https://www.cell.com/cell/pdf/S0092-8674(00)80949-6.pdf

Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine----each ofwhich also has psychomotor stimulant actions--may activate the docaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration. Attempts at a general theory of addiction are attempts to isr late--from a variety of irrelevant actionsmthose drug actions that are responsible for habitual, compulsive, nonmedical drug self-administration. The common assumption of addiction theorists is that general principles of addiction can be learned from the study of one drug and that these principles will have heuristic value for the study of other drugs. Thus far, attempts at a general theory of addiction have failed to isolate common actions that can account for addiction across the range of major drug classes. A major stumbling block has been the psychomotor stimulants--amph etamine and cocainemwhich do not readily fit models traditionally based on depressant drug classes. The present article offers a new attempt at a general theory of addiction. It differs from earlier theories (e.g., Collier, 1968; Himmelsbach, 1943; Jaffe & Sharpless, 1968; Jellinek, 1960; Kalant, 1977; Lindsmith, 1947; Solomon & Corbit, 1974) in that it is based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on the common denominator of the socalled depressant drugs~opiates, barbiturates, alcohol, and others. We take up two topics before presenting the new theory. First, we briefly discuss the heuristic value of a biological approach and suggest that the biologist's distinction between homology and analogy offers a useful insight. Next we discuss the shortcomings of earlier theories--variants of dependence theory. Then we outline the new theory and review the relevant evidence for its three major assertions: (a) that all addictive drugs have psychomotor stimulant actions, (b) that the stimulant actions of these different drugs have a shared biological mechanism, and (c) that the biological mechanism of these stimulant

A psychomotor stimulant theory of addiction

The three-dimensional structure of acetylcholinesterase from Torpedo californica electric organ has been determined by x-ray analysis to 2.8 angstrom resolution. The form crystallized is the glycolipid-anchored homodimer that was purified subsequent to solubilization with a bacterial phosphatidylinositol-specific phospholipase C. The enzyme monomer is an alpha/beta protein that contains 537 amino acids. It consists of a 12-stranded mixed beta sheet surrounded by 14 alpha helices and bears a striking resemblance to several hydrolase structures including dienelactone hydrolase, serine carboxypeptidase-II, three neutral lipases, and haloalkane dehalogenase. The active site is unusual because it contains Glu, not Asp, in the Ser-His-acid catalytic triad and because the relation of the triad to the rest of the protein approximates a mirror image of that seen in the serine proteases. Furthermore, the active site lies near the bottom of a deep and narrow gorge that reaches halfway into the protein. Modeling of acetylcholine binding to the enzyme suggests that the quaternary ammonium ion is bound not to a negatively charged "anionic" site, but rather to some of the 14 aromatic residues that line the gorge.

https://science.sciencemag.org/content/sci/253/5022/872.full.pdf

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein

This article offers a reformulation of the negative reinforcement model of drug addiction and proposes that the escape and avoidance of negative affect is the prepotent motive for addictive drug use. The authors posit that negative affect is the motivational core of the withdrawal syndrome and argue that, through repeated cycles of drug use and withdrawal, addicted organisms learn to detect interoceptive cues of negative affect preconsciously. Thus, the motivational basis of much drug use is opaque and tends not to reflect cognitive control. When either stressors or abstinence causes negative affect to grow and enter consciousness, increasing negative affect biases information processing in ways that promote renewed drug administration. After explicating their model, the authors address previous critiques of negative reinforcement models in light of their reformulation and review predictions generated by their model.

/pdf/addiction-motivation-reformulated-an-affective-processing-3dezd2dpj3.pdf

Addiction motivation reformulated: an affective processing model of negative reinforcement.

Ligand-binding assays are used for determination of minute amounts of substances in the bloodstream. Such assays require a receptor that specifically binds the substance of interest. The receptor used is often an antibody, but antibodies require special handling and a costly production procedure. We have used molecular imprinting, a method for creating selective recognition sites in synthetic polymers, to prepare polymers that mimic antibody combining sites. Molecular imprints made against theophylline and diazepam showed strong binding and cross-reactivity profiles similar to those of antibodies. Here we describe a new radiolabelled ligand-binding assay, the molecularly imprinted sorbent assay, which uses antibody mimics. This assay accurately measures drug levels in human serum, with results comparable to those obtained using a well established immunoassay technique. Antibody mimics, which are stable and readily prepared by molecular imprinting, may provide a useful general alternative to antibodies.

Drug assay using antibody mimics made by molecular imprinting

on pharmacology and the rational use of drugs, 42 authors share the herculean task of reviewing the flood of recent literature. Under single or dual authorship they contribute the 76 chapters in the 18 sections. The "liberal use of extract (fine) type as a space-saving device" allows nearly twice as much material under one cover. Although portions printed in smaller type "are of somewhat lesser importance," in most cases it will be necessary and profitable to read these. For example, extract type is used to narrate the historical background and to discuss complex structure-activity relationships, significant laboratory and clinical studies, the types of preparations, dosages and routes of administration, side effects and adverse reactions, and the therapeutic uses. Each chapter offers a complete and up-to-date review. Usually, enough information is given so that

The pharmacological basis of therapeutics

1. Eserine, by combining reversibly with rat brain cholinesterase, has been shown to protect the enzyme against irreversible inactivation by DFP in vitro . The degree of protection varied directly with the concentration of eserine used. It is concluded that this phenomenon might explain the mechanism by which prophylactic eserine protects cats against DFP poisoning in vivo .

2. Of nineteen other anticholinesterase drugs similarly tested, two showed marked protection (prostigmin and carbamylcholine), six afforded relatively slight protection (pilocarpine, nicotine, atropine, choline, procaine and morphine) and eleven showed none (methylene blue, strychnine, atabrine, quinine, sodium fluoride, thiamin, cysteine, sodium p-amino-benzoate, acetyl-beta-methylcholine, acetyicholine and Intocostrin). The protective property does not appear to depend on the potency of anticholinesterase activity alone, but also on the ability of a compound to compete with DFP for a specific active group of the cholinesterase molecule.

George B. Koelle

Papers

The pharmacological basis of therapeutics

Protection of cholinesterase against irreversible inactivation by di-isopropyl fluorophosphate in vitro

The chronic toxicity of di-isopropyl fluorophosphate (DFP) in dogs, monkeys and rats.

Transmission of impulses in peripheral nerves treated with di-isopropyl fluorphosphate (dfp)

The pharmacology of di-isopropyl fluorophosphate in man.