Journal of Psychopharmacology

During the past decade, results from radioligand studies comparing platelet α2-adrenoreceptors in depressed patients and healthy volunteers have been inconsistent, especially when related to the known functional characteristics of these receptors. Despite the availability of radioligands for α2-adrenoreceptors, inherent methodological problems exist which make data from these studies difficult to interpret. The authors review the overall data from radioligand studies using [3H] clonidine and [3H] yohimbine of platelet α2-adrenoreceptors in depressed patients and healthy volunteers. Theoretical and methodological issues are critically examined in the light of recent findings. Finally, alternative strategies for studying α 2-adrenoreceptors in clinical populations are considered.

Depression is a common illness which affects some 3% of the population per year. At least 25% of those with marked depression do not consult their general practitioner and in half of those who do the illness is not detected. Depression is easy to recognize when four or five of the core symptoms have been present for 2 weeks which often coincides with some occupational and social impairment. The core symptoms are depressed mood, loss of interest or pleasure, loss of energy or fatigue, concentration difficulties, appetite disturbance, sleep disturbance, agitation or retardation, worthlessness or self blame and suicidal thoughts. A diagnosis of depression is made when five of these core symptoms, one of which should be depressed mood or loss of interest or pleasure, have been present for 2 weeks. Four core symptoms are probably sufficient. Response to antidepressants is good in those with more than mild symptoms. When there are only few or very mild depressive symptoms evidence of response to antidepressants is more uncertain. Antidepressants are effective, they are not addictive and do not lose efficacy with prolonged use. The newer antidepressants have fewer side effects than the older tricyclics, they are better tolerated and lead to less withdrawals from treatment. They are less cardiotoxic and are safer in overdose. Antidepressants should be used at full therapeutic doses. Treatment failure is often due to too low a dose being used in general practice. It may be difficult to reach the right dose with the older tricyclics because of side effects. To consolidate response, treatment should be continued for at least 4 months after the patient is apparently well. Stopping the treatment before this is ill-advised as the partially treated depression frequently returns. Most depression is recurrent. Long-term antidepressant treatment is effective in reducing the risk of new episodes of depression and should be continued to keep the patient well.

Eight healthy young males were administered single doses of lorazepam (4 mg), clonazepam (4 mg), alprazolam (2 mg) or placebo, and their performance on behavioral tasks was monitored for 7 h. Lorazepam and clonazepam impaired performance on subcritical tracking, a primarily neuromotor task, for 2-4 h longer than alprazolam. Although the duration of impairment of the digit symbol substitution task was less discrepant for the three drugs, clonazepam and lorazepam still affected performance for a longer period of time than alprazolam. The rapid development of acute tolerance was indicated by clockwise hysteresis curves for all the drugs on the SCT task and for clonazepam and alprazolam on the DSS task. The maximum effect, effect offset rate and duration of the drug effect are discussed in relation to molecular structure and receptor affinity.

The effects of single doses of lofepramine (70 mg), dothiepin (50 mg) and placebo on memory and psychomotor function were compared in a cross-over study with 12 healthy volunteers. Dothiepin produced a differential pattern of effects across the range of memory assessments used, impairing episodic memory and slowing learning in a procedural task but not affecting working, semantic or implicit memory. Dothiepin also impaired performance on two attentional tasks, slowed down reaction times and increased subjective sedation. Lofepramine was similar to placebo on nearly all objective measures, but produced effects similar to dothiepin on critical flicker fusion threshold, salivary flow and most EEG wavebands. It is concluded that, unlike lofepramine, acute dosage with dothiepin is associated with sedative effects and impairments of concentration and memory.

Pre-natal exposure to benzodiazepines has been associated with neurobehavioral alterations in human and animal studies. To evaluate effects of pre-natal exposure on subsequent efficacy of benzodiazepine ligands, we exposed mice to lorazepam, 2 mg/kg/day, during days 14-20 of gestation and evaluated offspring at 6 weeks of age using pentylenetetrazol-induced convulsions. Mice exposed to lorazepam were similar to vehicle-exposed and untreated mice in pentylenetetrazol threshold. However, lorazepam-exposed mice had a reduced threshold after an acute dose of lorazepam compared to vehicle-exposed and untreated mice. For the proconvulsant inverse agonist compound FG 7142, threshold was also reduced after pre-natal lorazepam exposure compared to the other treatment groups. These data indicate that pre-natal lorazepam exposure is associated in mature mice with a shift in benzodiazepine efficacy toward the inverse agonist range of the benzodiazepine spectrum.

The discriminative stimulus effects of the nicotine antagonist mecamylamine have been investigated to characterize further its behavioural effects and its interactions with (-)-nicotine. Rats were trained to discriminate the effects of mecamylamine from saline in a two-bar operant conditioning procedure with food reinforcers presented on a tandem schedule of reinforcement. Mecamylamine (3.5 mg/kg s.c.) acquired strong stimulus control over behaviour and there was only a small reduction in overall rates of responding. The mecamylamine stimulus generalized completely to some ganglion-blocking drugs (order of relative potency: pentolinium > mecamylamine > pempidine) but it did not generalize to other ganglion-blockers (hexamethonium, trimetaphan and chlorisondamine). The mecamylamine stimulus also failed to generalize to (-)-nicotine, to muscarinic antagonists (atropine and scopolamine) or to excitatory amino acid antagonists (dizocilpine, phencyclidine and D-CPPene). Mecamylamine, pempidine, hexamethonium, trimetaphan, (-)-nicotine, scopolamine, phencyclidine, dizocilpine and D-CPPene were tested up to doses that reduced overall rates of responding. Tests also showed that (-)-nicotine did not antagonize the response to mecamylamine. The discriminative stimulus produced by mecamylamine may originate at nicotinic receptors but whether these are located centrally or peripherally is unclear. There was no evidence that either muscarinic or excitatory amino acid receptors were involved in mediating the effect.

Sprague-Dawley rats were trained to discriminate between saline (SAL) and an ethanol-nicotine mixture (0.5 g/kg ethanol plus 0.5 mg/kg nicotine) administered 15 min prior to a 15-min drug discrimination training session under a FR-10 schedule of reinforcement. The mixture dose ratio was adjusted after training to obtain a drug mixture with which both individual drugs contributed about equally to the stimulus control (1.0 g/kg ethanol plus 0.3 mg/kg nicotine). The animals were then retrained for 32 sessions using this new mixture. After training, neither nicotine nor ethanol, when tested singly, engendered > 90% mixture-appropriate responding up to test doses that suppressed responding. Complete generalization occurred when the training doses of either nicotine or ethanol were administered in combination with various doses of the alternate drug element. (+)Nicotine, amphetamine and caffeine engendered dose-dependent increases in responses emitted on the mixture-appropriate lever. Pentobarbital and chloral hydrate only partially generalized to the training mixture. However, depressant/stimulant combinations of chloral hydrate+caffeine and pentobarbital+amphetamine produced complete generalization. The data suggest: (1) drug mixtures are not normally perceived as new entities distinct from their component elements; (2) training dose ratio may influence the characteristics of mixture discriminations; (3) stimulus element saliency may be a factor determining the nature of discriminative control by drug mixture cues; and (4) the ethanol-nicotine cue was most likely based on non-specific depressant/stimulant effects of these drugs.

When animals are exposed to a stimulus that has no consequences they are subsequently impaired in learning that this stimulus predicts an important event, such as footshock. This retarding effect of stimulus pre-exposure is called latent inhibition (LI) and is reliably disrupted by amphetamine, antipsychotics having an opposite effect. The present experiments investigated whether agents which affect serotonergic transmission also attenuate LI, using a conditioned suppression of drinking procedure. The results showed that the 5-HT2 antagonist ritanserin (2.0 mg/kg), and the 5-HT1b agonist RU 24969 (0.5 and 10.0 mg/kg) attenuated LI by increasing learning in pre-exposed animals, whilst the effects of the 5-HT1a agonist 8-OH-DPAT (0.38 mg/kg), though in a similar direction, were not significant. These experiments provide partial support for the involvement of serotonin in LI. Since amphetamine-induced attenuation of LI has been proposed as a model for the attentional deficits found in acute schizophrenia, these results are discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder.

The 5-HT3 receptor antagonist ondansetron has provided a somewhat equivocal profile in a number of animal models of anxiety. The present study assessed the effects of this compound in two ethological test batteries. The Fear/Defense Test Battery (F/DTB) and the Anxiety/Defense Test Battery (A/DTB) have been developed to investigate antipredator defensive reactions in rats. The F/DTB measures behavioural reactions of wild- trapped rats to human threat, while the A/DTB assesses behavioural responding in laboratory rats as a consequence of exposure to a domestic cat, and to cat odour per se. Ondansetron (0.001-0.10 mg/kg) failed to provide any reliable and consistent profile of anxiety/fear reduction in either test battery. In addition to the elucidation of drug effects, previous studies have provided clear evidence of gender differences with female rats showing higher levels of defensiveness than males in the A/DTB. Until now, no such differences have been observed with wild-trapped rats in the F/DTB. Thus, the present study indicated a clear gender difference with females exhibiting greater defensiveness. This finding is discussed with reference to the general decrease in defensiveness of the first generation animals compared with their wild-trapped parents.

The effects of ipsapirone and cannabidiol (CBD) on healthy volunteers submitted to a simulated public speaking (SPS) test were compared with those of the anxiolytic benzodiazepine diazepam and placebo. Four independent groups of 10 subjects received, under a double-blind design, placebo or one of the following drugs: CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg). Subjective anxiety was evaluated through the Visual Analogue Mood Scale (VAMS) and the State-trait Anxiety Inventory (STAI). The VAMS anxiety factor showed that ipsapirone attenuated SPS-induced anxiety while CBD decreased anxiety after the SPS test. Diazepam, on the other hand, was anxiolytic before and after the SPS test, but had no effect on the increase in anxiety induced by the speech test. Only ipsapirone attenuated the increase in systolic blood pressure induced by the test. Significant sedative effects were only observed with diazepam. The results suggest that ipsapirone and CBD have anxiolytic properties in human volunteers submitted to a stressful situation.