Naloxone inhibits oxytocin release at orgasm in man.

We examined the effect of naloxone on plasma oxytocin levels during sexual activity in men. Eight normal men took part in a double-blind, two-period, cross-over design. Mean plasma oxytocin rose to 362% of baseline values at orgasm with placebo (saline) but showed no increase with naloxone (P less than 0.01). While naloxone had no effect on heart rate or blood pressure at orgasm, a decrease in the level of subjective arousal and pleasure at orgasm was noted. We conclude that opioid receptor blockade with naloxone has an inhibitory effect on the neural pathways mediating the oxytocin response at orgasm.

Changes in oxytocin and vasopressin secretion during sexual activity in men.

We measured plasma oxytocin (OT) and arginine vasopressin (AVP) concentrations in 13 normal men during sexual arousal and ejaculation. Mean plasma AVP increased from 1.4 +/- 0.2 (+/- SE) to 5.3 +/- 1.7 pmol/L (P less than 0.05) during arousal, but there was no significant change in OT. In contrast, at ejaculation mean plasma OT rose from a basal value of 1.4 +/- 0.3 to 7.3 +/- 0.6 pmol/L (P less than 0.01) and then fell to basal concentrations in 30 min. AVP, however, had returned to basal levels at the time of ejaculation and remained stable thereafter. We conclude that in man AVP is secreted during sexual arousal, and there is, subsequently, a selective release of OT at the time of ejaculation.

Enhanced startle reactions to acoustic stimuli in patients with obsessive-compulsive disorder.

OBJECTIVE: Anxiety states induced experimentally or occurring naturally potentiate the startle reflex elicited by sudden sensory stimuli in both animals and human beings. The authors investigated whether patients with obsessive-compulsive disorder (OCD) show exaggerated startle reactions to acoustic probes, especially during negative-affect-toned stimuli, compared with healthy subjects. METHOD: Ten patients with OCD and 10 age- and sex-matched comparison subjects were shown a series of film clips. Two of the film clips had positive valence, two had negative valence, and two had relatively neutral valence. The subjects' eyeblink startle response was measured in reaction to startle-eliciting stimuli presented three times binaurally during each film clip. RESULTS: Patients with OCD produced larger startle reflexes and shorter latencies to onset of startle response than the comparison subjects over the entire session. CONCLUSIONS: Patients with OCD were excessively responsive to startle-eliciting stimuli. This effect may be associated with the development or maintenance of OCD.

Urinary excretion of dimethyltryptamine in liver disease.

The urinary excretion of N,N-dimethyltryptamine (DMT) was higher in patients with severe liver disease than in normal subjects. This difference remained significant when patients with all grades of hepatic encephalopathy were excluded. Patients with liver disease whose mental states were normal excreted amounts of DMT similar to those of patients with a hospital diagnosis of schizophrenia.

Functional MRI study of the cognitive generation of affect.

OBJECTIVE: The authors investigated, by whole brain functional magnetic resonance imaging (MRI), the neural substrate underlying processing of emotion-related meanings. METHOD: Six healthy subjects underwent functional MRI while viewing 1) alternating blocks of pairs of pictures and captions evoking negative feelings and the same materials irrelevantly paired to produce less emotion (reference pairs); 2) alternating blocks of picture-caption pairs evoking positive feelings and the same materials irrelevantly paired to produce less emotion; and 3) alternating blocks of picture-caption pairs evoking positive feelings and picture-caption pairs evoking negative feelings. RESULTS: Compared with the reference picture-caption pairs, negative pairs activated the right medial and middle frontal gyri, right anterior cingulate gyrus, and right thalamus. Compared with the reference picture-caption pairs, positive pairs activated the right and left insula, right inferior frontal gyrus, left splenium, and left precuneus. Compared with the negative picture-caption pairs, positive pairs activated the right and left medial frontal gyri, right anterior cingulate gyrus, right precentral gyrus, and left caudate. CONCLUSIONS: Contrasts of both 1) negative and reference picture-caption pairs and 2) positive and negative picture-caption pairs activated networks involving similar areas in the medial frontal gyrus (Brodmann's area 9) and right anterior cingu-late gyrus (areas 24 and 32). The area 9 sites activated are strikingly similar to sites activated in related positron emission tomography experiments. Activation of these same sites by a range of evoked affects, elicited by different methods, is consistent with areas within the medial prefrontal cortex mediating the processing of affect-related meanings, a process common to many forms of emotion production.

No effect of naloxone on plasma oxytocin in normal men.

The role of endogenous opiates in the control of the secretion of oxytocin in the basal state in healthy male volunteers was investigated with the opiate antagonist naloxone. There was no change in plasma oxytocin levels, assessed for a 120 min period following the intravenous administration of naloxone (10 mg). Although there was no effect of opiate receptor blockade with naloxone in this basal situation, further studies are needed to evaluate the possible role of opioid regulation of oxytocin during lactation and parturition.

The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles.

In order to investigate mechanisms by which the adrenal 11 beta-hydroxylase inhibitor metyrapone might exert its antidepressant effect, we used gas chromatography to analyse the 24 h urinary steroid profiles from six females with major depression taking part in a trial of metyrapone (2-4 g/day) as an antidepressant. Due to concurrent administration of hydrocortisone (30 mg/day), plasma cortisol levels were not significantly reduced. Treatment with metyrapone resulted in greatly increased urinary excretion of 11-deoxy corticosteroids, including the GABA-modulatory steroid tetrahydro-11-deoxycorticosterone (from 68 +/- 34 to 219 +/- 75 micrograms/24 h, p < .05). Metyrapone also had multiple extra-adrenal effects on corticosteroid metabolism, including inhibition of the peripheral conversion of cortisone to cortisol as demonstrated by a significant decrease in the ratio of 11 beta-hydroxy/11-oxo metabolites of cortisol (from 0.81 +/- 0.08 to 0.46 +/- 0.04, p < .01). The decreased Montgomery-Asberg Depression Rating Scale scores seen during treatment with metyrapone did not correlate with changes in plasma cortisol, but did correlate significantly with total 11-deoxycortisol metabolites (r = 0.778, n = 12, p < .01). We conclude that, in addition to decreased cortisol synthesis, increased secretion of cortisol precursors and reduced local bioavailability of cortisol may play a role in the antidepressant effect of metyrapone.

Measurement of the GH and other responses to clonidine at different times of the day in normal subjects.

The growth hormone response to clonidine may be impaired in some patients with endogenous depression. To determine whether or not this change is due to a circadian variation in the GH response to clonidine, this measure has been studied in normal subjects at 0900, 1800 and 2100 hr. Similar responses were obtained at 0900 and 1800 hr. The responses at 2100 hr could not be interpreted, as the baseline plasma GH was raised. At no time of day were there impaired GH responses similar to those found in endogenous depression. The effects of clonidine upon blood pressure and alertness were similar at the three times studied, providing no support for any circadian rhythm in the function of the alpha 2-adrenoceptors that mediate these effects of clonidine.

The effects of alaproclate on the pupillary responses to tyramine, phenylephrine and pilocarpine in depressed patients.

Nine depressed patients were treated with alaproclate, a selective 5-HT uptake inhibitor, for 3 weeks in a dose of 400 mg daily. The pupillary responses to tyramine, phenylephrine, and pilocarpine eye drops were measured on consecutive days before, after 1 week and after 3 weeks of treatment. The tyramine-induced mydriasis was unaffected by alaproclate, suggesting that it does not significantly inhibit the reuptake of noradrenaline. The pilocarpine-induced miosis and the phenylephrine-induced mydriasis were both enhanced after 1 week but not after 3 weeks of treatment. This suggests that alaproclate acutely increases the responsiveness of postsynaptic muscarinic and alpha 1 adrenoceptors.

Effect of cigarette smoking on prepulse inhibition of the acoustic startle reflex in healthy male smokers.

The present study investigated the effects of cigarette smoking on prepulse inhibition (PPI) of the acoustic startle reflex in healthy men. Cigarette smoking in a group of overnight smoking-deprived smokers increased PPI as compared to the smoking-deprived condition. This finding is consistent with previous animal studies showing that nicotine increases PPI of the acoustic startle reflex. In addition, cigarette smoking also reduced startle amplitude during the first 6-7 min of the post-smoking session.

Changes in the sensitivity of the central alpha- and beta-adrenergic systems during desmethylimipramine treatment as assessed by plasma growth hormone response in the baboon.

The tricyclic antidepressant desmethylimipramine (DMI) 2.5 mg/kg IM was administered to adolescent baboons once daily for 21 days, to investigate changes in alpha- and beta-noradrenergic function. Prior to DMI treatment, plasma growth hormone (GH) responses to the intravenous infusion of an alpha 2-adrenergic receptor agonist, clonidine, or a beta 2-adrenergic antagonist, ICI 118,551, were determined. DMI, 2.5 mg/kg, administered acutely did not stimulate the release of GH (up to 4 h post injection). The GH response to clonidine was decreased 4 h after DMI, 2.5 mg/kg. Alterations in plasma GH response to clonidine and ICI 118,551 were evident during and after chronic DMI administration. The GH response to clonidine was significantly diminished after 2 days, and gradually returned to the pretreatment amplitude over 7-21 days of treatment, with an overshoot 2 days after DMI withdrawal. After 21 days of DMI administration the GH response to ICI 118,551 was significantly enhanced, and remained consistently elevated during a withdrawal period of 21 days. These changes in the response to an alpha-adrenergic agonist and a beta-adrenergic antagonist indicate that the long term regulatory changes in receptor sensitivity, occurring between 2 and 21 days of DMI treatment, compensate for the acute effects of DMI on these responses.

Clinical studies of the effect of (+) and (-)-oxaprotiline upon noradrenaline uptake.

In six normal male subjects the mydriatic effect of tyramine eye drops was inhibited by 1 day's treatment with desipramine and the (+)- but not the (-)-enantiomer of oxaprotiline. In the same experiment, the secretion of melatonin was increased after treatment with (+)- but not with (-)-oxaprotiline. The effects of (+)-oxaprotiline and of desipramine treatment were similar, as were those of (-)-oxaprotiline and placebo. These findings extend to clinical studies the demonstration in animal experiments of stereo-specificity for the effects of (+)- and (-)-oxaprotiline upon noradrenaline uptake. A comparison of the effects of the two enantiomers should provide an ideal strategy for studying effects of noradrenaline uptake blockade in clinical studies.

Changes in noradrenergic neuroendocrine responses following repeated seizures and the mechanism of action of ECT.

To investigate the mechanism of action of ECT in depression, functional changes in central noradrenergic systems, resulting from a series of electroshock- or photic-induced seizures have been evaluated in baboons. The plasma growth hormone (GH) response to IV infusion of an alpha 2-noradrenergic agonist clonidine (0.02 mg/kg) or a beta 2-adrenergic antagonist, ICI 118,551 (0.02 mg/kg) has been measured before, during and up to 15 days after the series of seizures. Electroshock (ECS) or sham ECS was given with standard clinical premedication (atropine, methohexital, suxamethonium and oxygen ventilation) seven times over 15 days. Plasma GH responses were unchanged 24 h after one or seven ECS. An enhanced GH response occurred 7 and 15 days after the seventh ECS. Sham ECS (seven times in 15 days) produced no changes in GH response to clonidine. The plasma GH response to ICI 118,551 was apparently decreased 1 and 7 days after the seventh ECS. Photic seizures were induced seven times in 15 days in baboons which were primed with a subconvulsant dose of D,L-allylglycine (180 mg/kg), but were otherwise drug-free. Plasma GH responses to clonidine were enhanced 1 and 7 days after the seventh photically induced seizure. It is concluded that in the primate there is an enhancement of a central alpha 2-noradrenergic response during 1-15 days after a sequence of generalised seizures. The time course of this enhancement appears to be influenced by drugs given directly before the seizures.

Effect of acute subcutaneous nicotine on prepulse inhibition of the acoustic startle reflex in healthy male non-smokers.

In a double-blind placebo-controlled trial, the effects of two doses (6 micrograms/kg, 12 micrograms/kg) of acute SC nicotine were investigated on prepulse inhibition (PPI) of the acoustic startle reflex in healthy non-smoker male volunteers. Each subject received three injections [placebo (saline), 6 micrograms/kg nicotine, 12 micrograms/kg nicotine] on separate occasions, 2 weeks apart. No influence of either 6 micrograms/kg or 12 micrograms/kg nicotine was observed for the amplitude and habituation of the startle response over pulse-alone stimuli, relative to the saline-treated condition. Percent of PPI (expressed as percent reduction of non-prepulse trials) was significantly greater, but PPI as measured by absolute difference scores was not significantly different, when subjects were given the 12 micrograms/kg dose of nicotine than saline. There was an increase in percent of PPI from saline through low to high doses of nicotine, but PPI observed under the low dose did not differ significantly from either the high dose or placebo. These results provide some support for previous findings showing an enhancement in PPI by cigarette smoking in overnight smoking-deprived smokers and by acutely administered nicotine in experimental animals. The findings indicate that previously observed effects of smoking on percent of PPI in smoking-deprived subjects were not attributable to the restoration of a deficit induced by smoking withdrawal, but represent a direct pharmacological action of nicotine.

Effect of clonidine on the human acoustic startle reflex.

The present study investigated in healthy human volunteers whether clonidine reduced the amplitude of the acoustic startle reflex and whether this effect, if found, was due to an accelerated rate of habituation. Subjects were presented with startle-eliciting noise-bursts after intravenous (iv) infusion of clonidine (1.5 microgram/kg) and saline on separate days. Clonidine significantly reduced the amplitude of the acoustic startle reflex (as indexed by the eyeblink component) relative to the saline treated condition. This effect was neither due to an accelerated rate of habituation of the startle reflex nor to the sedative effect of clonidine. These findings complement an earlier report (Morgan et al. 1993) that yohimbine augments the amplitude of the startle reflex in man. Taken together, the two reports indicate a new model for the clinical investigation of central alpha2 adrenoceptor function in humans.

Effects of acute administration of d-amphetamine and haloperidol on procedural learning in man.

The effects of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers using a between-subjects double-blind design in a procedural learning task, thought mainly to involve unconscious/automatic learning. The results showed: (1) d-amphetamine facilitated response speed, whereas haloperidol inhibited it, in comparison to placebo; (2) the linear increase in procedural learning corresponded with pharmacological manipulation of degree of dopaminergic activity, i.e. subjects given haloperidol showed the least, and subjects given d-amphetamine the greatest, procedural learning. The implications of these findings are discussed in relation to investigation of abnormalities of procedural learning processes in schizophrenia.

Effects of sex steroids on protein synthesis in cultured human lymphocytes.

In cultured human lymphocytes, oestrogen and progesterone at concentrations found in plasma during the normal menstrual cycle, significantly increase the incorporation of [35S] methionine into protein and, in addition, both hormones significantly alter the relative synthesis of certain proteins. At concentrations found in plasma during pregnancy, some changes are augmented while others are reversed. These specific sex-steroid-induced changes in protein synthesis provide possible peripheral biological markers of hormone action which may be tested for their association with predisposition to, and/or onset of, conditions such as postpartum psychiatric illness.

Contribution of psychological and social factors to psychotic and non-psychotic relapse after childbirth in women with previous histories of affective disorder.

Twenty-six women with a history of bipolar or schizoaffective disorder, 17 women with histories of major depressive disorder and 45 control women without any previous psychiatric history were assessed in the 9th month of pregnancy on selected psychosocial measures. No subject was a 'case' as defined by the Research Diagnostic Criteria (RDC) from this time until the delivery. Within 6 months postpartum, 22 (51%) of the women with histories of mental illness were categorised as having relapsed (RDC case). Twelve women developed a psychosis (mania, hypomania or schizomania) and these illnesses occurred only in women with histories of affective or schizoaffective psychosis whereas 10 other women who became depressed after delivery came equally from the women with histories of psychosis (N = 5) as from those with histories of major depression (N = 5). Three (7%) control women also developed postpartum non-psychotic depressive disorders. Multivariate analyses suggest that different psychosocial factors contribute to the recurrence of affective and schizoaffective psychosis after delivery as opposed to non-psychotic postpartum affective disorders. A non-psychotic illness was predicted by antenatal neuroticism and a severe life event before illness onset. A recurrence of psychosis postpartum was predicted by a history of mania, hypomania or schizomania, a more recent psychiatric admission and reported marital difficulties. In this sample of women, life stress led to postpartum depression irrespective of the subject's past history and the high rates of recurrence of affective or schizoaffective psychosis (47%) probably mainly reflected a pre-existing physiological or psychological vulnerability which may have been exacerbated by, or contributed to, marital difficulties.

Treatment of major depression with metyrapone and hydrocortisone.

Eight inpatients with Major Depression were treated with metyrapone and hydrocortisone in a balanced order placebo-controlled single-blind cross-over study. The hydrocortisone dose (30 mg daily) was a physiological replacement dose and the metyrapone dose was titrated against plasma cortisol in order to keep cortisol within physiological limits. The treatment resulted in a significant reduction in depressive symptoms. This placebo-controlled study replicates the results of several uncontrolled studies but leaves open for further study the mechanism by which the combined administration of metyrapone and hydrocortisone might exert its antidepressant effect.

Affective modulation of the startle response in depression: influence of the severity of depression, anhedonia, and anxiety.

BACKGROUND: The amplitude of the startle reflex response is known to be influenced by the concomitant presentation of affect-toned material--if it is positive affect-toned, the reflex is inhibited, and if it is negative affect-toned, the reflex is augmented. Abundant evidence demonstrates the utility of the affect-startle paradigm as a significant tool for measuring both positive and negative emotions. We applied this paradigm to study emotional reactivity in depression, particularly in relation to symptoms of depression, anhedonia, and anxiety. METHODS: Depressed patients (22) and controls (22) were shown a series of film clips, consisting of two clips with positive valence, two with negative valence, and two with relatively neutral valence. The startle response was measured in reaction to the acoustic startle-eliciting stimuli presented three times binaurally during each clip. RESULTS: Highly depressed and anhedonic patients, relative to controls, showed a reduced mood (self-ratings) and a lack of startle modulation in response to affective film clips whereas patients relatively low on depression/anhedonia displayed a reduced mood only with pleasant clips and a normal pattern of affective startle modulation. Anhedonia and depression were highly positively correlated but neither correlated with anxiety. Anxious patients displayed larger reflexes across all clips and showed a reduced mood modulation with pleasant, but not unpleasant, clips. LIMITATIONS: The large majority of patients was medicated with antidepressants which may have influenced the results. CONCLUSIONS. Reactivity to pleasant stimuli is diminished in patients suffering from low levels of depression and/or anhedonia, but reactivity even to unpleasant stimuli seems compromised at high levels of depression and/or anhedonia. Anxiety is associated with hyperstartle responding.