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Thirty drug-free patients fulfilling the DSM-III criteria for major depression serially underwent the dexamethasone suppression test (DST), thyroid stimulating hormone (TSH) test and a growth hormone (GH) challenge test with oral desipramine. Fifty-three per cent of the sample showed a blunted GH response, 47% were DST non-suppressors while 26% had a blunted TSH response. Eighty per cent of patients showed some biological abnormality. There was no clear association between any of these abnormalities. Neither was there any association between the neuroendocrine parameters studied and the severity of depression or patient gender. There was a trend for increasing GH blunting and DST non-suppression with increasing age.

Prolactin response to buspirone challenge was examined in eight normal healthy male and six healthy female volunteers. A significant increase in prolactin levels was noted around 90 min following oral administration of buspirone hydrochloride. When subjects were tested on two further occasions it was found that responses in males were consistently reproducible while responses in females varied throughout the menstrual cycle with maximum responses occurring premenstrually. It is postulated that increased sensitivity of the 5HT receptor premenstrually may explain the variability in females.

Desipramine, the monoamine reuptake inhibitor, acts predominantly on noradrenergic neurones, and via alpha-2 receptors brings about the release of growth hormone in normal healthy subjects. Thirteen patients with a diagnosis of irritable bowel syndrome, 10 normal controls and eight patients with peptic ulcer disease were each given a challenge test of desipramine 1 mg/kg body weight. Growth hormone release over a 3 h period was monitored. A blunted response was defined as a failure of growth hormone levels to rise at least 5 mU/l above baseline. Of the 13 patients with irritable bowel syndrome 11 showed such a blunting. The results suggest abnormal central alpha-2 receptor functioning in irritable bowel syndrome.

Intracellular recordings were made from pyramidal CA1-neurones of the hippocampal slice preparation. Bath application of a wide variety of neuroleptics was found to depress the slow afterhyperpolarization, which is mediated in these neurons by a calcium-dependent potassium conductance occurring following a burst of spikes. The depression of this conductance took place in the presence of calcium spikes of normal amplitude and duration, and except in the case of trifluoperazine, without alteration in resting membrane potential or input resistance.

Rats were administered haloperidol (0.5 mg/kg/day) for 21 days. Twenty percent of locus coeruleus (LC) neurons recorded were not spontaneously active, while no such neuron was observed in control animals. A further 22% of neurons (spontaneously active) had rates greater than 2 standard deviations from the mean of LC control cells. These results reveal that haloperidol has profound effects on LC neurons that develop with prolonged administration, indicating a possible role of brain noradrenergic systems in clinical effects (and possible side-effects) of this neuroleptic.

Recent studies have renewed interest in the role of acetylcholine (ACh) in the cognitive changes associated with ageing and dementia. Deficits in cortical choline acetyltransferase (ChAT) in Alzheimer's disease have been consistently demonstrated, while other research has suggested a connection between deterioration of cortical ACh fibres and dementia. However, despite clear biochemical and anatomical evidence for a fall in ACh in dementia, results of therapeutic trials with cholinergic agonists, precursors and cholinesterase inhibitors have been inconsistent. Such findings suggest that cortical cholinergic disorders are not wholly a function of simple biochemical change; alterations of impulse flow along cholinergic fibres could well be as debilitating. An important extrinsic source of cortical ACh innervation derives from neurones diffusely located in rat basal forebrain, denoted the nucleus basalis (NB). We have now investigated the impulse conduction properties of cortically projecting, putatively cholinergic NB axons in adult and aged rats and have found that conduction latencies from NB to frontal cortex are significantly longer (by 51%) in aged animals. In addition, systematic analysis varying cortical stimulation depth revealed that these longer latencies are due entirely to decreased conduction velocities in the subcortical fibre projections. Indeed, intracortical velocities were virtually identical in the two groups. Our results indicate that ageing occasions a decrease in the temporal fidelity of impulse flow in the cholinergic input to the cortex from the NB, a previously overlooked but potentially important element in cognitive deficits that occur with age.

Cortically projecting, putatively cholinergic neurons in the area of globus pallidus (corresponding to nucleus basalis) were identified by antidromic activation from frontal cortex in anesthetized rats. These cells exhibited heterogeneous physiological properties, yielding spontaneous discharge rates of 0-40 Hz, a variety of impulse amplitudes and waveforms, and a wide range of conduction latencies from frontal cortex (1-13 ms). In addition, many cells were found to be antidromically activated from neighboring cortical sites 1-2 mm apart.

Haloperidol (0.5 mg/kg, i.p.) increased impulse activity of every noradrenergic locus coeruleus neuron tested in chloral hydrate anesthesized rats. Mean discharge rate increased from 1.4 +/- 0.2 Hz before to 2.7 +/- 0.4 Hz at 45 min after injection, with significantly increased activity occurring by 15 min post-drug. Elevated activity was apparent for at least 2 h following haloperidol. These results reveal that haloperidol has profound effects on brain noradrenergic neurons, indicating a possible site of action for effects of this neuroleptic agent.

Platelet-rich plasma from healthy controls was pre-treated with neuroleptics of the phenothiazine, butyrophenone or benzamide variety before aggregation with one of the following agonist agents: ADP, adrenaline, 5-HT, collagen, platelet activating factor or ristocetin. All compounds effective as antipsychotics, except sulpiride, depressed aggregation. Unmedicated schizophrenics showed aggregation responses indistinguishable from healthy controls. However, within days of treatment with either trifluoroperazine or haloperidol responses became abnormal in acutely psychotic patients. Increased responses to 5-HT and depressed responses to platelet activating factor were detected. After 4 weeks of treatment responses tended to return to normal. Aggregation responses were normal in those patients on long-term depot neuroleptics.

Single neurons in the basal forebrain (nucleus basalis area) were antidromically activated from the frontal or parietal cortex in anesthetized rats. Wide ranges of antidromic latencies were observed overall, with frontal and parietal stimulation yielding values ranging from 1.0 to 26.0 ms and 1.6-24.0 ms, respectively. Individual neurons often exhibited multiple antidromic latencies, such that deeper sites of stimulation or greater stimulation amplitudes generally yielded discretely different, shorter latencies than more superficial sites or lower amplitudes of stimulation. Single neurons were also often driven from neighboring sites (1-2 mm apart) within the frontal cortex, but no cell was coactivated from both frontal and parietal cortices. Finally, patterns and rates of spontaneous activity varied markedly among these cortically projecting neurons, with some cells being non-spontaneous and others exhibiting tonic rates of 30-40 Hz. Impulse waveforms also differed among driven cells, from relatively low-amplitude, negative spikes to large-amplitude, entirely positive spikes in unfiltered signals. These results indicate that cortically projecting, putatively cholinergic neurons in the basal fore-brain form a physiologically heterogeneous population in terms of impulse conduction velocity, spontaneous discharge, and spike waveforms. Our finding of multiple antidromic latencies and driving from neighboring sites indicate that these fibers may be highly branched in local terminal fields, but that individual cells may project exclusively to a single cortical area. Faster conduction velocities for deep compared to superficial cortical stimulation sites imply that these fibers may become non-myelinated upon entering cortical terminal fields, or that they may become markedly thinner as they travel within the cortex. This system of cholinergic cortical afferents differs in many physiologic aspects from the other non-thalamic cortical input systems of catecholamine or indoleamine neurons.

Six bipolar patients in a manic episode were treated with the calcium antagonist verapamil. A decrease in the level of psychopathology was noted in 5 of the 6, though there was a tendency for patients to relapse in the third week of treatment. Cortisol levels decreased steadily with clinical improvement while growth hormone levels tended to rise. In contrast to traditional antipsychotics verapamil did not alter prolactin levels. Its neuroendocrine profile suggests its therapeutic effects are not mediated by dopamine receptor blockade.

Thirty severely depressed patients who were resistant to tricyclic antidepressant therapy were randomly allocated to treatment either with electroconvulsive therapy (ECT) or addition of lithium (Li) to the tricyclic. Twenty-one of the 30 patients significantly improved at the end of 3 weeks of treatment. There were no differences in improvement rates between the two groups. However, the patients treated with a Li/tricyclic combination improved more rapidly, showing significant alterations in mental state by day 7. It is suggested that in otherwise physically healthy patients who are tricyclic nonresponders, the addition of Li may be a more rapid treatment than the use of ECT.