Journal of Psychopharmacology

Stable dominance hierarchies were determined in pairs of male Lister hooded rats, by repeated observation of agonistic behaviour at the onset of the dark phase of the light-dark cycle. No lasting alterations in dominance behaviour were caused by subjecting the dominant member of the pair either to restraint stress or to defeat by another dominant animal. However, defeat of the dominant animal by a male of the aggressive Tryon Maze Dull (TMD) strain caused a loss of dominant status in the home cage which lasted at least 7 days. Repeated weekly defeat by TMD animals decreased both home cage dominance behaviour and consumption of a palatable sucrose solution, relative to non-defeated animals; both behaviours were normalized in defeated animals by 3 weeks of treatment with the tricyclic antidepressant imipramine.

The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kg×2; MDMA 20 mg/kg×8; D-fenfluramine 12.5 mg/kg×8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT_1A and 5-HT₂ receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT_1A or 5-HT₂ receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.

Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads to kindling accompanied by reduction in γ-aminobutyric acid (GABA) receptor function, whereas chronic continuous administration may result in behavioural effects in the opposite direction from those of acute FG 7142. In the present study, we have investigated the effects of continuous administration of low doses of FG 7142 on the response to an acute challenge dose of FG 7142 in an ethologically based model of anxiety. Rats treated continuously for 14 days with FG 7142 delivered by osmotic minipump at a rate of 1.2-1.5 mg/kg/day showed sensitisation to the anxiogenic effects of a challenge dose of FG 7142 (6 mg/kg), as measured in the elevated plus-maze. This was not accompanied by any change in benzodiazepine/GABA receptor coupling, as assessed by the 'GABA shift'. These results indicate that continuous low-dose treatment with FG 7142 can elicit sensitisation to the behavioural effects of FG 7142, but that this is unlikely to be mediated by changes in benzodiazepine/GABA receptor coupling.

The technique of drug discrimination was used to examine the ability of the highly selective α₂-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α ₁-adrenoceptors or I₂ imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α₂-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α₂-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α₂-adrenoceptor antagonist L659,066. However, the α₂-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I₂ imidazoline receptors over α₂-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I₂ receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α₁-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

The selective, brain penetrant, 5-HT_1D receptor agonist SKF 99101H (10-30 mg/kg i.p.) caused a dose-related fall in rectal temperature in guinea pigs which lasted longer than 2 h. Sumatriptan (1.0-100 mg/kg i.p.), a selective 5-HT_1D agonist which does not penetrate the brain, did not produce hypothermia, suggesting that peripheral mechanisms are not critically involved in the response. The hypothermia induced by SKF 99101H (30 mg/kg i.p.) was dose-dependently blocked by the 5-HT_1D receptor antagonists GR 127935 (0.01-1 mg/kg i.p.) and GR 125743 (0.01-3 mg/kg i.p.), confirming the role of 5-HT_1D receptors. Mianserin (0.3-10.0 mg/kg i.p.) and granisetron (0.1-3.0 mg/kg i.p.) were inactive, suggesting that 5-HT_2A/2B/2C or 5-HT ₃ receptors play no significant role in the generation of the hypothermic response. Nor was the hypothermia reversed by prazosin (0.03-1.0 mg/kg i.p.), idazoxan (0.03-1.0 mg/kg i.p.) or scopolamine (0.01-0.3 mg/kg i.p.), thereby excluding mediation by α₁- and α₂-adrenoceptors and muscarinic receptors. WAY 100635 (0.1-1.0 mg/kg) significantly potentiated the effect of SKF 99101H. The antagonists, when given alone, had no effect on body temperature, with the exception of prazosin (0.1 and 1.0 mg/kg). Three days of treatment with parachloroamphetamine (30 mg/kg i.p.) depleted forebrain 5-HT by ∼ 75% in frontal cortex, hypothalamus, hippocampus and striatum, but failed to alter the hypothermic response to SKF 99101H. The hypothermia is, therefore, unlikely to be mediated by 5-HT_1D receptors located on 5-HT neurons. SKF 99101H-induced hypothermia in the guinea pig may serve as a useful model for investigation of centrally acting 5-HT _1D receptor antagonists.

We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT_1A receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT_1A receptor partial agonist ipsapirone, the 5-HT _1B/1D/2C agonist TFMPP, the 5-HT_1A antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT ₂ receptor antagonist ketanserin and the 5-HT₃ receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT_1A receptors.

The effects of lorazepam (0.25 mg) twice a day on several cognitive and performance tasks, pictures test, digit-symbol substitution test (DSST), choice reaction time (CRT) and critical flicker fusion (CFF), were investigated in healthy students. A double-blind independent group design was used to compare placebo and lorazepam (30 volunteers in each group). After randomisation, all subjects received placebo for 3 days (D), followed by 14 days of treatment, with either lorazepam or placebo. Subjects completed a battery of tests at Do, then D₃, D₇ , D₁₀ and D₁₄. D₃ performance was poorer in the lorazepam group except for CFF (ascending values and total values), yet the only significant improvement was in total reaction time on the CRT test. However, a significant improvement of performance was shown at D₇, D₁₀ and D₁₄ in the lorazepam group compared with the control group (except in recognition reaction time). The current study shows that low repeated doses of lorazepam are able to produce small improvements in some aspects of psychomotor and cognitive functions in healthy volunteers. Different points are discussed to explain the performance improvement: training effect, tolerance effect, partial inverse agonist effect and the possible release of cholecystokinin.

The persistence of deficits in cognitive performance in major depressive patients taking maintenance antidepressant medication was assessed by examining groups of patients in clinical remission, stable on one of a range of tricyclics or selective serotonin re-uptake inhibitors (SSRIs) for at least 3 months, compared with controls. Measures of critical flicker fusion (CFF), choice reaction time (CRT), subjective sedation, and anticholinergic side-effect score were made. Tricyclic antidepressants (TCAs) produce a significant deficit in critical flicker fusion threshold compared both to controls and SSRIs. Similar effects were seen with choice reaction times which were significantly affected by age. Sedation scores were significantly higher with TCAs than SSRIs. Anticholinergic side effects were strongly related to CFF, less so to visual analogue sedating scales and not significantly to CRT. The effect measured by CFF is different from sedation, and may be related to the anticholinergic potency of the drug; it may be considered a drug-induced pseudodementia. This effect represents a risk factor for accidents during maintenance therapy and may impair work and leisure performance. The relative risk of weight gain with TCAs compared to SSRIs in women was 5.92 (95% CI 1.79-19.50).

An experiment was carried out to determine whether a low dose of alcohol produced different behavioural effects in healthy volunteers to those suffering from an upper respiratory tract illness. Ninety-nine subjects were tested, with 48 subjects being assigned to the alcohol condition and 51 to the juice only condition. A dose of 1.5 ml of vodka per kg body weight was used and the alcohol manipulation was double-blind. Approximately half of the subjects in each condition were healthy and the others had upper respiratory tract illnesses, probably colds. Subjects with colds reported an increase in negative affect and were slower at performing psychomotor tasks. Few main effects of alcohol were obtained. Of major interest were the interactions between health status and alcohol conditions. The alcohol improved the mood of healthy subjects but produced greater negative moods in subjects with colds. Similarly, performance of selective and sustained attention tasks showed different effects of alcohol in healthy and ill subjects.

Neurochemical investigations of Tourette's syndrome (TS) suggest that the symptoms of this disorder may be the result of an imbalance among several neurotransmitter and/or neuromodulator systems. Neurochemicals which have been studied included: catecholamines; acetylcholine; tryptophan and its metabolites; the amino acids γ-aminobutyric acid (GABA), glutamate, phenylalanine and p-tyrosine; trace amines; opioid peptides; cyclic AMP and androgenic hormones. A suitable animal model of TS would do much to advance our understanding of this disorder, and there are some interesting recent developments in this regard.

The therapeutic efficacy and reduction in side effects claimed for new antischizophrenic drugs such as clozapine and risperidone have been ascribed to their heightened affinity for serotonin 5-HT₂ receptors rather than D-2 receptors. A case for α₂-adrenoreceptor antagonism has recently been argued. We have confirmed that at least one atypical property of risperidone (a rapid decrement in its ability to depress self-stimulation) can be partly prevented by an α₂-adrenoreceptor agonist (clonidine) but not by a 5-HT ₂ receptor agonist (DOI). This result supports the suggested role of α ₂-adrenoreceptor antagonism in counteracting extrapyramidal effects during treatment with risperidone.

A sizeable minority of depressed patients, estimated at 15-20%, suffer chronic symptoms which often persist despite appropriate treatment. The search for new, more efficacious pharmacotherapies has included testing existing medications for additional therapeutic effects, such as in combination treatment. Four treatment- refractory patients who presented to the authors for clinical care are described, in which the combination of bupropion and sertraline was effective for a major depressive episode. None of the patients experienced adverse effects. Two carried the diagnosis of unipolar depression, and two, bipolar disorder. All had prior adequate, but ineffective, separate trials of buproprion and a selective serotonin re-uptake inhibitor (SSRI), including sertraline. All had chronic depression with multiple failed medication treatments, arguing against the alternative explanation that their improvement represented a placebo response or spontaneous remission. The efficacious combination of sertraline and bupropion may be due to synergism of its two distinct antidepressant mechanisms involving serotonergic, dopaminergic and noradrenergic systems.