mechanisms of drug addiction: focus on positive reinforcing properties of morphine

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DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS
23
MECHANISMS OF DRUG ADDICTION:
FOCUS ON POSITIVE REINFORCING
PROPERTIES OF MORPHINE
TOOMAS KIVASTIK
TARTU 1996
DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS
23
DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS
23
MECHANISMS OF DRUG ADDICTION:
FOCUS ON POSITIVE REINFORCING
PROPERTIES OF MORPHINE
TOOMAS KIVASTIK
TARTU UNIVERSITY
PRESS
Department of Pharmacology, University of Tartu, Estonia
Dissertation is accepted for the commencement of the degree of Doctor of
Medical Sciences on October 16, 1996 by the Council of the Faculty of
Medicine, University of Tartu, Estonia
Opponents: Professor Izjaslav Lapin, M.D., Ph.D., Bechterew Institute of
Psychoneurology, St. Petersburg
Professor Eero Vasar, M.D., Ph.D., University of Tartu
Commencement: December 18, 1996
© Toomas Kivastik, 1996 Tartu Ülikooli Kirjastuse trükikoda
Tiigi 78, EE2400 Tartu
Tellimus nr. 408
CONTENTS
LIST OF ORIGINAL PUBLICATIONS 7
ABBREVIATIONS 8
1. INTRODUCTION 9
2. REVIEW OF LITERATURE 10
2.1. Reinforcement theory 10
2.2. Principal models of drug addiction 10
2.3. Role of sensitization 11
2.4. Animal models of drug addiction 11
2.5. Positive reinforcing properties of morphine: neurochemical
basis 14
2.5.1. Role of opioid receptors 14
2.5.2. Role of brain dopamine 16
2.5.3. Role of nitric oxide 19
3. AIMS OF THE STUDY 20
4. MATERIALS AND METHODS 22
4.1. Animals 22
4.2. Drugs 22
4.3. Conditioned place preference 23
4.4. Conditioned place aversion 24
4.5. Analgesia and rectal temperature 24
4.6. Catatonia 24
4.7. Chronic morphine treatment 25
4.8. Locomotor activity 25
4.9. Yawning behaviour 25
4.10. Stereotypy 26
4.11. Statistics 26
5. RESULTS 27
5.1. Opioid receptors 27
5.1.1. Effect of opioid receptor antagonists on morphine-in-
duced place preference 27
5.1.2. Effect of opioid receptor antagonists on morphine-
induced catatonic state, antinociception, and hyperther­
mia 27
5.2. Dopamine receptors 29
5.2.1. Effect of quinpirole and preclamol on place preference
induced by morphine and cocaine 29
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5.2.2. Effect of acute morphine administration on quinpirole-
induced yawning in rats 31
5.2.3. Effect of naloxone on quinpirole-induced yawning in
morphine-p retreated rats 31
5.2.4. Effect of SCH23390 on quinpirole-induced yawning in
morphine pretreated rats 31
5.2.5. Effect of morphine withdrawal on quinpirole-induced
yawning behaviour in rats 32
5.2.6. Effect of acute morphine treatment and morphine with­
drawal on locomotor activity in rats. Influence of mor­
phine withdrawal on quinpirole-induced hypolocomotion 32
5.2.7. Effect of morphine withdrawal on quinpirole-induced
stereotyped behaviour in rats 33
5.3. Nitric oxide 33
5.3.1. Effect of NO synthase inhibitor L-NOARG on morphine-
induced place preference 33
5.3.2. Effect of NO synthase inhibitor L-NOARG on U50,488-
induced place aversion 34
6. DISCUSSION 35
6.1. Role of opioid receptor subtypes in positive reinforcing proper­
ties of morphine 35
6.2. Role of brain dopamine in morphine and cocaine reinforcement 36
6.3. Dopamine D2/D3 receptors and morphine-induced behavioral
sensitization 39
6.4. Role of nitric oxide in positive reinforcing properties of mor­
phine 41
7. CONCLUSIONS 43
8. REFERENCES 44
SUMMARY IN ESTONIAN 54
ACKNOWLEDGMENTS 57
PUBLICATIONS 58
LIST OF ORIGINAL PUBLICATIONS
This study is based on the following publications:
I Kivastik, T., Vuorikallas, K., Piepponen, T. P., Zharkovsky, A., Ahtee, L.
Morphine- and cocaine-induced conditioned place preference: effects of
quinpirole and preclamol. Pharmacology Biochemistry and Behavior, 54:
371-375, 1996.
II Kivastik, T., Rutkauskaite, J., Zharkovsky, A.
Nitric oxide synthesis inhibition attenuates morphine-induced place pref­
erence. Pharmacology Biochemistry and Behavior, 53: 1013-1015, 1996.
III Zharkovsky, A., Moisio, J., Kivastik, T., Ahtee L.
Role of dopamine receptors in the dual effect of naloxone on quinpirole-
induced yawning in morphine pretreated rats. Naunyn — Schmiedeberg's
Archive of Pharmacology, 347: 478^482, 1993.
IV Piepponen, T. P., Katajamäki, J., Kivastik, T., Zharkovsky, A., Ahtee, L.
Behavioural and neurochemical sensitization of morphine-withdrawn rats
to quinpirole. Pharmacology Biochemistry and Behavior, 54: 787-792,
1996.
V Piepponen, T. P., Kivastik, T., Katajamäki, J., Zharkovsky, A., Ahtee, L.
Involvement of opioid (LLI -receptors in morphine-induced conditioned
place preference in rats. Submitted to Pharmacology Biochemistry and
Behavior. Accepted 24 November 1996
Articles are reprinted with permission of copyright owners
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ABBREVIATIONS
DPDPE [D-Pen2,D-Pen5]enkephalin
DSLET [D-Ser2,Leu5]enkephalin-Thr6
GABA gamma-aminobutyric acid
ICV intraeerebroventricular(ly)
IP intraperitoneal(ly)
IV intravenous(ly)
L-NOARG N^-nitro-L-arginine
NMDA N-methyl-D aspartate
6-OHDA 6-hydroxydopamine
7-OH-DPAT 7-hydroxy-(2-N,N-dipropylamino)-tetraline
SC subcutaneous(ly)
VTA ventral tegmental area
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1. INTRODUCTION
"For thousands of years we have pursued altered mental
states and other-wordly insights, whether through prayer
and meditation, through art or sexual ecstacy, or through
psychoactive substances" (R.Campbell-Johnston, The
Times, August 14, 1996).
Drug addiction is defined as a behavioral syndrome consisting of compulsive
pattern of drug use, characterized by overwhelming involvement with the use of
a drug, the securing of its supply, and a high tendency to relapse after with­
drawal [abstinence] (Jaffe, 1975). In other words, in the case of addiction the
use of a drug appears to dominate over behaviors that once had a higher value,
the ones essential for the organism's survival and well-being included. This
intrinsic feature of addiction is well characterized by the term motivational
toxicity (Bozarth and Wise, 1985).
In the contemporary world drug addiction has become a major health prob­
lem. Despite the vast amount of scientific information available, the ability of
drugs to create addiction is still poorly understood, and research in this area is
characterized by controversial findings. Furthermore, no effective treatment is
available as yet.
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2. REVIEW OF LITERATURE
2.1. REINFORCEMENT THEORY
The most popular approach has been the behavioristic one, that is, to analyze
the addiction process within the framework of drug reinforcement theory
(which is an extension of operant psychology). Accordingly, drug addiction is
viewed as a behavior controlled by its consequences, which means that "... the
behavior of drug taking is governed by the direct and immediate consequences
of that behavior — drug administration and the ensuing pharmacological ac­
tions of the drug" (Bozarth, 1987). The term reinforcement is used in order to
describe the relationship between the behavior and its consequences. By nature
reinforcement can be either positive or negative. In the case of positive rein­
forcement the presentation of a stimulus (i.e., the drug) increases the frequency
(or probability) of the behavior that presentation of the stimulus is contingent
upon; whereas negative reinforcement refers to a situation in which the fre­
quency of the behavior is increased by the removal of the stimulus (e.g., with­
drawal syndrome). It is important to note that reinforcement merely describes
the changes in the probability of behavior and does not offer any physiological
or psychological explanations to this.
Reward is another term that is widely used in the present context. It is, un­
fortunately, somewhat ill-defined and therefore used in the literature in many
different meanings. Many researchers refer to reward interchangeably with re­
inforcement, and the present study will do the same.
2.2. PRINCIPAL MODELS OF DRUG ADDICTION
There are two general models of drug addiction that have evolved from rein­
forcement theory. According to the negative reinforcement model, addictive
behavior (drug seeking and drug taking) is sustained because of the state that is
alleviated by drugs. In this model the central role is given to the aversive con­
sequences of drug withdrawal. The second model concentrates on the positive
reinforcing properties of a drug, asserting that addictive behavior is sustained
not because of the condition that the drugs remove or lessen, but because of the
state the drugs produce.
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