations

Part of the Psychology Commons

Recommended Citation Clark, Rodney D., "Within-Subject and Between-Subjects Evaluation of the Effects of Hallucinogenic Drugs in Pigeons Responding Under Two Variations of a Fixed-Consecutive-Number Schedule" (1990). Dissertations. 2078. https://scholarworks.wmich.edu/dissertations/2078

This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. WITHIN-SUBJECT AND BETWEEN-SUBJECTS EVALUATION OF THE EFFECTS OF HALLUCINOGENIC DRUGS IN PIGEONS RESPONDING UNDER TWO VARIATIONS OF A FIXED-CONSECUTIVE-NUMBER SCHEDULE

Rodney D. Clark

A Dissertation Submitted to the Faculty of The Graduate College in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Department of Psychology

Western Michigan University Kalamazoo, Michigan December 1990

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. WITHIN-SUBJECT AND BETWEEN-SUBJECTS EVALUATION OF THE EFFECTS OF HALLUCINOGENIC DRUGS IN PIGEONS RESPONDING UNDER TWO VARIATIONS OF A FIXED-CONSECUTIVE-NUMBER SCHEDULE

Rodney D. Clark, Ph.D.

Western Michigan University, 1990

The purpose of the present study was twofold: To determine the

effects of LSD (0.03 - 1.0 mg/kg), mescaline (0.3 - 5.6 mg/kg), and

DMT (0.3 - 3.0 mg/kg) on the performance of pigeons under two vari

ants on an FCN schedule and to determine whether these effects dif

fered substantially as a result of experimental design (i.e., within-

subject or between-subjects). Under this schedule, food was deliv

ered whenever subjects responded between eight and 12 times on one

response key (work key), then responded once on a second key (rein

forcement key). Under one version, (FCN-S®), an external discrimi

native stimulus was correlated with the completion of the response

requirement on the work key; no such stimulus change was programmed

to occur under the other schedule (FCN).

Although small differences were apparent, within-subject and

between-subjects comparisons yielded comparable results. In the

absence of drug, accuracy (percent reinforced runs) was higher under

the FCN-S® schedule. LSD and DMT had little effect on accuracy under

either the FCN or the FCN-S® schedule. Mescaline, in contrast, re

duced accuracy under both of these schedules.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INFORMATION TO USERS

The most advanced technology has been used to photograph and reproduce this manuscript from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer.

The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction.

In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.

Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book.

Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order.

University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA 313/761-4700 800/521-0600

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS

This dissertation is respectfully dedicated to my parents Robert

and Effie Clark without whose help and encouragement this work, as

well as much else, would not be possible.

I would like to acknowledge the helpful support of Dr. Alan

Poling who served as my advisor. I would also like to thank Drs.

David Lyon, Jack Michael, and C. Dennis Simpson for serving as

members of my committee. Special posthumous thanks go to Dr.

Frederick Gault for his help in the early stages of my research.

Rodney D. Clark

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Order Number 9114733

Within-subject and between-subjects evaluation of the effects of hallucinogenic drugs in pigeons responding under two variations of a fixed-consecutive-number schedule

Clark, Rodney Dexter, Ph.D.

Western Michigan University, 1990

UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106

ACKNOWLEDGEMENTS...... i i

LIST OF FIGURES ...... iv

CHAPTER

I. INTRODUCTION ...... 1

Hallucinogens: An Historical Overview...... 4

II. E X P E R I M E N T ...... 11

M e t h o d s ...... 11

S u b j e c t s ...... 11

Apparatus...... 11

Behavioral Procedure ...... 12

Pharmacological Procedure...... 14

R e s u l t s ...... 15

Discussion...... 22

APPENDICES

A. Investigator Certification Review by the Institu tional Animal Care and Use Committee...... 28

BIBLIOGRAPHY...... 30

ill

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES

1. Effects of LSD, Mescaline, and DMT on the Percent Reinforced Runs of Individual Subjects for Within- Subject and Between-Subjects Comparisons...... 17

2. Effects of LSD, Mescaline, and DMT on the Rate of Responding of Individual Subjects for Within- Subject and Between-Subjects Comparisons...... 19

3. Effects of LSD, Mescaline, and DMT on Conditional Probability Functions of Individual Birds for Within-Subject and Between-Subjects Comparisons Under Both Variants of the Fixed-Consecutive- Number Schedule ...... 22

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER I

INTRODUCTION

The discipline known as behavioral pharmacology resulted from the seemingly unlikely wedding of traditional pharma cology and Skinnerian psychology and has existed for little more than three decades. Two fundamental principles inte grate the field. The first is that the effects of drugs are lawful and thereby subject to scientific study. The second is that the behavioral effects of drugs merit atten tion in and of themselves (Poling, 1986, p. 4).

Behavioral pharmacologists employ a variety of methods to

scientifically study the behavioral effects of various drugs.

Characteristically, these methods are similar to those employed in

the experimental analysis of behavior and involve the use of within-

subject designs to examine intensively drug effects in individual

subjects (Poling, 1986; Thompson & Schuster, 1968). The potential

advantages of this approach to drug research were articulated in 1956

at a conference called "Techniques for the Study of the Behavioral

Effects of Drugs," sponsored by the New York Academy of Sciences and

chaired by Skinner and Dews (Annals, 1956). They have been restated

since by a number of authors (e.g., Iverson & Iverson, 1975; Poling,

1986; Sidman, I960; Thompson & Schuster, 1968).

Despite the wide utility of within-subject experimental designs

in behavioral pharmacology, there are research questions that demand

between-subjects designs. As McKim (1986) notes:

The type of design used by the behavioral pharmacologist is usually determined by the type of dependent variable being

with permission of the copyright owner. Further reproduction prohibited without permission. 2

measured in the experiment. If the measure is stable from day to day, like eating, within-subject designs can be used, but if the dependent variable is subject to syste matic change, then the researcher is forced to use a between-subject(s) design (p. 2).

Between-subject designs can also be used with dependent vari

ables that are stable across time. Several authors writing from the

perspective of behavior analysis have argued that, in situations

where the research question affords the use of either a within-

subject design or a between-subjects design, the former should be em

ployed (e.g., Johnston & Pennypacker, 1980; Poling, 1986; Sidman,

1960). Among the alleged advantages of within-subject designs are

sensitivity to across-subject variability in response to a drug,

nondependence on inferential statistics, and economy in terms of

subjects used.

A fundamental empirical question that has been essentially ig

nored is whether the use of a within-subject experimental design to

answer a research question would yield a significantly different re

sult than that obtained with a between-subjects design. In an

attempt to provide some data relevant to this issue, the present

study examined degree of stimulus control as a determinant of the

three hallucinogenic drugs, lysergic acid diethylamide (LSD), mesca

line, and.N-N-dimethyltryptamine (DMT), on the performance of pigeons

responding under a fixed-consecutive-number (FCN) schedule of food

delivery. Two parallel studies were conducted to examine this ques

tion. One employed a within-subject design (i.e., a multiple sched

ule), whereas the other employed a between-subjects design.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Under the FCN schedule, food is delivered if subjects respond a

fixed number of times (e.g., 8-12) on one response operandum (the

work key), then emit a single response on a second operandum

(reinforcement key). Premature switching or responding on the

reinforcement operandum before the response requirement on the work

operandum is completed resets the response requirement. In one vari

ant of the FCN schedule, a discriminative stimulus (e.g., change in

the color of key illumination) is correlated with the completion of

the response requirement on the work operandum, whereas under the

other no such stimulus change is arranged. The addition of the ex

ternal discriminative stimulus substantially improves accuracy (per

centage of reinforced response runs) without affecting overall rate

of responding. Thus, any differences in drug-induced changes in

accuracy under the two procedures cannot be attributed to differences

in control rates of responding (i.e., rate-dependent effects) but

rather reflect the stimulus control exercised by the external

discriminative stimulus.

Several studies (e.g., Laties, 1975; Schlinger, Wilkenfield, &

Poling, 1988; Szostak & Tombaugh, 1981) have shown that the addition

of a discriminative stimulus reduces the disruptive effects of

various drugs (e.g., d-amphetamine, methylphenidate, scopolamine,

pimozide). This, however, does not always occur. For example,

Picker, Leibold, Endsley, and Poling (1986) reported that ethosuxi-

mide failed to disrupt responding under FCN schedules regardless of

whether a stimulus change accompanied completion of the response

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. requirement on the work key. The effects of LSD, mescaline, and DMT

on responding under FCN schedules have not been reported. These

drugs, LSD in particular, have, however, been the subject of consid

erable research interest, as summarized below and reviewed in detail

by Appel, Poling, and Kuhn (1982), and Poling and Appel (1982).

Hallucinogens: An Historical Overview

Following its synthesis in 1938 and its discovery as a halluci

nogen in 1943, LSD has presented difficult problems for the legal and

social systems of the United States and many other countries.

Discovered as a result of systematic pharmacological investigations,

LSD has been the center of both legitimate and illegitimate interest.

For example, in the early 1950s, researchers speculated that hallu

cinogenic drugs might reveal something about the basis of psychotic

disorders.

An early hypothesis, suggested by Osmond and Smythies (1952),

implicated endogenous hallucinogens in the manifestation of schizo

phrenia. These posited hallucinogens, like LSD, produced marked

perceptual distortions, which are a part of the symptoms of schizo

phrenia. According to its framers, the validity of this model could

be examined by administering chronic doses of various hallucinogenic

drugs under differing behavioral paradigms and examining the data for

evidence of tolerance. If tolerance developed to exogenous halluci

nogens, so the tenuous argument went, endogenous hallucinogens could

not be responsible for schizophrenia, for tolerance would also

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. develop to their effects. Early experiments did not support the

endogenous hallucinogen hypothesis because tolerance to the behavior-

altering effects of LSD and similar hallucinogens almost always

developed following protracted exposure to the drugs (Appel &

Freedman, 1968).

In contrast, later investigations revealed certain assays under

which tolerance to the behavior-disrupting effects of various

hallucinogens failed to develop (Hadorn, Mandell, & Segal, 1976). It

is now apparent that whether or not tolerance develops to the behav

ioral effects of a given hallucinogenic drug depends on the particu

lar species, drug, and behavior being studied. Despite this, the

endogenous hallucinogen model of schizophrenia is no longer popular.

In large part, this reflects the failure of neuropharmacologists to

isolate endogenous substances with LSD-like properties.

Interestingly, LSD and related drugs were used to treat as well

as to model psychotic conditions. The underlying assumption here was

that the altered perceptions produced by LSD were a window to the

mind or the unconscious, and therefore especially revelatory to a

therapist. This is untrue and hallucinogens are not accepted therapy

for any behavior disorder (Appel et al., 1982).

In terms of its more nefarious uses, LSD has been used in clan

destine operations on unsuspecting persons by various U.S. and for

eign governmental agencies. One of the more infamous cases concerned

the deliberate administration of LSD to a civilian chemist employed

by the government in late 1953. The chemist, Frank Olson, was given

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LSD in his drink without his knowledge and shortly thereafter

suffered a severe panic reaction. Two weeks later, Dr. Olson was

dead. His death was the result of a fall from the window of a tenth-

story Manhattan hotel room. His family, who knew nothing of the LSD,

was told that his death probably was due to an accidental fall, but

there was a chance of suicide. In 1975, the unethical behavior of

the government operatives was publicly exposed and the possible role

of LSD in the death of Dr. Olson became apparent. This expose

precipitated investigations into other inappropriate uses of LSD by

the government.

Well before the inappropriate use of LSD by government agencies

became public knowledge, the drug had gained popularity as a recrea

tional drug among members of several subcultures in the United

States. Two figures emerged in the early 1960s who had a tremendous

impact on the social use of LSD and other hallucinogenic drugs. They

were the Harvard professors Timothy Leary and Richard Alpert.

Together they conducted legitimate early research on human subjects

with LSD. But shortly thereafter, their use of the scientific method

became, at best, questionable. Among other irregularities, they

began conducting research without the supervision of a medical

doctor, conducting research outside the confines of the laboratory,

and using undergraduate students as subjects. These practices soon

came to the attention of university administrators, and Leary and

Alpert were dismissed from their positions at Harvard in late 1963.

By the mid-1960s both Leary and Alpert were openly advocating the use

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. of hallucinogens, particularly LSD, as methods of gaining spiritual

fulfillment. "Tune in, turn on, drop out" was their slogan, and a

kind of psalm for the religious movement which Leary founded. In his

church, called the League of Spiritual Development, LSD was used as a

sacrament.

Leary and Alpert were not, of course, the first to use percep

tion-altering substances for religious purposes (see Ray & Ksir,

1988). Indigenous peoples of North, Central, and South America have

used the perception-altering activity of various plants for religious

purposes for hundreds of years. Indeed, the Native American Church,

organized in 1912, uses ritualistic consumption of mescaline as a

sacrament. Unlike Leary's church, however, the Native American

Church is a confederation of tribes that have used peyote (mescaline)

since pre-Columbian times for religious purposes. Hallucinogens have

thus played a positive role in the social fabric of the cultural

traditions of the native peoples of North, Central, and South Ameri

ca. In contrast, hallucinogens have played a rather negative role in

the cultural traditions of Europe, of which modern America may be

seen as an extension. For example, during the European middle-ages

people experiencing hallucinations as a result of eating bread made

from grains containing ergot fungus were often considered to be

possessed by the devil. Thus, to consider hallucinations as a good

experience was somewhat counter to the long-standing cultural tradi

tion of America of which Leary and Alpert were products.

Following the incidents at Harvard in the early 1960s, LSD and

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. other hallucinogens gained ever-increasing acceptance in the emerging

drug culture. By 1966, LSD had been classified as an illegal sub

stance and penalties for possession and sale were enacted. Nonethe

less, the illicit use of LSD and related hallucinogenic agents like

mescaline continued to increase. In the late 1960s, however, data

were collected that linked the use of LSD with chromosomal damage.

These data, unconfirmed as they were, were seized upon by the news

media and portrayed as fact. They probably played some role in the

declining popularity of hallucinogenic drugs that emerged during the

1970s. By that time, concern with other drugs of abuse began to

overshadow the national concern with the effects of LSD and other

major hallucinogens. Interestingly, a wealth of data on the

dependence-producing liability of LSD indicates that it is not addic

tive in the same fashion as other highly abused drugs such as opi

ates, alcohol, and nicotine (Poling & Appel. 1982).

Since the 1960s, the behavioral effects of LSD and other hallu

cinogens have been examined in some detail. These effects are re

viewed by Appel et al., (1982), McKim, (1986), Poling and Appel

(1982) and Seiden and Dykstra (1977). In brief, these drugs are not

self-administered by nonhumans. They generally reduce high-rate

operant responding (as occurs under fixed-ratio schedules), but

slightly increase low-rate operant responding. The drugs have no

selective effect on punished responding, but appear to interfere with

avoidance behavior at doses that leave escape responding intact. LSD

and similar hallucinogens (including mescaline and DMT) have

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. perceptible effects in two-response drug discrimination procedures,

and these effects are similar across agents. The effects of halluci

nogens on discriminated operant behavior are hard to summarize, but

the drugs do not inevitably disrupt performance as might be expected

given the perceptual distortions they produce in humans. For exam

ple, in studies involving matching-to-sample procedures with pigeons,

Berryman, Jarvik, and Nevin (1962) found little impairment of accura

cy even with LSD doses that appreciably reduced response rates.

Relatively few recent studies dealing entirely with the behav

ioral effects of hallucinogenic drugs have appeared. Most recent

research involving hallucinogens has been designed to characterize

the behavioral actions of neurotransmitter systems and the pharmaco

logical mechanisms by which hallucinogens exert their behavioral

effects (Colpart & Jenssen, 1983; Minnema & Rosecrans, 1984). For

example, techniques such as two-key drug discrimination paradigms

have been useful in characterizing the role of the neurotransmitter

serotonin in the behavioral actions of hallucinogenic drugs. Browne

and Ho (1975) have reported data that implicate serotonin in the

central actions of the discriminative stimulus properties of mesca

line. These researchers studied serotonin receptor blockade via

three different CNS serotonin antagonists: cinanserin, methysergride,

and cyproheptadine. Each of these centrally acting CNS antagonists

altered the discriminative stimulus actions of mescaline. More

recently, however, Colpart, Niemegeers, and Jenssen (1982) have shown

that methysergride and cyproheptadine only partially antagonize the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10

discriminative stimulus effects of LSD thus implicating slightly

different pharmacological mechanisms of action than those with

mescaline. In addition, these researchers have examined the antago

nist actions of a reputed "pure" LSD antagonist, pirenperone. It now

appears that LSD and DMT interact primarily with serotonergic neurons

(McKim, 1986). But the neuropharmacology of these agents is complex,

and it is impossible to explain adequately all of their effects in

terms of neurochemical actions.

Neuropharmacological mechanisms of action are not of particular

relevance to the present study, which is a straightforward method

ological examination of the overt behavioral effects of three hallu

cinogenic drugs. The purpose of the present study was twofold: (1)

To determine the effects of LSD, mescaline, and DMT on the perfor

mance of pigeons under two variants on an FCN schedule, and (2) to

determine whether these effects differed substantially as a result of

experimental design (i.e., within-subject or between-subjects).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER II

EXPERIMENT

Methods

Subjects

Twelve experimentally-naive White Carneaux pigeons, maintained

at approximately 80£ of their free-feeding body weights, served as

subjects. Supplemental grain was given following daily experimental

sessions to maintain these reduced weights. Each subject was indi

vidually housed with continuous access to grit and water in a con

stantly illuminated room. Prior to beginning the study, procedures

for both experiments were approved by the Institutional Animal Care

and Use Committee at Western Michigan University (Appendix A).

Apparatus

Four Lehigh Valley Electronics (BRS/LVE, Lehigh Valley, PA)

operant conditioning chambers were used, each measuring 32 cm long,

36 cm :high, 35 cm wide. In each chamber. 3 response keys 2.5 cm in t diamater were located 23 cm from the bottom of the front panel,

approximately 5.5 cm apart. Only the center key and right side key

were used in the present study. An opening centered on the front

panel 7.5 cm above the floor provided access to a hopper filled with

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12

mixed grain when the hopper was raised. When raised, the hopper was

illuminated by a 7-watt white bulb. A 7-watt bulb centrally located

33 cm above the chamber floor provided ambient illumination. White

masking noise was constantly provided. Scheduling of all experimen

tal events and data collection were accomplished through the use of a

Digital Equipment Corp. (Maynard, MA) PDP/8E minicomputer with

interface and software (SUPERSKED) provided by State Systems, Inc.

(Kalamazoo, MI).

Behavioral Procedure

Initially, keypecking was generated by a forward-pairing auto

shaping procedure described elsewhere (Brown & Jenkins, 1968). Once

keypecking was reliably established, subjects were randomly divided

into 3 groups of 4. One of those groups was used in a within-subject

comparison of the effects of LSD, mescaline, and SMT under FCN and

FCN-S® schedules. The other 2 groups were used in a comparable

between-subjects comparison. To aid in explicating procedures, the

treatment of birds in the between-subjects comparison will be de

scribed initially.

During the initial training session for the group exposed to the

FCN schedule, the 2 operative response keys were illuminated white

and at least 1 keypeck response on the right response key (work key)

followed by a keypeck on the center response key (reinforcement key)

produced 3 seconds access to mixed grain. Twenty consecutive re

sponses (upper limit) on the work key or multiple responses on the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. reinforcement key produced a 2 second timeout. During the timeout,

the chamber was totally darkened and responses had no programmed con

sequences . Over the next few sessions, the number of responses

required on the work key, before a response on the reinforcement key

was reinforced, was rapidly increased to 8. Under the terminal FCN

schedule, either food or a putative conditioned reinforcer (0.5

second hopper flash) was presented (these events alternated) whenever

subjects responded between 8 and 12 times on the work key and then

responded once on the reinforcement key; all other response pat

terns produced a 2 second timeout and reset the response requirement

on the work key.

For the second group of subjects in the between-subjects compar

ison exposed to the FCN— schedule, conditions were exactly the same

as for those exposed to the FCN schedule, with the exception that the

color of the work key was changed from white to red when the minimum

designated response requirement on the work key was completed. This

requirement was initially 1 but was rapidly increased across sessions

to 8. Responding more than 8 times but less than 13 times on the

work key had no effect on the color of key illumination. At the end

of timeouts the response keys were again illuminated to white.

Subjects in the within-subject comparison were exposed to FCN

and FCN-S® schedules identical to those described above. However,

for those subjects, the schedules were arranged in alternating 5 min

ute blocks under a multiple schedule, with the initial schedule

selected at random each day. For all birds, a single 30-minute

with permission of the copyright owner. Further reproduction prohibited without permission. 14

session was conducted at about the same time each day from Monday

through Saturday.

Pharmacological Procedure

For subjects in the between-subjects comparison, when the per

centage of reinforced runs showed no visible trend across 5 con

secutive sessions 5 doses of LSD (0.03, 0.1, 0.3, 0.56, and 1.0), 4

doses of mescaline (0.3, 1.0, 3.0, and 5.6) and 5 doses of N,N-

dimethyltryptamine (0.3, 0.56, 1.0, 1.7, and 3.0) were administered.

For all drugs, the lowest dose did not appear to be behaviorally

active and the highest dose reduced mean group rate of responding by

at least 20% in at least one group of subjects. Drugs were given in

a BBVDBBVD design where B represents baseline sessions (no injec

tion), V vehicle control sessions, and D drug sessions. LSD and

associated vehicle control injections were administered IM 30 minutes

prior to the start of the session. Mescaline, DMT, and vehicle

injections were administered IM 15 minutes prior to the start of the

experimental session. All drugs and vehicle control injections were

given in volumes of 1 ml/kg. All injections were administered in a

non sequential order across drugs and doses that varied across birds.

Solutions of LSD, mescaline, and DMT (Sigma Chemical Co., St. Louis,

✓ •' MO) were dissolved in distilled water and prepared fresh bi-weekly.

The drug regimen for birds in the within-subject comparison was

identical to that described for subjects in the between-subjects

comparison. For the former group of subjects, percent reinforced

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15

runs under both components of the multiple schedule (i.e., the FCN

and FCN-s") were considered in assessing initial stability.

Results

For each subject, the percentage of reinforced runs (accuracy),

overall rate of responding and frequency distributions of run lengths

were recorded during each session. Overall rate of responding was

calculated by taking the total number of responses on both response

keys (work and reinforcement keys) and dividing by session time,

excluding the time occupied by food presentation, hopper flashes, and

timeouts. The percentage of reinforced runs (reinforced response

runs/[reinforced response runs + nonreinforced response runs] x 100)

reflects the proportion of response runs during which a pigeon made

between 8 and 12 responses on the work key and then responded once on

the reinforcement key. Responding fewer than 8 times on the work key

and then responding once on the reinforcement key or responding 13

consecutive times on the work key were recorded as nonreinforced

response runs. Conditional probability functions were computed from

run length distributions to determine possible drug-induced changes

in response patterns. These probabilities can be computed for a

response run of any given length by dividing the total number of

response runs by the total number of response runs for that particu

lar run-length, minus the number of runs that have been completed

before that particular run-length. These functions reflect the

conditional probability of switching to the reinforcement key after

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16

completing individual response runs consisting of between 0 and 12

responses on the work key. When errors do occur, these functions

will provide information regarding changes in the proportional

distribution of error types, i.e., multiple responses on the rein

forcement key, 13 consecutive responses on the work key, or switch

ing to the reinforcement key before completing at least 8 consecutive

responses on the work key (Laties, 1972). To facilitate comparison

of the results from the between-subjects and within-subject determi

nations, data collected under the two experimental configurations are

presented side-by-side in all figures. Although there were subtle

differences in the results yielded by within-subject and between-

sub jects designs, results were generally comparable.

Figure 1 presents data for percent reinforced runs under all

experimental conditions. When compared either within or between

subjects, percent reinforced runs in the absence of drug was

consistently and substantially (i.e., over 20%) higher under the PON

s'* schedule than under the FCN schedule. Neither LSD or DMT consis

tently affected percent reinforced runs under either of these sched

ules. For these drugs, there were sizeable differences in perfor

mance across birds at each drug dose, and mean group percent rein

forced runs was not substantially below the control level at any

dose.

Unlike LSD and DMT, mescaline appeared to reduce percent

reinforced runs at some doses. With the highest (5.6 mg/kg) dose of

this drug, mean group percent reinforced runs was substantially below

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. \7

g € 3 ■o > 3 ■o > 1 1 <3 I I I ■J. __ 1 *> 1 1 3 1 1 8 3 J r t s r __ I • ■ • • o o 4 e • H O * * a __ I

___

* * 1 t 1 I | 1 o o 0 8 S S S 8 o S e o S 8 L _

- _

° b - b 0 s - _

8 8_H e Si P a / V V ■ 0 —— • o - d r / o • ■ *o o — g * ! ”J • L_ 1. 1 1 1 o o i --- 1

I I 8 1 • 8 - »£ _ I I L 0 8 S S 8 8 8 — 8 . j. *1 o PERCENT REINFORCED RUNS H Subjects Comparisons Runs of Individual Subjects for Within-Subject and Between- I B | » “I M y “ S - / 2 - O o< o< O 1 _ A -I’’ 00 00 | t

t t ' ■ ° . . c S -

l. l. I l l i i O S 8 S § 8 ■ ■ / ®0 - - Figure 1. Effects of LSD, Mescaline, and DMT on the Percent Reinforced 8 (M “ -3 e (M e 8 b DMT CMO/KO) Reproduced with permission ofthe copyright owner. Further reproduction prohibited without permission. 18

the control level under both the FCN-s" and the FCN schedules. There

was, however, differential sensitivity across birds when this dose

was administered. At 5.6 mg/kg mescaline, one bird in the within-

subject comparison exhibited no change in accuracy under the FCN-S^

schedule and an increase in accuracy relative to control values under

the FCN schedule. All other subjects exhibited substantial reduc

tions in accuracy at this dose.

For birds in the within-subject comparison, the mean group per

cent reinforced runs also was substantially below the control level

under both of these schedules at the 3.0 mg/kg dose. This effect was

evident in the performance of three of four individual birds. The

exception was the same subject that did not exhibit reduced accuracy

at 5.6 mg/kg mescaline. In contrast to its effects in the within-

sub ject comparison, 3.0 mg/kg mescaline did not appear to reduce

accuracy for subjects in the between-subjects comparison. When

mescaline was associated with reduced accuracy, percent reinforced

runs were similar under the FCN and the FCN-S® schedules. Relative

change with respect to control performance was greater under the

latter schedule, where control percent reinforced runs was higher.

Rate data are presented in Figure 2. Considerable individual

variability is evident in these data during control and drug condi

tions. In general, for both within-subject and between-subjects

comparisons, control rates were higher under the FCN-S® schedule.

LSD had no systematic effect on response rates for birds in the

between-subjects comparisons. For birds in the within-subjects

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 19

RESPONSES PER MINUTE ° 8 § a 8 S <,8 8 8 3 3 o S3 8 S 8 8 1------1-1---1---1---1 I 1_____1___I___I___I ' '' i ' ' I-=^=7 -l^r- -1 7 o M o 8 S

o COMPARISON BETWEEN-SUBJECTS COMPARISON WITHIN-SUBJECT

a 8 1-----1----1----1----1----1 * I----1----1_____I_____I_____11 I '' 1 I I 5-1

8 8 3 3 _i___ i 8 8 3 3 8 8 3 8 -I__ I J— I— I__ I -I___ L. _J___ I

o o • M II6 s s

i— i______i— » ■ w5 n 3"

p _

Figure 2. Effects of LSD* Mescaline, and SMT on the Rate of Responding of Individual Subjects for Within- Subject and Between~Subjects Comparisons

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 20

comparison, the highest dose (1.0 mg/kg) was associated with apparent

rate reductions tinder both the FCN-s'* and the FCN schedules. Other

doses produced no obvious effects.

Under all conditions, relatively low rates of responding were

evident at the highest dose of mescaline (5.6 mg/kg). Rate reduc

tions were also evident at 3.0 mg/kg, except under the FCN-S^1 sched

ule for subjects in the between-subjects comparison. Lower doses of

mescaline did not obviously affect response rate.

When mean group performance is considered, DMT appeared to pro

duce generally dose-dependent decreases in responding under both the

FCN-S^ and the FCN schedules for birds in the between-sub jects com

parison, and under the FCN-S® schedule for birds in the within-

sub ject comparison. However, this effect was not clearly evident in

the performance of individual birds.

Conditional probability functions are shown in Figure 3. This

figure presents for each drug data from one randomly-selected bird

from the within-subject comparison and data from one randomly-

• T) selected bird from the FCN-S and the FCN groups in the between-

sub jects comparison. It is evident from this figure that the FCN-S^

and the FCN schedules engendered distinctly different patterns of

responding. This occurred regardless of whether the schedules were

arranged within or between subjects. In the absence of drug, respond

ing under the FCN-S^ schedule was characterized by runs of 8 to 10

responses on the work key before switching to the reinforcement key.

When errors did occur, these were usually restricted to the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CONDITIONAL PROBABILITY IH NSBET OPRSN EWE-UJCS COMPARISON BETWEEN-SUBJECTS COMPARISON IN-SUBJECT WITH

Figure 3. Effects of LSD, Mescaline, and DMT on Conditional Probability Functions of Individual Birds for Within- Subject and Between-Subjects Comparisons Under Both Variants of the Fixed-Consecutive-Number Schedule

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 22

beginnings of sessions and typically consisted of multiple responses

on the reinforcement key. Much flatter conditional probability

functions were obtained under the FCN schedule, where the probability

of switching to the reinforcement key generally increased as a

function of the number of consecutive responses emitted on the work

key. Under this schedule, almost all errors consisted of switching

to the reinforcement key before completing the minimum requirement of

8 responses on the work key. No clear evidence of drug effects on

conditional probability functions is evident in Figure 3. For some

birds, however, mescaline at the two highest doses generally shifted

the functions leftward (i.e., increased the likelihood of premature

switching).

Discussion

The present study was designed (a) to explore the effects of

LSD, mescaline, and DMT under FCN and FCN-S® schedules; and (b) to

determine whether within-subject versus between-subjects arrangements

of the schedules affected results. On whole, it does not appear that

results differed significantly as a function of whether within-

sub ject or between-subjects comparisons were arranged. Several

pieces of evidence support this conclusion. Under the two arrange

ments, in the absence of drug:

1. Comparable levels of accuracy were observed under the FCN

schedule. This is clearly evident if mean group performance is

compared.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23

2. Comparable levels of accuracy were observed under the FCN-S®

schedule. Accuracy was higher under this schedule than under the FCN

schedule, which is consistent with the results of prior studies

utilizing within-subject (e.g., Schlinger, et a l ., 1988), and

between-subjects designs (e.g., Picker, Leibold, Endsley, & Poling,

1986).

3. Although considerable variability was evident across

subjects in rate of responding, response rates under the FCN and FCN-

S D schedules did not systematically differ as a result of whether

those schedules were arranged on a within-subject or a between-

sub jects basis.

As discussed previously, drug effects under the FCN and FCN-S®

schedules were similar regardless of whether those schedules were

arranged within-subject or between-subjects. In summary, mescaline

at certain doses reduced accuracy under both the FCN and the FCN-S®

schedules, whereas LSD and DMT failed to affect accuracy at any dose.

Research using a number of procedures indicates that behavior

strongly controlled by a discriminative stimulus is in many cases

less affected by drugs than is similar behavior that is stimulus-

controlled to a lesser degrees (Laties, 1975; Thompson, 1978). This

relation is evident in the results of several studies in which drugs

from diverse classes reduced accuracy to a greater extent under an

FCN schedule than under a comparable FCN-S® schedule (e.g., Laties,

1972; Mechner & Latranyi, 1963; Picker et al., 1986; Szostak &

Tombauch, 1981.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24

In view of this, it is interesting that, in the present study,

the addition of an external discriminative stimulus did not reduce

the disruptive effects of mescaline, the only one of the three drugs

tested that appreciably reduced accuracy. Although accuracy in the

absence of the drug was considerably higher under the FCN-S^ schedule

than under the FCN schedule, accuracy at a given dose of mescaline

was comparable under the two schedules. This indicates that the

addition of an external discriminative stimulus did not accentuate

the disruptive effects of either drug. Similar results have been

previously reported for chlorpromazine, methsuximide, and mepheny-

toin, which produced comparable reductions in accuracy under FCN and

FCN-S® schedules (Laties, 1972; Schlinger et a l ., 1988). These data

and those from the present study indicate that the degree of stimulus

control does not always modulate a drug's behavioral actions, al

though it does so in many cases. The variables that determine

whether or not degree of stimulus control modulates a drug's behav

ioral actions are unknown (Thompson, 1978).

In the present study, only mescaline appreciably reduced

accuracy. Mescaline is a phenethylamine hallucinogen that interacts

primarily with neuradrenergic neurons, whereas LSD and DWT are

indolaklylamine hallucinogens with primari Xy serotonergic effects

(Ray & Ksir, 1990). Whether this accounts for the differences

observed in the present study is moot. The three hallucinogens

produce similar subjective effects (Browne & Ho, 1975), cross

tolerance occurs with them, and they affect schedule-controlled

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25

responding similarly (Harris, Snell, & Loh, 1977). In view of this,

it does not appear that the different neuropharmacological actions of

these drugs necessarily translate into different behavioral effects.

In the present study, mescaline strongly disrupted accuracy only

at doses that also substantially reduced response rates, and neither

LSD nor DMT were studied at doses that produced comparable rate re

ductions. Perhaps doses of LSD and DMT higher than those used in the

present study appreciably reduce accuracy under FCN and/or FCN-S®

schedules. Because a major goal of the study was to examine drug

effects under similar within-subject and between-subjects designs,

doses and drug regimens were selected prior to the onset of experi

mentation. Higher doses of LSD and DMT, though of interest given

empirical findings, could not be incorporated into either the within-

subject or between-subjects studies without violating random selec

tion. Nonetheless, the highest doses of LSD and DMT were behav-

iorally active as indicated by decreased response rates. Moreover,

doses of LSD and DMT similar to those used in the present study have

shown to be behaviorally active in other studies (Appel et al., 1982;

Browne & Ho, 1975; Harris et al., 1978).

Although within-subject and between-subjects designs yielded

similar findings in the present study, more time was required to

complete the between-subjects experiment. Overall, 792 subject-hours

were required to complete the within-subject experiment, whereas

1,120 subject-hours were required to complete the between-subjects

experiment. Despite this difference, fewer calendar days were

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26

required to complete the between-subjects study than to complete the

within-subject parallel. This reflects the fact that initial

stability required more sessions to develop for birds in the within-

sub ject comparison.

It is certainly not possible on the basis of the present data to

argue for the general superiority of within-subject or between-

subjects designs in behavioral pharmacology. In fact, the between-

subjects component of the present study actually involved a within-

subject determination of dose-response relations. The study was

between-subjects with respect to the comparison of drug effects under

FCN and FCN-S® schedules, but within-subject with respect to dose-

response determinations under these schedules. In a pure between-

sub jects design, a separate group of subjects would be exposed to

each condition of interest (i.e., drug dose and schedule). Under the

conditions of the present study, this would have required a minimum

of 26 independent groups ([2 schedules x 4 doses x 3 drugs] + a

control group under each of 2 schedules). This, obviously, is un

feasible. But, with other experimental questions, a pure between-

sub jects design would be feasible. Such a design would inevitably

yield data that are fundamentally different, and less informative,

from those obtained in the present study. For example, such data

would necessitate statistical analysis and would not reveal

across-subjects variability in control performance and sensitivity to

drug effects. Because of this, pure between-subjects designs appear

to be less suitable than within-subjects or mixed designs for

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27

analyzing the behavioral effects of drugs.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Appendix A

Investigator Certification Review by the Institutional Animal Care and Use Committee

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29

attachment A

INVESTIGATOR CERTIFICATION

Title of Project g.vJMjj*£V>o»> o f TH£ gffiScTU dr DfbJCaS o» A FwZ-0 ScW CiVU

if any of the above procedures are changed, I will submit a new protocol.

I understand that any failure to comply with theAnimal Welfare Act, the provisions of theOPHS Guide for the Care and Use of Laboratory Animals and requirements set down by the IACUC may result in the suspension of my animal studies. _ t7 A o f a V * Signature: CPrincipaiinvestigator Department Oate

REVIEW BY THE INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE

Disapproved > / Approved ______Approved with the provisions listed below

Provisions: or Explanation »re y u e * Xfi in u s u J

P . J ) : ______. t a l n h x IACUC:uc Chairperson 'Q . Date

Researcher's Acceptance of Provisions:

Signature: Principal Investigator Oate

IACUC Chairperson Final Approval Oats

Approved IACUC Number 0 0 5 ______/

Revised J u n e, 1988

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. BIBLIOGRAPHY

Altman, J. L., & Appel, J. B. (1975). LSD and fixed interval responding in the rat. Pharmacology Biochemistry & Behavior. _3, 151-155.

Annals of the New York Academy of Sciences (1956). Volume 65, 247- 256.

Appel, J. B. (1968). The effects of psychotomimetic drugs on animal behavior. In D. Efron (Ed.) Psychopharmacology: A review of progress 1957-1967 (pp. 1211-1222). Washington, DC: U.S. Public Health Service.

Appel, J. B., & Freedman, D. X. (1968). Tolerance and cross tolerance among psychotomimetic drugs. Psvchopharmacologia. 13. 267-274.

Appel, J., Poling, A., & Kuhn, D. (1982). The behavioral pharma cology of psychotomimetics. In F. Hoffmeister & G. Stille (Eds.), Handbook of experimental pharmacology (pp. 45-56). New York: Springer-Verlag.

Berryman, R., Jarvik, M. E., & Nevin, J. A. (1962). Effects of pen tobarbital, lysergic acid diethylamide, and chlorpromazine on matching behavior in the pigeon. Psvchopharmacologia. 3, 60-65.

Brown, P. L., & Jenkins, H. M. (1968). Auto-shaping the pigeons keypeck. Journal of the Experimental Analysis of Behavior. 11. 1-8.

Browne, R. G., & Ho, B. T. (1974). Role of serotonin in the dis criminative stimulus properties of mescaline. Pharmacology Bio chemistry & Behavior. 3, 429-435.

Cole, J. M., & Pieper (1973). The effects of N,N-DMT on operant behavior in squirrel monkeys. Psvchopharmacologia. 29. 107-112.

Colpart, F. C., Niemegeers, C. J. E., & Jenssen, P. A. J. (1982). A drug discrimination analysis of lysergic acid diethylamide (LSD): In vivo agonist and antagonist effects of purported 5-hydroxy- tryptamine antagonists and of pirenperone, a LSD-antagonist. Journal of Pharmacology and Experimental Therapeutics. 221(1). 206-214.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31

Colpart, F. C., & Janssen, P. A. J. (1983). A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharma- cology. 22(8), 1001-1005.

Hadorn, D., Mandell, A. J., & Segal, D. S. (1976). The effects of chronic mescaline administration on operant behavior in the pigeon. Behavioral Biology. 17. 403-409.

Harris, R. A., Snell, D., & Loh, H. H. (1977). Effects of d- amphetamine, monohydroxyamphetamines, and hallucinogens on schedule controlled behavior. Journal of Pharmacology and Experimental Therapeutics. 204(1). 103-117.

Iverson, S. D., & Iverson, L. L. (1975). Behavioral pharmacology. New York: Oxford Press.

Johnston, J. M., & Pennypacker, H. S. (1980). Strategies and tactics of human behavioral research. Hillsdale, NJ: Lawrence Erlbaum.

Ksir, C., & Nelson, S. (1977). LSD and d-amphetamine effects on fixed interval responding in the rat. Pharmacology Biochemistry & Behavior. 6, 269-272.

Laties, V. G. (1972). The modification of drug effects on behav ior by external discriminative stimuli. Journal of Pharma cology and Experimental Therapeutics. 183(1), 1-13.

Laties, V. G. (1975). The role of discriminative stimuli in modu lating drug action. Federation Proceedings. 34(9), 1880-1888.

Laties, V. G . , & Weiss, B. (1966). Influence of drugs on behavior controlled by internal and external stimuli. Journal of Pharmacology and Experimental Therapeutics. 152(3) . 388-396.

Laties, V. G . , Wood, R. W., & Rees, C. D. (1981). Stimulus control and the effects of d-amphetamine in the rat. Psycho- pharmacology. 75. 227-232.

McKim, W. A. (1986). Drugs and behavior. Englewood Cliffs, NJ: Prentice-Hall.

Mechner, F. (1958). Probability relations within response sequences under ratio reinforcement. Journal of the Experimental Analysis of Behavior. .1, 109-121.

Mechner, F., & Latranyi, M. (1963). Behavioral effects of caffeine, methamphetamine, and methylphenadate in the rat. Journal of the Experimental Analysis of Behavior. 6, 331-342.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 32

Minnema, D. J., & Rosecrans, J. A. (1984). Amphetamine and LSD as discriminative stimuli: Alterations following neonatal monoamine reductions. Pharmacology Biochemistry & Behavior. 20, 95-101.

Mokler, D. J., Soutdt, K. W., & Rech, R. H. (1985). The 5-HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs. Pharmacology Biochemistry & Behavior. 22, 677-682.

Osmond, H., & Smythies, J. (1952). Schizophrenia— A new approach. Journal of Mental Science. 98. 309-315.

Picker, M., Leibold, L., Endsley, B., & Poling, A. (1986). Modu lation of the behavioral effects of anticonvulsant drugs by an external discriminative stimulus in the pigeon. Journal of Pharmacology and Experimental Therapeutics. 238(2). 529-535.

Picker, M . , Heise, J. W . , & Dykstra, L. A. (1987). Evaluation of the effects of opioid antagonists and antagonists under a fixed- consecutive-number schedule in rats. Pharmacology Biochemistry & Behavior. 27, 73-80.

Poling, A. (1986). A primer of human behavioral pharmacology. New York: Plenum Press.

Poling, A., & Appel, J. B. (1982). Dependence-producing liability of LSD and similar psychotomimetics. In F. Hoffmeister & G. Stille (Eds.), Psychotropic agents (pp. 111-118). Berlin: Springer- Verlag.

Ray, 0. S., & Ksir, C. (1988). Drugs, society. & human behavior (4th ed.) St. Louis: Times Mirror/Mosby.

Schlinger, H., Wilkenfield, J., & Poling, A. (1988). Effects of methsuximide and mephenytoin on the responding pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus. Psychopharmacology. 95. 216-221.

Seiden, L. S., & Dykstra, L. A. (1977). Psvchopharmacologv: A biochemical and behavioral approach. New York: Van Nostrand Reinhold.

Sidman, M. (1960). Tactics of scientific research. New York: Basic Books.

Szostak, C., & Tombaugh, T. W. (1981). Use of a fixed-consecutive- number schedule of reinforcement to investigate the effects of pimozide on behavior controlled by internal and external stimuli. Pharmacology Biochemistry & Behavior. 15. 609-617.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 33

Thompson, D. M. (1978). Stimulus control and drug effects. In D. E. Blackman and D. J. Sanger (Eds.) Contemporary research in behavioral pharmacology.( p p . 159-207). New York: Plenum Press.

Thompson, T., & Schuster, C. R. (1968). Behavioral pharmacology. Englewood Cliffs, NJ: Prentice-Hall.

Wagman, W. D., & Maxey, G. C. (1969). The effects of scopolomine hydrobromide and methyl scopolomine hydrebromide upon the discrimination of interioceptive and exterioceptive stimuli. Psvchopharmacologia. 15. 220-228.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.