The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.

Dopamine, learning and motivation

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

Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations.

Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Control rats initiate self-administration of d-amphetamine and achieve stable injection rates within 7-10 days. Rats in which dopamine nerve terminals in nucleus accumbens were destroyed by bilateral microinjections of 6-hydroxydopamine (6-OHDA) did not initiate self-administration of d-amphetamine when tested for as long as 19 days. In rats previously trained to self-administer d-amphetamine, 6-OHDA injections into nucleus accumbens abolished d-amphetamine self-administration. These results suggest that dopaminergic nerve terminals in nucleus accumbens are necessary for both the acquisition and maintenance of d-amphetamine self-administration.

Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on d-amphetamine self-administration.

After labeling the caudate nucleus of spinal-sectioned cats with 3H-dopamine and perfusing the cerebroventricular system, d - or l -amphetamine, amantadine or tyramine was added to the perfusion inflow. All four drugs caused a concentration-related efflux of 3H-dopamine into the ventricular effluent. When the experiment was repeated using cats with chronic lesions of the nigro-striatal dopaminergic fibers, the drug-evoked efflux was greatly reduced. When similar lesions were made during perfusate collection. a significant drop in 3H-dopamine efflux occurred. The ability of amphetamine and amantadine to increase 3H-dopamine efflux was markedly decreased by this acute lesion; the efflux indueed by tyramine was unaffected. Low concentrations of amphetamine or amantadine but not tyramine, potentiated the efflux of 3H-dopamine elicited by low frequency nigro-striatal pathway stimulation. Thus, the efflux of 3H-dopamine evoked from central dopaminergic synapses by amphetamine and amantadine is primarily dependent upon the impulse activity of neurons in the nigro-striatal pathway; the release by tyramine, although arising from the same terminals, is not dependent upon ongoing impulse activity.

Involvement of nigro-striatal neurons in the in vivo release of dopamine by amphetamine, amantadine and tyramine.

The activity of 5-hydroxytryptaminergic neurons has been estimated from measurements of: (1) concentrations of 5-hydroxyindoleacetic acid; (2) the ratio of the concentrations of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine; (3) the rate of accumulation of 5-hydroxytryptophan following the administration of an aromatic l-amino acid decarboxylase inhibitor (e.g., NSD 1015); (4) the rate of accumulation of 5-hydroxytryptamine, and the rate of decline of 5-hydroxyindoleacetic acid following the administration of a monoamine oxidase inhibitor (e.g., pargyline). The purpose of the present study was to compare these different methods under conditions of changing neuronal impulse traffic produced by electrical stimulation of 5-hydroxytryptaminergic neurons. Male rats anesthetized with chloral hydrate were killed following 0, 15, or 30 tain of electrical stimulation of the dorsal raphe nucleus at a frequency of 0, 5, or 10 Hz. The concentrations of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan in nucleus accumbens, amygdala, suprachiasmatic nucleus, and dorsomedial nucleus were measured using HPLC coupled to an electrochemical detector. In each brain region, stimulation elicited an increase in the concentration of 5-hydroxyindoleacetic acid and the 5-hydroxyindoleacetic acid/5-hydroxytryptamine concentration ratio in saline-treated animals and an increase in 5-hydroxytryptophan accumulation in NSD 1015-treated animals, but did not alter the concentration of 5-hydroxytryptamine or 5-hydroxyindoleacetic acid in pargyline-treated rats. The results of this study indicate that although the first three methods serve as valid indices of 5-hydroxytryptaminergic neuronal activity, the pargyline-dependent techniques are not responsive to changes in the rate of 5-hydroxytryptamine nerve firing.

A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus.

Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: Effects of apomorphine, l-DOPA, amantadine, amphetamine and other psychomotor stimulants ☆

The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs.

Kenneth E. Moore

Papers

Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on d-amphetamine self-administration.

Involvement of nigro-striatal neurons in the in vivo release of dopamine by amphetamine, amantadine and tyramine.

A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus.

Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: Effects of apomorphine, l-DOPA, amantadine, amphetamine and other psychomotor stimulants ☆

The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs.