Effect of acute methadone withdrawal on prostaglandin E-stimulated 3H-cyclic adenosine monophosphate accumulation in human platelets.

The effect of acute methadone withdrawal was studied on PGE1-sensitive platelet adenylate cyclase of 8 former heroin addicts who had been stabilized with methadone. During acute methadone withdrawal there was a significant increase in PGE1-sensitive platelet adenylate cyclase activity, which correlated with the severity of withdrawal symptoms. This suggests that PGE1-sensitive adenylate cyclase and cyclic adenosine monophosphate (cyclic AMP) are involved in the human addictive process.

Diagnostic subgroups of affective disorders and their urinary excretion of catecholamine metabolities.

Previous reports have indicated that some depressed patients excrete less than normal quantities of 3-methoxy-4-hydroxyphenyl glycol (MHPG). The authors present data indicating that a subgroup of depressed patients who excrete less than normal quantities of MHPG may be identified by the application of explicit clinical criteria. They found no significant difference in the excretion of normetanephrine (NM), metanephrine (M), and 3-methoxy-4-hydroxymandelic acid (VMA) among any of the diagnostic subgroups or between each patient group and a healthy comparison group. However, depressed patients diagnosed as having primary affective disorder and bipolar illness excreted significantly less MHPG than did the healthy comparison group.

Growth hormone catecholamines in affective disease.

The authors studied growth hormone (GH) release after insulin-induced hypoglycemia (HI) in relation to urinary MHPG, the major metabolite of central norepinephrine. There was a significant linear correlation of urinary MHPG levels and GH peaks after HI in unipolar depressed patients and in manic patients; however, GH peaks in manic patients shifted downward on the GH axis in comparison to the unipolar depressive patients. The authors suggest that such shifts in the GH response may occur as a result of abnormalities of other neurotransmitter systems also known to facilitate GH release.

Symptomatic reactive hypoglycemia during glucose tolerance test in lithium-treated patients.

Glucose, insulin, glucagon, and cortisol responses during a five-hour oral glucose tolerance test (GTT) were evaluated in nine patients with bipolar affective disorders who were receiving lithium treatment and in seven control patients with bipolar affective disorders who were not receiving any treatment. Both the lithium-treated and the control patients were in stable mood at the time of GTT. During GTT mean nadir serum glucose of 48 +/- 2 mg/dL in the lithium-treated patients was significantly lower (P less than 0.001) than mean nadir serum glucose of 62 +/- 2 mg/dL observed in the control subjects. Seven of these nine lithium-treated patients, but none of the control patients, experienced hypoglycemic symptoms coinciding with low serum glucose concentration. In response to hypoglycemia, mean serum cortisol significantly rose (P less than 0.01) to 22 +/- 3 micrograms/dL in the lithium-treated patients, whereas mean serum cortisol levels gradually declined to 10 +/- 2 micrograms/dL in the control patients at 300 minutes. Despite symptomatic postglucose hypoglycemia, plasma glucagon levels in the lithium-treated patients were similar to those observed in the control patients. These findings suggest that chronic lithium treatment is associated with a symptomatic and biochemical hypoglycemia during GTT, which is characterized by a rise in serum cortisol but by lack of appropriate rise in plasma glucagon concentrations.

Neuropeptides differentially effect various forms of morphine tolerance.

Two different forms of tolerance to morphine were shown to develop. One form, environment dependent (ED), was associated with cues paired with the arrival of the drug. The second form of tolerance, environment independent (EI), was not dependent on any cues. ED tolerance was induced using a multiple injection model in which a cue (orange scent) preceeded each morphine injection (ip). After 12 days the animals were tolerant to the i.p. injection. However if morphine was injected i.c.v. tolerance was no longer evident. EI tolerance was induced by a pellet implant method. These animals were tolerant to morphine regardless of the route of administration. Peptides arginine vasopressin (AVP) and cyclo (Leu-Gly) (cLG) were tested for their ability to alter tolerance. AVP was found to facilitate the development of ED tolerance but had no effect on EI tolerance. On the other hand cLG blocked the development of EI tolerance without affecting ED tolerance. The determination of brain morphine levels indicated that the ED tolerance produced by this method is dispositional while EI tolerance is functional.

In vivo down-regulation of rat striatal opioid receptors by chronic enkephalin.

Administration of methionine enkephalin (ICV) to rats for 5 days resulted in the development of physical dependence as exemplified by a hypothermic response which peaked 2-8 hours after initiation of withdrawal. Twenty-four hours post-withdrawal, opioid receptor binding was determined in the striatum using a selective delta receptor ligand. These studies revealed a decreased in the number of receptors. Bmax decreased from 193 +/- 20.4 fmoles/mg protein in controls to 136 +/- 9.7 fmoles/mg protein in enkephalin treated rats. This difference is significant at p less than 0.001. Existing evidence suggests that this decrease in binding is predominantly due to a decrease in delta receptors. Hence, the present findings indicate that delta receptor down-regulation in vivo may be an important mechanism in the adaptive response to chronic exposure to an endogenous opioid peptide.

Differential down-regulation of delta opioid binding sites during physical dependence on methionine enkephalin in the rat.

Post-synaptic receptor modulation is thought to be one important mechanism involved in the adaptation of a neuronal system during chronic exposure to a drug. However, initial studies of opioid receptor regulation following chronic in vivo administration of narcotic agonists, such as morphine, reported no down-regulation in the number of opioid receptors in the brain. Subsequent studies, employing in vitro preparations, have reported evidence of opioid receptor down-regulation under specific conditions. It remains to be determined whether the in vitro phenomena of opioid receptor plasticity is relevant to the intact mammalian central nervous system. The data in this report shows that chronic in vivo administration the opioid peptide methionine enkephalin, results in a significant, regionally specific down-regulation of delta opioid receptors in rat brain: 30% decrease in receptor density in the striatum; no change in hypothalamus.

Radio-frequency analysis of the effect of haloperidol and cyclo (leucyl-glycyl) on apomorphine-induced stereotypy.

Our previous studies indicated that the peptide cyclo(leucyl-glycyl) (cLG) prevents the development of supersensitivity to dopamine in several animal models at both biochemical and behavioral levels. We therefore tested cLG in a paradigm more commonly used to model tardive dyskinesia, namely chronic haloperidol administration to rats. We found that cLG administered subcutaneously at a dose of 8 mg/kg, blocked about 50% of the supersensitizing effects of of haloperidol on apomorphine-induced stereotypic behaviors. Further, we used a novel method, radio-frequency analysis, that quantifies sniffing and other stereotypic movements. Unlike methods that rely on visual observation of stereotypy and utilize an ordinal scale, these measurements are rated by an automatic motility monitor and utilize a ratio scale. Unlike other automated motility monitors, this device can distinguish between various forms of stereotypic behaviors. Since parametric statistics can be used, there is a significant improvement in the efficiency of the task of rating and comparing stereotypy scores.

Characteristics of receptors and enzymes in brains of human alcoholics.

Acute and chronic ethanol administration to animals has been shown to produce changes in the turnover of numerous neurotransmitters, as well as to change the characteristics of certain neurotransmitter receptors. In the present study, brains obtained from human alcoholics and matched control subjects were examined for similar changes. In frontal cortex, the affinity of opiate receptors for dihydromorphine was significantly reduced in brains of alcoholics. Judging from animal studies, this change may reflect alterations in opiate receptor-effector coupling processes. No changes were observed in muscarinic cholinergic or beta-adrenergic receptors in humans, in contrast to animals, possibly because of the protracted abstention from alcohol among the alcoholic patients prior to death. Similarly, no changes in the activities of choline acetyltransferase, tyrosine hydroxylase or MAO-B were observed in brains of alcoholics as compared to the control population. Our studies suggest that many of the alterations witnessed during alcohol intoxication and withdrawal in animals may be more subtle in humans, or may be reversible with abstinence.

Regulation of neuronal adenylate cyclase.

It appears that several components function in a spirit of integrated cooperation toward the intracellular regulation of neurotransmitter responsiveness. We have demonstrated that cytoskeletal proteins might interact with GNs and that GNs and GNi might interact with one another. At this juncture, it appears that both of these phenomena might occur only in cells of neural origin. Calmodulin and antidepressants may also affect adenylate cyclase in nervous tissue alone. The effects of AAGTP are different in nervous tissue from other tissues, and experiments with that nucleotide have led to the discovery of a new, 32 kDa GTP-binding protein which appears only in neural crest cells. Appreciation of the intricacies of signal transduction through the adenylate cyclase system are developing along with our understanding of that system. When combined with the complexity of neurotransmitter responsiveness, comprehension of the combined systems remains in its infancy, destined to grow as well as to surprise and delight all who are interested.

Anxiety and mood fluctuation during the normal menstrual cycle.

Eleven women with an average age of 23 were evaluated daily for pregnanediol excretion, mood, and behavioral fluctuations during the menstrual cycle. Subjects carefully screened for present and preexisting psychopathology experienced only minor fluctuations in rating on the Moos Menstrual Distress questionnaire (MDQ), only the water retention achieving significance. The other scales on the MDQ and the Spielberger State Anxiety Scale had nonsignificant premenstrual elevations.

The effect of chronic met-enk on various dopamine systems in the rat.

Morphine and enkephalins act preferentially via different receptors, mu and delta, respectively. Chronic administration of morphine or methionine enkephalin results in development of physical dependence. Data from our laboratory suggests that there are some differences in the effect of these two opioids with regards to certain neurochemical systems.

Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories.

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.

Cyclo (Leu-Gly) attenuates the striatal dopaminergic supersensitivity induced by chronic morphine.

Cyclo(Leu-Gly) (CLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), has direct effects on dopamine (DA) mediated behaviors as well as on D-2 DA receptors. Endogenous opioids, as well as morphine have also been implicated as neuromodulators of dopaminergic function. We studied these interactions in an animal model in which chronic morphine administration induces a dopaminergic supersensitivity that can be detected during the 48 hour (h) period following withdrawal of morphine. At 24 h following morphine withdrawal, there was a 3.5-fold increase in stereotypic behavior in rats following a challenge dose of apomorphine (APO) (0.5 mg/kg). By 48 h this effect had disappeared. Co-administration of CLG (8 mg/kg s.c.) with morphine attenuated the development of the behavioral supersensitivity to APO. D-2 DA receptor binding analysis indicated that parallel molecular changes occurred. There was a morphine-induced increase in the affinity (+167 percent) in antagonist (i.e. 3H-spiroperidol displaced by butaclamol) binding at 24 h after withdrawal. Co-administration of CLG with morphine attenuated these DA receptor changes at 24 hours which is consistent with the peptide's effect on stereotyped behavior. However, antagonist binding parameters did not parallel changes in behavior at 48 h. Agonist binding was then studied by examining DA displaceable 3H-spiroperidol (75 pM) binding to the D-2 DA receptor. Two receptor subpopulations D-2-HI and D-2-LO were revealed. Morphine caused an increase in the affinity for agonist binding to the D-2-HI site (83-fold increase). Affinity changes at the D-2-HI site correlated positively and strongly with the behavioral changes in all groups at both 24 and 48 h. We conclude that changes in agonist binding to D-2 DA receptors rather than antagonist binding is more consistent with the behaviors induced by morphine and CLG.