Irl Extein

Changes in lymphocyte beta-adrenergic receptors in depression and mania.

The beta-adrenergic receptors were studied in vitro in lymphocytes obtained from patients with major affective disorders and controls. Specific L-[3H]-dihydroalprenolol binding was decreased in both depressed and manic patients compared to controls and euthymic patients. Isoproterenol-stimulated, but not prostaglandin El-stimulated, cyclic adenosine-3,5-monophosphate production was decreased in manic and depressed patients. These results suggest decreased lymphocyte beta-receptor functioning in depression and mania. This decrease may be an index of changes in brain beta-receptors in mania and depression, or may simply reflect homeostatic regulation of peripheral beta-receptors in response to stress-induced increases in circulating catecholamines.

Behavioral and biochemical effects of FK 33-824, a parenterally and orally active enkephalin analogue

The pentapeptide FK33-824 is a synthetic analogue of the naturally occurring met-enkephalin (Roemer et al., 1977). This compound was synthesized in a successful effort to enhance the potency and systemic absorption of metxadenkephalin (figure 25.1). As reviewed throughout this book, there is a growing body of laboratory and clinical evidence that the endorphins have a role in many important CNS functions. It follows that the clinical effects of a drug such as FK33-824, which exhibits the spectrum of action of the endorphins and can be synthesized and administered with relative ease, should be carefully investigated.

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidin, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.

Dopamine-mediated behavior produced by the enkephalin analogue FK 33-824.

Intraperitoneal injection of FK 33-824 produced apomorphine-like stereotyped behavior in rats. Antagonism of this stereotypy by naloxone and neuroleptics suggests that FK 33-824 can activate opiate and dopamine receptors in the brain. Because increased dopaminergic neuronal activity is thought to be involved in schizophrenia and dopamine-mediated stereotypy has been used as an animal model for this illness, these results are consistent with an involvement of endogenous opiate-like peptides in schizophrenia. This involvement provides a possible mechanism for the reported improvement in schizophrenic psychosis produced by naloxone.

Endorphins and Affective Illness

The discovery of specific opiate receptors (Simon et al., 1973; Pert and Snyder, 1973) and the identification of naturally occurring peptides possessing opiatelike activity (endorphins) (Hughes et al., 1975; Li and Chung, 1976; Li et al., 1976; Bradbury et al., 1976; Chretien et al., 1976) have led to considerable research and speculation regarding the relationship of the endorphin system to psychiatric illness (Usdin et al., 1979; Verebey et al., 1978). The mood-altering and calming effects of exogenous opiates (Jaffe and Martin, 1975), the regional brain distribution of opiate receptors (Goldstein, 1976; Goldstein and Cox, 1977), and the behavioral effects of administered endorphins to rats (Bloom et al., 1976) suggested potential relationships between the endogenous opioid systems and emotional behavior. Although initial endorphin-behavioral hypotheses focused on etiologic relevance to schizophrenia (Bloom et al., 1976; Segal et al., 1977), alterations in endorphin function have been hypothesized to be reflected in disorders of mood (Byck, 1976; Belluzzi and Stein, 1977; Gold and Byck, 1978).

Endorphin Dysfunction in Panic Anxiety and Primary Affective Illness

The discovery of endogenous substances with opioid activity, the endorphins, in man and other species (Hughes, 1975; Pert et al.,1975; Simon, 1975) has stimulated recent investigations attempting to determine the role of these morphinelike substances in the brain. Thus far, two pentapeptides have been identified in the brain with potent opiate agonist activity. While recent studies and hypotheses have suggested a role for opioid peptides in mania, anxiety, psychosis, pain perception, motor behavior, and neuroendocrine regulation (Gold and Byck, 1978; Gold et al., 1977, 1979a; Kleber and Gold, 1978), little attention has been given to how these opioid peptides and receptors interact with other neurotransmitter systems to produce opiatelike effects and how this information might lead to a neural substrate for the signs, symptoms, and affects associated with opiate withdrawal and panic states in man (Gold and Pottash, 1980).