Outline of the studies

This thesis compiles the experimental studies on several drugs, which modulate drug dependence phenomena in rodents. The main part of the studies is related to the morphine withdrawal (chapters 3-7), while a minor part is dealing with cocaine psychic dependence (chapter 9).

Part 1: Drug Dependence and Harmful Use of Drugs Chapter 1

In both men and animals, drug dependence phenomena have continuously been studied over the past decades. However, much confusion and discussion was (and is still) going on about terms such as dependence, abuse, addiction, etc. Therefore, these and other terms are firstly defined, while in the second part of this chapter, several classes of dependence-producing drugs are described. The characteristics of these drugs are discussed in respect to dependence, tolerance and withdrawal, and also some information related to their behavioral effects and mechanism of action is provided.

Part 2: Opioid Dependence Chapter 2

This chapter starts with a classification of opioids and their receptors and is followed by information related to morphine dependence phenomena, particularly tolerance and withdrawal syndrome.

Part 3: Morphine Withdrawal Syndrome - Experimental Studies Chapter 3

It has been shown that during morphine withdrawal, an enhanced release of several neurotransmitters occurs, including L-glutamate. The excitatory amino acid (EAA) Lglutamate, released presynaptically, activates the postsynaptically localized N-methyl-Daspartate (NMDA)-glutamate receptors (Fig. 1). Since the opioid withdrawal syndrome is a reflection of neuronal and behavioral excitation, we studied the role of the excitatory glutamate system in the opioid withdrawal. We demonstrated that administration of NMDA receptor antagonists attenuated naloxone-precipitated withdrawal syndrome in morphine-dependent mice.

Chapter 4 and 5

Following the demonstration that NMDA receptor blocking agents attenuated morphine withdrawal syndrome (chapter 3), we postulated that endogenous compounds synthesized in response to stimulation of NMDA receptors may also play a role in the expression of opioid withdrawal syndrome. Among these compounds is the "new" peripheral and central neurotransmitter nitric oxide (NO). NMDA receptor mediated Ca z* entry into the cell may stimulate Cat' dependent NO synthase (NOS) enzyme in some neurons, resulting in the formation of NO (Fig. 1). In order to examine the effect of this neurotransmitter on naloxone-precipitated withdrawal syndrome, we blocked the NO synthesis in both morphine-dependent mice (chapter 4) and rats (chapter 5) by NOS inhibitors. These two studies showed that the expression of the naloxone-precipitated withdrawal syndrome in morphine-dependent mice and rats can be affected by inhibition of NO synthesis. We suggest that these preclinical studies justify clinical trials of NOS inhibitors in drug-dependent subjects.

Fig. 1. Nitric oxide (NO) is produced following N-methyl-D-aspartate (NMDA) receptor activation and subsequent increase in intracellular Ca2+. NO diffuses to adjacent glia and/or other neurons where it induces a wide variety of actions.

Glu = glutamate;   ± > = stimulation;    > = inhibition/blockade. (1)   Blockade of NMDA receptors by diverse NMDA receptor blocking agents. Results are described in chapter 3.

(2)   Blockade of NO synthesis by NO synthase (NOS) inhibitors. Results are described in chapters 4 and 5

Chapter 6

There are indications that some peptides released in cerebrospinal fluid (CSF) may modulate opioid withdrawal. In this study, we showed that the CSF of spontaneous morphine-abstinent donor rat precipitates in morphine-dependent recipient rat an opioid withdrawal syndrome. During this CSF-induced morphine withdrawal syndrome a decrease of the peak latency of visual evoked potentials was registered, indicating an enhanced central excitability. The CSF-induced morphine withdrawal syndrome is behaviorally less severe and electrophysiologically less prominent, but qualitatively identical to the naloxone-induced abstinence. However, in contrast to naloxone, the CSF from spontaneous morphine-abstinent rat does not exert a contraction of isolated morphine-dependent guineapig ileum. Chromatographic analysis of the CSF has shown that a putative "withdrawal substance" is present only in the CSF of spontaneous morphine-abstinent rats, but not in the CSF of naive or morphine-dependent rats. The "withdrawal substance" is a hydrophobic compound, without naloxone-like properties. However, further analysis of the biochemical structure and bioactivity are necessary.

Chapter 7

Studies, performed earlier at the Department of Pharmacology, Erasmus University Rotterdam, have shown that ibogaine may attenuate naloxone-precipitated withdrawal in morphine-dependent rats. It has been also claimed that ibogaine is an anti-addictive drug, presently undergoing a clinical trial in several countries. However, norharman is an endogenous physiological substance, with a biochemical structure related to ibogaine. Both drugs are indole derivatives with psychotogenic properties. Therefore, we performed a comparative study with these drugs in relation to the expression of opioid withdrawal syndrome. We have shown that norharman (parenteral administration) had a more prominent anti-withdrawal effect than ibogaine. It is known that norharman binds at the asubunit of the gamma-amino butyric acid (GABA) receptor-complex. This physiological substance and the GABA receptor-complex might be a target for further elucidation of drug dependence phenomena.

Part 4: Drug Dependence induced by Psychostimulants

Chapter 8

This chapter gives a general description of psychostimuIants, with recent data mainly related to the cocaine dependence

Part 5: Cocaine Dependence - Experimental Study Chapter 9

We examined the effect of ibogaine treatment on cocaine self-administration in rats. In this study ibogaine was selected for two reasons. Our earlier experiments have shown that ibogaine attenuates morphine withdrawal in rats. In addition, the non-controlled observations in humans demonstrated that ibogaine interrupts drug dependence on alcohol, amphetamine and nicotine. We have shown that ibogaine is a long-lasting interruptor of cocaine self-administration in cocaine-dependent rats. These preclinical studies justify a clinical trial of ibogaine in drug-dependent subjects, which presently takes place in several countries.

Concluding remarks and some suggestions for further research are given at the end of this thesis

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