Journal of Psychopharmacology

Fahey, Jeanne M. ;Pritchard, Gary A. ;Grassi, Jeffrey M. ;Pratt, John S. ;Shader, Richard I. ;Greenblatt, David J.

doi: 10.1177/026988119901300301pmid: 10512074

Previous work in our laboratory has demonstrated region-specic effects for chronic alprazolam on binding and function at the GABAA receptor. The present study evaluated regional changes in mRNA expression of several subunits of the GABAA receptor following chronic alprazolam administration that might underlie these effects. Mice received alprazolam (2 mg/kg/day) or vehicle via subcutaneously implanted osmotic pumps for 1, 7, 14 or 28 days. In situ hybridization histochemistry was performed on tissue sections using [35S]dATP oligonucleotide probes corresponding to the a1 and g2 subunits of the GABAA receptor. Specic hybridization was clearly demonstrated and a1 subunit mRNA expression in frontoparietal cortex (layers IIIV) on day 1 of infusion was reduced in animals receiving alprazolam compared to vehicle. On subsequent days, there were no alterations in the levels of a1 subunit mRNA in the frontoparietal cortex, hippocampus or dentate gyrus. Expression of g2subunit mRNA was increased on day 1 in the frontoparietal cortex (layer VI), hippocampus and dentate gyrus. mRNA expression was also increased in the dentate gyrus on day 28 of infusion. Comparison of the present study with the results of chronic treatment with other benzodiazepines clearly demonstrates that the pattern of mRNA subunit alterations obtained is both treatment- and region-specic. This makes a de¢nitive conclusion regarding benzodiazepines and their interactions with GABAA receptors di¤cult at best.

Kapczinski, Flávio ;Quevedo, João ;Curran, H. Valerie ;Fleminger, Simon ;Toone, Brian ;Cluckie, Alice ;Lader, Malcolm

doi: 10.1177/026988119901300302pmid: 10512075

Brain uptake of 123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors.The peak uptake was delayed in patients across all brain regions. The uptake in occipital cortex was higher in low albumin cirrhotics. Patients with low albumin also presented a more delayed peak uptake in occipital cortex and a higher volume of distribution of iomazenil in plasma, compared to patients with normal albumin levels and controls. The changes in brain uptake (delayed peak uptake and increased maximal uptake in occipital cortex) appears to reflect changes in the pharmacokinetics of the ligand, particularly in cirrhotics with low levels of plasma albumin. The curve of brain uptake of the tracer was modelled into a two compartments equation, which seems to provide a practical and reliable method to calculate the slopes of acquisition and decay, time to peak and maximal acquisition.

Bitsios, P. ;Philpott, A. ;Langley, R. W. ;Bradshaw, C. M. ;Szabadi, E.

doi: 10.1177/026988119901300303pmid: 10512076

It has been shown previously that the amplitude of the acoustic startle reflex is enhanced, and the amplitude of the light reflex reduced, when subjects anticipate an aversive event, compared to periods when subjects are resting (`fear-potentiated startle reflex' and `fear-inhibited light reflex'). We examined whether the anxiolytic diazepam would reverse the effects of threat on the startle and pupillary reflexes. Twelve male volunteers participated in three weekly sessions in which they received oral treatment with placebo, diazepam 5 mg and diazepam 10 mg, according to a balanced crossover double-blind design. One hour after ingestion of the treatments, miotic responses to light pulses and electromyographic responses of the orbicularis oculi muscle to sound pulses were elicited during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with a signicant increase in the amplitude of the electromyographic (EMG) response, a signicant reduction of the miotic response amplitude, and an increase in self-rated anxiety. Diazepam attenuated all these effects of THREAT. Diazepam did not affect the amplitude of the miotic response under the SAFE condition, but did suppress the EMG response under this condition.These results confirm the validity of the fear-potentiated startle reflex and fear-inhibited light reflex as laboratory models of human anxiety, and reveal some differences between the effects of diazepam on the two reflexes.

Wingrove, Janet ;Bond, Alyson J. ;Cleare, Anthony J. ;Sherwood, Roy

doi: 10.1177/026988119901300304pmid: 10512077

Many studies have reported correlations between measures of aggression and indices of serotonergic function, but most have studied patient or o¡ender populations and relatively few have investigated plasma concentrations of the serotonin precursor tryptophan.This study investigates the relationship between plasma concentrations of tryptophan and trait hostility, depression and anxiety in male healthy volunteers. Sixty-seven healthy male volunteers gave blood samples and completed trait questionnaires. Plasma tryptophan was positively correlated with the BussDurkee Hostility Inventory Total score and Motor Aggression subscale, but not with the Attitudinal Hostility subscale or with trait anxiety or depression. In conclusion, there is evidence for an association between high concentrations of plasma tryptophan and aggressive behaviour in men, presumably mediated by some aspect of central serotonergic function, which seems unlikely to be explained by high trait anxiety or depression.

Johnstone, Eve C. ;Owens, David G. C. ;Crow, Timothy J. ;Davis, John M.

doi: 10.1177/026988119901300305pmid: 10512078

This study is an analysis of findings of a follow-up study of 105 patients with functional psychotic illness who had participated in a random and blind 4-week trial of pimozide, lithium, both and placebo. The intention was to examine the question of whether a 4-week delay in initiating antipsychotic treatment has a detrimental effect 2.5 years later. Detailed follow-up measures included need for care over the 2.5 years, treatments required, occupational decline, police contact, substance misuse, psychopathology and cognitive function. There was no evidence at all that those initially randomized to placebo had a poorer outcome in terms of any of these variables. It is concluded that a 4-week delay in initiating active treatment in patients with functional psychosis has no long-term adverse effects.

Dursun, S. M. ;Wright, N. ;Reveley, M. A.

doi: 10.1177/026988119901300306pmid: 10512079

The antisaccade task can be used to test the voluntary control of saccadic eye movements (SEMs). In many disorders with postulated hyperdopaminergic neurotransmission, there are reports of abnormalities in SEMs. To further investigate this, the role of dopamine in SEMs, performance on an antisaccade task was examined in subjects with a history of amphetamine use (a dopamine releaser and reuptake inhibitor). A prospective design was employed in a teaching hospital setting. Six subjects (five males) with a history of amphetamine use were compared to 24 normal controls. None of the subjects were using any other substances, except alcohol and nicotine, as determined by urine screening, which we believe limited the sample size. For subjects who used amphetamine before the task, the presence of amphetamine was confrmed by urinalysis. All subjects completed the antisaccade task. Both error rates and latency rates during the antisaccade task were compared between the amphetamine users and controls. The amphetamine users had signifcantly increased error rates and latencies. These results may suggest that increased error rates and latencies during antisaccade tasks may be due to increased dopamine transmission, which is similar to the fndings in schizophrenia.

Ravizza, L.

doi: 10.1177/026988119901300307pmid: 10512080

Two hundred and fifty patients participated in a 6-month, double-blind study to evaluate safety and e¤cacy of a medium-term treatment with amisulpride 50 mg/day versus amitriptyline 2575 mg/day in dysthymia. Patients in treatment groups (165 amisulpride; 85 amitriptyline) were well balanced for demographic and baseline characteristics. A total of 139 patients (93 amisulpride, 46 amitriptyline) completed the study with no statistically signifcant di¡erences in reasons for premature termination between the two groups. A tendency towards a higher incidence of treatment-emergent adverse events with amitriptyline was observed (73% versus 64% amisulpride). In the amitriptyline group, a statistically signifcantly higher incidence of central nervous system (41% versus 24%, p=0.004) and autonomic nervous system disorders (45% versus 16%, p50.0001) was reported. Conversely, endocrine disorders were more frequent with amisulpride (18% versus 7%, p=0.023). E¤cacy was a secondary end-point. Results of the symptom rating scales indicate that both drugs were equally e¡ective: 60% and 62% of patients under amisulpride and amitriptyline, respectively, achieved a reduction 550% of the Montgomery and Asberg Rating Scale total score at end-point. On the item `global improvement' of the Clinical Global Impression, 67% of amisulpride and 68% of amitriptyline patients were rated as `very much' or `much' improved. Results of the present study in a large patient population further confrm the safe use of amisulpride in dysthymia and support its administration upon a medium-term treatment period.

Stanford, S. Clare ;Salmon, Peter ;Mikhail, Ghada ;Gettins, Doreen ;Zielinski, Simon ;Pepper, John R.

doi: 10.1177/026988119901300308pmid: 10512081

This study investigated whether drug therapy explains why the concentration of arterial plasma catecholamines in patients who have received an orthotopic heart transplant (OHT) or coronary bypass and graft (CABG) is greater than in those with heart failure (HF).The results suggest that the differences in plasma catecholamine concentrations in these groups of patients could not be attributed to administration of any of the drugs studied here. An additional finding is that the use of aspirin is associated with a higher concentration of plasma noradrenaline, but not adrenaline. Patients who were taking aspirin also had a more positive mood, as rated by the Profile of Mood States; this was mainly because they had a lower fatigue score than did patients who were not taking this drug. In contrast, several agents (warfarin, Ca2+-channel blockers and `mixed cardiac' drugs), which had no effects on catecholamine overspill, were linked with negative mood; this was expressed consistently as a higher tension score. These findings suggest that drugs which are administered for their effects in the periphery could also influence patients' psychological status. With the possible exception of aspirin, this does not involve changes in spillover of catecholamines in the periphery.

Martin-Iverson, Mathew T.

doi: 10.1177/026988119901300320pmid: 10512082

There are conflicting reports as to whether or not the effects of dopamine agonist effects at reducing prepulse inhibition of the acoustic startle reflex develop sensitization with repeated treatments. In this experiment, rats (12 per each dose group) were treated for 10 days prior to startle-testing on each day with 0 (vehicle), 50, 200 or 800 mg/kg of apomorphine. Startle testing was conducted with each rat receiving no stimulus trials (null trials), startle pulse only trials (40 ms 105 dB white noise), prepulse only trials (20 ms 72 dB 5 kHz tone) and prepulse+pulse trials with a 100 ms stimulus onset asynchrony (SOA, i.e. the lead time from onset of prepulse to onset of pulse).The rats were then challenged after 57 days of withdrawal from the treatment regimen with a vehicle and apomorphine (200 mg/kg) injection with the order of injection counterbalanced. A range of SOAs and two different prepulse intensities (68 and 70 dB) were presented to every rat on the challenge tests. Sensitization developed during treatment to the increase in motor activity produced by the two higher doses, and to the increase in an orienting response produced by the prepulse stimulus in the highest dose group, but not to the prepulse inhibition effect of the drugs.The 50 mg/kg inhibitory autoreceptor selective dose decreased responses on the first of three blocks of both null trials and prepulse only trials. The two higher doses dose-dependently increased startle reflex amplitudes on the prepulse+pulse trials (reduced prepulse inhibition), but this effect did not exhibit sensitization during treatment.The lowest dose significantly increased prepulse inhibition relative to the vehicle-treated group on the first block of trials over days. After apomorphine challenge, sensitization to the effects of apomorphine on reducing prepulse inhibition was apparent for some dose groups at some SOAs. Sensitization to the effects of apomorphine on prepulse inhibition can be demonstrated upon a subsequent drug challenge if pretreatments are associated exclusively with the startle testing environment.

Silvestre, Jordi S. ;Fernández, Andrés G. ;Palacios, José M.

doi: 10.1177/026988119901300309pmid: 10512083

The objective of the present study was to assess the behavioural effects of rolipram, a specific cAMP phosphodiesterase (PDE4) inhibitor, in the elevated plus-maze (EPM) test in rats. Results showed that rolipram at the highest dose tested (0.1mg/kg) increased the percentage of both time spent and entries into open arms, although a decrease of locomotor activity in the EPM test was also observed. In contrast, diazepam (3.0 mg/kg) exhibited the typical profile of an anxiolytic in the EPM test, increasing the percentage of time spent and entries into open arms as well as locomotor activity. A posterior statistical analysis, however, established that the effects of both rolipram and diazepam on parameters denoting anxiolytic-like activity were statistically independent from those reflecting locomotor activity reduction. Furthermore, the effects of both rolipram and diazepam were shown to be distinct from those exhibited by tryciclic antidepressant imipramine which did not show any anxiolytic-like effects in the EPM test, although a reduction of locomotor activity was also detected. Although these preliminary results suggest that rolipram may have some anxiolytic-like properties on the EPM test in rats, such an interpretation should be taken cautiously due to the observed effects on locomotor activity, which could complicate the interpretation of results from rolipram and other PDE4 inhibitors in the current test and in other anxiety animal models.