(+)-Amphetamine binding to rat hypothalamus: relation to anorexic potency for phenylethylamines.

Saturable and stereospecific binding sites for (+)-[3H]amphetamine were demonstrated in membrane preparations from rat brain. The density of these binding sites varies among brain regions and is highest in the hypothalamus and brainstem. Specific (+)-[3H]amphetamine binding in hypothalamus is largely confined to synaptosomal membranes, rapidly reversible, and sensitive to both heat and proteolytic enzymes. Scatchard analysis of the equilibrium binding data revealed two distinct sites with apparent affinity constants of 93 and 300 nanomoles per liter, respectively. The effects of various psychotropic drugs as well as a number of putative neurotransmitters and related agonists and antagonists in displacing specific (+)-[3H]amphetamine binding demonstrate that these binding sites are not associated with any previously described neurotransmitter or drug receptors, but are specific for amphetamine and related phenylethylamine derivatives. Furthermore, the relative affinities of a series of phenylethylamine derivatives for (+)-[3H]amphetamine binding sites in hypothalamic membranes is highly correlated to their potencies as anorexic agents. These results suggest the presence of specific receptor sites in hypothalamus that mediate the anorexic activity of amphetamine and related drugs.

[1]  S. Paul,et al.  High affinity and stereospecific binding of [3H]d-amphetamine to rat brain. , 1982, European journal of pharmacology.

[2]  J. Comaty,et al.  Hypothalamic catecholamine systems in genetically obese mice (obob): Decreased sensitivity to reserpine treatment , 1980, Neuropharmacology.

[3]  S. Paul,et al.  Receptors for the age of anxiety: pharmacology of the benzodiazepines. , 1980, Science.

[4]  H. Mohler,et al.  Benzodiazepine receptor: demonstration in the central nervous system , 1977, Science.

[5]  C. Braestrup,et al.  Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Snyder,et al.  Opiate receptor in normal and drug altered brain function* , 1975, Nature.

[7]  D. Segal,et al.  Behavioral characterization of d- and l-amphetamine: neurochemical implications , 1975, Science.

[8]  J. Ahlskog.  Food intake and amphetamine anorexia after selective forebrain norepinephrine loss. , 1974, Brain research.

[9]  S. Snyder,et al.  Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain , 1973, Science.

[10]  A. Azzaro,et al.  Selectivity of release of norepinephrine, dopamine and 5-hydroxytryptamine by amphetamine in various regions of rat brain. , 1973, Biochemical pharmacology.

[11]  K. E. Moore,et al.  Release of endogenously synthesized catechols from the caudate nucleus by stimulation of the nigro-striatal pathway and by the administration of d-amphetamine. , 1973, Brain research.

[12]  S. Snyder,et al.  Differential effects of D- and L-amphetamine on behavior and on catecholamine disposition in dopamine and norepinephrine containing neurons of rat brain. , 1971, Brain research.

[13]  S. Leibowitz.  Reciprocal hunger-regulating circuits involving alpha- and beta-adrenergic receptors located, respectively, in the ventromedial and lateral hypothalamus. , 1970, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Margules.  Alpha-adrenergic receptors in hypothalamus for the suppression of feeding behavior by satiety. , 1970, Journal of comparative and physiological psychology.

[15]  L. Stein,et al.  Release of norepinephrine from hypothalamus and amygdala by rewarding medial forebrain bundle stimulation and amphetamine. , 1969, Journal of comparative and physiological psychology.

[16]  J. Glowinski,et al.  EFFECT OF DRUGS ON THE UPTAKE, RELEASE, AND METABOLISM OF H3-NOREPINEPHRINE IN THE RAT BRAIN. , 1965, The Journal of pharmacology and experimental therapeutics.

[17]  J. Axelrod.  Studies on sympathomimetic amines. II. The biotransformation and physiological disposition of d-amphetamine, d-p-hydroxyamphetamine and d-methamphetamine. , 1954, The Journal of pharmacology and experimental therapeutics.

[18]  V. P. Whittaker,et al.  The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. , 1962, Journal of anatomy.