Neuroendocrine responses to a glucose challenge in substance users with high and low levels of aggression, impulsivity, and antisocial personality.

Plasma glucose concentrations, and plasma prolactin and cortisol responses to a 5-hour oral glucose tolerance test (OGTT) in 37 substance abusers, were examined to assess the relationship between varying degrees of antisocial personality, impulsivity, and aggressiveness and measures of endocrine function. Childhood and presenting aggression, impulsivity and antisocial personality features were evaluated by several self-report questionnaires. Those with high scores for psychopathic deviance (MMPI) differed in glucose levels following OGTT from those with low scores. Lower cortisol nadir levels were associated with higher scores on measures of antisocial personality and aggressiveness. Also, prolactin response to glucose was attenuated relative to baseline levels in the more antisocial and aggressive subjects. The results indicate that substance abusers with high levels of self-reported antisocial personality and aggressive behavior have altered neuroendocrine responses to glucose challenge, although there was no evidence of hypoglycemia. No one personality or behavioral trait, as measured by our test battery, more strongly predicted neuroendocrine responses to glucose administration. Thus, our data partially support other reports of altered neuroendocrine responses to stressful challenges in aggressive/antisocial individuals.

Impulsivity, aggression, and neuroendocrine responses to serotonergic stimulation in substance abusers.

Alterations in the activity of central serotonergic systems have been implicated in impulsive and aggressive behavior. We examined the neuroendocrine and psychological responses of 24 substance users with differing levels of aggressiveness and impulsivity to the oral administration of an indirect serotonin agonist fenfluramine (60 mg) or placebo given in a double-blind crossover design. All subjects were volunteers on a closed research ward and were abstinent from drugs for a minimum of 5 days. Baseline plasma prolactin (PRL) levels were greater in the groups with higher levels of self-reported aggressiveness and impulsivity. When adjusted for the baseline, PRL and cortisol responses 180 min after fenfluramine administration were significantly elevated in subjects with higher levels of aggressiveness and impulsivity. Peak cortisol levels were correlated with impulsivity. PRL and cortisol responses to fenfluramine were more strongly correlated with impulsivity than aggressiveness. Also, the more impulsive subjects reported a decrease in subjective states of depression, hostility and anxiety after drug treatment. These data further support the hypothesis of altered serotonergic activity in aggressive and impulsive behaviors.

Geographic distribution of human immunodeficiency virus markers in parenteral drug abusers.

Drug abuse treatment programs in six regions of the United States collaborated in a study aimed at monitoring trends in the seroprevalence of human immunodeficiency virus (HIV) antibodies. The wide disparities in HIV seroprevalence in the face of similarities in drug using behavior have important implications for prevention. In the New York City area (Harlem, Brooklyn), 61 per cent of samples (N = 280) obtained in late 1986 were positive, up from 50 per cent of samples (N = 585) in early 1985. In Baltimore, Maryland, 29 per cent of samples (N = 184) representing 11 programs were positive. In contrast, samples from programs distant from the Northeast corridor had far lower rates: Denver, Colorado 5 per cent (N = 100); San Antonio, Texas 2 per cent (N = 106); Southern California, 1.5 per cent (N = 413); and Tampa, Florida, 0 per cent (N = 102). Contrary to expectations, there was no corresponding difference in reported lifetime needle sharing experiences, which ranged from 70 per cent in New York to 99 per cent in San Antonio. HIV seropositivity was associated only with geographic location and ethnicity; however, because needle sharing is practiced by parenteral drug abusers in areas where seroprevalence is still relatively low, these areas are potentially vulnerable to the same catastrophic spread seen in the Northeast. A window of opportunity exists where prompt, vigorous, and aggressive efforts at prevention could have major impact.

Dissociation of the cardiovascular and prolactin-releasing activities of norvaline2-TRH.

The effects of thyrotropin-releasing hormone (TRH) and norvaline2-TRH (Nva2-TRH) on blood pressure, heart rate and plasma prolactin levels in conscious rats have been compared. Systemic injection of TRH or Nva2-TRH (1 mg/kg or 5 mg/kg) produced equipotent increases in plasma prolactin. On the other hand, while TRH significantly increases blood pressure and heart rate, Nva2-TRH was essentially inactive. Thus, two contrasting analogues are now available: 4-NO2-Im-TRH (Neuropeptides, 8, 63, 1986) has full cardiovascular activity and no PRL-releasing activity, while Nva2-TRH has no cardiovascular activity and full PRL-releasing activity of TRH.

Calcium-independent and calcium-dependent mechanisms regulate corticotropin-releasing factor-stimulated proopiomelanocortin peptide secretion and messenger ribonucleic acid production.

We have evaluated the role of calcium in basal and secretagogue-stimulated release of beta-endorphin and PRL and the levels of their respective mRNAs in primary cultured rat anterior pituitary cells. Treatment of anterior pituitary cells with the calcium channel blocker methoxyverapamil (D600; 10 microM) or with calcium-free medium for 1 h did not alter the basal release of beta-endorphin and only partially blocked CRF (10 nM)-stimulated beta-endorphin release. In contrast to these effects of D600 or calcium-free medium on corticotrophs, both of these test conditions decreased basal secretion of PRL from lactotrophs by 50-70% and completely blocked forskolin (10 microM)-stimulated PRL secretion. Although omission of calcium from the culture medium caused a 50% decrease in basal levels of both proopiomelanocortin (POMC) and PRL mRNA, treatment of cells with D600 did not significantly alter the basal levels of POMC or PRL mRNA. Treatment of cells with D600 partially blocked CRF-stimulated elevation of POMC mRNA and forskolin-stimulated elevation of PRL mRNA. The calcium agonist barium (1 mM) produced a 2-fold increase in both beta-endorphin and PRL release, which was blocked by D600. Treatment of cells with barium had no effect on POMC mRNA levels, but increased PRL mRNA levels. D600 treatment of cells partially blocked barium-stimulated PRL mRNA levels. These findings demonstrate a calcium-dependent as well as a calcium-independent component of CRF-stimulated beta-endorphin secretion and CRF-stimulated POMC mRNA elevation. In contrast, PRL secretion and biosynthesis appear to be totally calcium-dependent processes.

Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat.

The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hormone (TRH), 4-nitro-imidazole TRH (4-nitro-TRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoro-methyl-imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). None of the analogs were more potent than TRH in inducing cardiovascular changes. The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elicited a 4 to 5 fold increase in PRL at the higher dose. The present results suggest that the receptors for TRH-elicited PRL release differ from TRH-receptors involved in its cardiovascular actions.

Modulation of dopamine receptor supersensitivity by chronic insulin: implication in schizophrenia.

Haloperidol-induced increases in the number of dopamine receptors, as measured by [3H]spiperone binding to striatal membranes, do not occur in rats repeatedly treated with insulin in doses eliciting pronounced hypoglycemia. Given alone, however, insulin has no effect on [3H]spiperone binding in normal rats. These findings demonstrate a modulating effect of insulin on brain dopamine receptor sensitization. This effect might be relevant to the mechanism of insulin coma therapy in schizophrenia and is consistent with and supports the dopaminergic hypothesis of this disorder.

Differential effect of fluorinated analogs of TRH on the cardiovascular system and prolactin release.

The effects of thyrotropin-releasing hormone (TRH) and the TRH-analogs, 4-fluoro-Im-TRH (4-F-TRH) and 2-trifluoromethyl-Im-TRH (2-TFM-TRH), on the cardiovascular system and prolactin (PRL) release were examined in conscious rats. TRH (2.8 or 28 nmol) injected into the anterior hypothalamus produced dose-dependent increments in blood pressure and heart rate; plasma PRL was increased twofold after the higher dose of TRH. 4-F-TRH had effects similar to those of TRH on both the cardiovascular and PRL response. In contrast, the 2-TFM-TRH was significantly less active than TRH or 4-F-TRH in eliciting tachycardia, yet was noticeably more potent in affecting PRL release. These data suggest that the receptors for TRH-induced PRL release may be different from TRH-receptors which mediate central cardiovascular responses.

Cardiovascular and plasma prolactin responses to stereoisomers of phencyclidine.

The effect of phencyclidine (PCP) and dextro- and levorotatory isomers of its derivatives 1-(1-phenylcyclo-hexyl)-3-methylpiperidine [(+)-PCMP and (-)-PCMP] (5 mg/kg, SC) on blood pressure (BP), heart rate (HR) and plasma prolactin (PRL) were examined. PCP and (+)-PCMP but not (-)-PCMP increased BP and HR and suppressed plasma PRL.

Effects of phencyclidine on rat prolactin, dopamine receptor and locomotor activity.

Plasma prolactin (PRL) was decreased in naive rats sacrificed 30 min after phencyclidine (PCP) administration (10 mg/kg, s.c.). There was, however, no decrease in plasma PRL 30 min after s.c. injection of PCP (10 mg/kg) on the 29th day following 28 days of chronic PCP administration. These data suggest the development of tolerance to the PRL-suppressive effect of PCP as result of long-term administration of the drug. The Bmax of [3H]-spiperone binding to rat striatal membranes was decreased 24 hrs after 28 days of PCP treatment without change in affinity (Kd). No indication of the development of tolerance in these rats was found with regard to the locomotor-stimulating effect of PCP. The plasma PRL-suppressive effect of the PCP analog PCMP was found to be stereospecific; (-) PCMP was much less potent than (+)-PCMP.

Lithium and the prevention of dopamine receptor supersensitivity in diabetic rats.

Dopamine receptors were increased in rats made diabetic by alloxan; however, chronic lithium treatment substantially reduced the number of dopamine receptors. These findings may be relevant to the effects of lithium in psychiatric disorders.

Dopamine receptor binding is increased in diabetic rats.

The binding of [3H]spiperone, a dopamine receptor ligand, to striatal membranes was increased 30 to 35 percent in rats made diabetic with alloxan or streptozotocin. Binding of [3H]spiperone was normal in rats made diabetic with alloxan but treated with insulin. Thus the number of dopamine receptors and central dopaminergic transmission may be altered in diabetes.