Drug Dependence: A Pharmacological Analysis *

Summary The main thane of this lecture is the study of drug‐dependence through its interactions with other pharmacologically or physiologically active substances, particularly those known to interact with endogenous humoral mechanisms. A study of the interactions of atropine para‐chlorophenylalanine, and indomethacin with an acute morphine dependence in the rat has shown that the intensity or direction or action of the modifying drug may be determined by (I) the particular withdrawal effect studied and (2) whether the drug is given before dependence induction or before withdrawal. From this we infer that morphine dependence is multipartite as regards mediators involved, and that the involvement of acetylcholine, 5‐hydroxytryptamine and prostaglandin(s) in certain parts of dependence is intimate. Other drugs interacting with dependence include those that block catecholamine synthesis and those inhibiting protein synthesis. At the whole animal level, the most important property of a drug of dependence is its ability to reinforce positively and sometimes also negatively its self injection. In other words, drugs of dependence alter in favour of reward the balance of the reward‐punishment relationship in the brain and their withdrawal reverses this. With drugs having physical withdrawal effects, psychic dependence may simply be one part of a multipartite structure. From the evidence discussed, two general implications for dependence mechanisms emerge. First, catecholomines are probably involved in drug‐induced reward, because (a) amphetamine euphoria is inhibited by α‐methyltyrosine, (b) self‐stimulation in rats is inhibited by drugs blocking catecholamine synthesis, and (c) some of the most rewarding drugs of dependence (opioids, cocaine and amphetamine) interact with catecholamines. We do not know which of dopamine and noradrenaline might be the main catecholamine concerned, but present experimental evidence favours noradrenaline. Second, mechanisms proposed to account for physical dependence may also apply to psychic dependence. These considerations enable us to re‐examine, by means of particular cases, the general hypothesis that tolerance and for dependence might arise through a drug‐induced, Actaptive change in the number (or efficiency) of receptors. In one case, where the receptor involved interacts with drug to produce a response, receptor multiplication might be expected to produce sensitization, rather than tolerance, to that response, without dependence. If the receptor interacts with drug to produce no effect (e.g. sequestration of drug molecule), then receptor multiplication would lead1 to tolerance, but not dependence. In a second case, if the receptor is for an endogenous neurohumoral mediator or its precursor and not for drag, its change in number would lead to tolerance associated with dependence, as probably occurs with morphine. In a third case, if the receptor is both for drug and for endogenous neurohumoral substance, then its e in number would lead to dependence without tolerance, as probably occurs with cocaine.