David J. Nutt

Increased central alpha2-adrenoceptor sensitivity in panic disorder

Cardiovascular responses to an intravenous challenge dose of clonidine (1.5 μg/kg) were measured in eight patients with DSM III panic disorder. In comparison with an age- and sex-matched control population panic patients showed significantly greater falls in systolic and diastolic blood pressure, with similar falls in heart rate. These observations support the view of a biological abnormality in panic disorder.

Optimizing the pentetrazol infusion test for seizure threshold measurement

Seizure thresholds in mice were determined using the pentetrazol infusion method. Concentration of infusate and rate of infusion were varied to assess the optimal parameters for seizure threshold detection. Seizure threshold elevations were produced by flurazepam and threshold decreases by FG 7142. An infusion rate of 1.1 ml min−1 was best for detecting both increases and decreases in threshold. However a concentration of 2.5 mg ml−1 gave optimal measurement of elevations in threshold whereas decreased thresholds were best detected with a concentration of 10 mg ml−1.

The neuroendocrine effects of oral imipramine

The release of growth hormone, prolactin and cortisol following oral imipramine was studied in nine fit young men. Imipramine 100 mg, but not 40 mg, led to reliable rises in the circulating levels of all three hormones in the majority of subjects. These responses are likely due to the enhancement of central noradrenergic and serotonergic function as a result of reuptake inhibition. The safety, sensitivity and reliability of these responses make imipramine 100 mg orally a potentially valuable neuroendocrine challenge test.

Mice and rats are sensitized to the proconvulsant action of a benzodiazepine-receptor inverse agonist (FG 7142) following a single dose of lorazepam

Rats and mice were treated with lorazepam (1.0 mg/kg) or its vehicle. Six h later seizure threshold to i.v. pentylenetetrazole was determined following treatment with the benzodiazepine-receptor inverse agonist FG 7142, the antagonist Ro 15-1788 or a second dose of lorazepam. Although lorazepam alone was anticonvulsant 6 h after its administration, animals pretreated with lorazepam were more sensitive to the proconvulsant action of FG 7142 and less sensitive to the effects of a second treatment with lorazepam.

The effects of drugs acting at the GABAA-receptor/ionophore after chemical kindling with the benzodiazepine receptor ligand FG 7142

1 Repeated administration of the β‐carboline benzodiazepine receptor ligand FG 7142 produces sensitization to its effects so that full seizures develop (chemical kindling); initially it is only proconvulsant. The present study investigated alterations in the function of drugs which act at the different sites at the γ‐aminobutyric acid (GABA) benzodiazepine receptor complex, after repeated administration of FG 7142. 2 In FG 7142 kindled mice decreased anticonvulsant and hypothermic effects of the GABA agonist muscimol were observed. The hypothermic effects of the GABA agonist progabide were reduced. In contrast a small increase in the hypothermic effect of pentobarbitone was seen. 3 The convulsant effects of bicuculline and picrotoxin were unaltered when they were given intravenously but marginally increased when they were given by the intraperitoneal route. No changes were seen in the hypothermic effects of these drugs. 4 No significant changes were seen in the convulsant or hypothermic effects of pentylenetetrazol. 5 These results suggest that kindling with FG 7142 may alter GABA receptor function.

The effect of clonidine on plasma MHPG: Evidence against tonic alpha2-adrenoceptor control of noradrenergic function

The effect of the alpha2-adrenoceptor agonist clonidine on plasma free MHPG levels was assessed in 12 normal volunteers. A significant fall in MHPG was produced by 1.5 μg·kg-1 clonidine IV whereas saline had no effect. The peak fall in MHPG correlated strongly with the area under the curve (AUC). In addition, a strong correlation was seen between basal MHPG and the extent of the clonidine-induced fall. This suggests that plasma MHPG levels are not simply a reflection of central alpha2-adrenoceptor function and argues against tonic alpha2-adrenoceptor-mediated inhibitory control of noradrenergic output.

A single dose of FG 7142 causes long-term increases in mouse cortical β-adrenoceptors

There is evidence that central monoamines are involved in the actions of benzodiazepines. We have investigated the effects of a single dose of the benzodiazepine partial inverse agonist, FG 7142, on radioligand binding to alpha 2- and beta-adrenoceptors in mouse cerebral cortex. We found that seven days after a single injection of FG 7142 there was a large increase in the density of beta-adrenoceptors. This rise was not detectable either 15-30 min, or 24 h after the injection and no statistically significant changes in alpha 2-adrenoceptor binding were found at any of these times. Administration of the benzodiazepine antagonist Ro 15-1788 at the same time as FG 7142 prevented the rise in beta-adrenoceptor density. We discuss the possibility that the beta-adrenoceptor upregulation is related to the behavioural effects of FG 7142.

The hypothermie response to clonidine is absent in alcohol withdrawal but returns in abstinence

Ethanol interacts with central norepinephrine (NE) neurons in a complex manner (for review, see Nutt and Glue 1986). During ethanol withdrawal, indices of peripheral and central NE activity are elevated (Potter et al. 1984; Hawley et al. 1985). One theory that may explain this increased activity is that there is an abnormality of alpha-2-adrenergic presynaptic autoreceptors that leads to a reduction in inhibitory feedback control of the central NE neurons of the locus coeruleus, thus producing increased NE firing (Cedarbaum and Aghajanian 1976). In alcoholics experiencing withdrawal. we have recently shown that the growth hormone response to clonidine, which may provide an index of postsynaptic alpha-2-adrenoceptor functioning, is blunted and that measures of presynaptic adrenergic activity, such as plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), are elevated. Other alpha-2-adrenoceptor-mediated responses, such as the hypotensive and sedative responses to clonidine, are also significantly attenuated (Nutt et al. 1988; Glue and Nutt 1987). During this research, we examined other physiological vari-

Effects of chronic treatment with benzodiazepine receptor ligands on cortical adrenoceptors.

We report the effects of kindling with the benzodiazepine partial inverse agonist, FG 7142 on adrenoceptor binding in mouse cerebral cortex. Twelve once-daily injections of FG 7142 caused a statistically significant increase in the density of both alpha 2- and beta-adrenoceptor binding sites, seven days after the last injection. Despite the marked effects of FG 7142 on adrenoceptors, there were no changes in either alpha 2- or beta-adrenoceptor binding after prolonged treatment with the benzodiazepine, flurazepam.

Changes in benzodiazepine/GABA receptor complex function in benzodiazepine-tolerant mice

Mice were given flurazepam, 40 mg k−1, IP, once daily for 7 consecutive days. Twenty-four and forty-eight hours after the last injection measurements were made of the effects on convulsion threshold, body temperature and locomotor activity, of drugs acting on the GABA receptor complex. Significant decreases were seen in the hypothermic and hypomobility effects of progabide at 48 h, but no significant changes were seen in the effects of pentylenetetrazol or pentobarbitone. The actions of picrotoxin in all three types of test and the convulsant action of bicuculline (IP) were significantly decreased at 24 h but not at 48 h. The convulsive, but not the hypothermic, effects of picrotoxin were increased at the 48 h interval. These results may suggest that the chronic benzodiazepine treatment decreased some aspects of GABA receptor function at 48 h after the last dose; however, such an effect probably does not explain the previously reported increases in the effects of inverse agonists following chronic agonist treatment.