Modulators of drug dependence phenomena

Modulators of drug dependence phenomena

Concluding remarks

The role of several modulators was examined on morphine and cocaine dependence phenomena in rodents. The results of these studies were presented in the experimental parts of this thesis. The conclusions of these studies with possible clinical relevance were briefly pointed out. Finally, some suggestions for further research were given.

•   Antagonists of excitatory amino acid receptors (NMDA-type) and inhibitors of NO synthesis attenuated the expression of morphine withdrawal syndrome in both rats and mice.

We concluded that NO is an important neurotransmitter in respect to several withdrawal signs. This might be due to a facilitatory effect of NO on the release of various brain neurotransmitters and corresponding changes in the transmitter balance and functional activity of central neurons. We are suggesting that these preclinical studies of NO synthase inhibitors justify clinical trials of NO synthase inhibitors in drug-dependent subjects.

•   A putative "withdrawal substance" released in the cerebrospinal fluid (CSF) of spontaneous morphine-abstinent donor rats induces a withdrawal syndrome in morphine-dependent recipient rats. This putative "withdrawal substance" is hydrophobic and has no naloxone-like properties.

The presence of a "withdrawal factor" is a challenge for the further biochemical characterization of this substance and CSF of drug-dependent subjects. The question arises whether a "withdrawal substance" is a consequence or causally related to drug withdrawal phenomena.

•   Norharman prevented the expression of the naloxone-induced withdrawal syndrome. A somewhat similar (although less prominent) effect was observed in ibogaine treated morphine-dependent rats.

•   Ibogaine treatment of cocaine-dependent rats significantly decreased the cocaine-intake.

It is of importance to note that norharman as a physiological substance exerts antiwithdrawal properties. Although the chemical structure of ibogaine is similar to norharman, these two substances may have a different mechanism of action. lbogaine acts as a competitive NMDA antagonist, which might be an underlying mechanism of action of this alkaloid. The mechanism of action of norharman might be more related to the GABA receptor-complex on which this physiological substance has a binding place.

Suggestions for further research

•   The biochemical analysis of the CSF of drug-dependent subjects and further study of bioactive properties of the "withdrawal substance" found in the CSF of spontaneous morphine-abstinent rats is one of the forthcoming aims to study.

•   It is of importance to examine the synthesis and release of central NO and other neurotransmitters during morphine dependence and withdrawal syndrome, in the absence and presence of NOS inhibitors, in order to elucidate the role of NO in corresponding behavioral changes, occurring during opioid withdrawal.

•   There are indications that eicosanoids, the metabolic products of arachidonic acid may contribute to the mechanism of opioid withdrawal diarrhoea. Therefore, the interactions between disturbed production of arachidonic acid metabolites and the severity of naloxone-precipitated withdrawal diarrhoea in morphine-dependent animals is one of the subjects which deserves an attention to be studied.

• The glutamate-NMDA-NO system has a profound influence on many neurotransmitters, including the endogenous opioid peptides. We have already demonstrated that the glutamate-NMDA-NO system is involved in the expression of morphine withdrawal signs. The dopamine release induced by enkephalins, depends on involvement of glutamatergic transmission via NMDA receptors. Therefore, the interaction between the endogenous opioid peptides or exogenous opioids and EAA-glutamate system deserves to be studied.

•   It has been demonstrated that in the plasma of alcoholics and heroin addicts the level of norharman is increased. Further research in respect to the mechanism of action of norharman (the role of the GABA receptor-complex) and its effects in other types of drug dependence (alcohol, benzodiazepines, etc.) is worthwhile to study. The ability of ibogaine to modify drug seeking behaviour in the self-administration animal model, suggests a possible use of ibogaine in the treatment of human drug dependence and thereby warranting further study on its mechanism(s) of action.

• The impression could be raised that drug dependence phenomena could be totally explained as pharmacological processes. However, the social interactions are very important factors, which play a prominent role in human drug dependence phenomena. However, in most of the performed animal studies, social interactions have not been included. To my opinion, it is worthwhile to study drug dependence phenomena in animals housed in groups versus solitary housed animals.