Showing papers in "Psychopharmacology in 1988"

Is the forced swimming test a suitable model for revealing antidepressant activity

Abstract: The forced swimming test is reviewed. This test appears to be suitable for detecting antidepressant activity in rats but not in mice. Difference in experimental procedure may account for the different sensitivity to drugs of the two animal species.

Dopaminergic stimulation disrupts sensorimotor gating in the rat.

Abstract: Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125–4.0 mg/kg) and d-amphetamine (0.5–4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.

Attenuation of scopolamine-induced impairment of spontaneous alternation behaviour by antagonist but not inverse agonist and agonist β-carbolines

Abstract: Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.

The effects of chronic antidepressant treatment in an animal model of anxiety.

Abstract: We have examined the anxiolytic activity of acute and chronic antidepressant treatment in an animal model of anxiety involving novelty-suppressed feeding. Rats were food deprived for 48 h, placed into a novel environment containing food, and the latency to begin eating was recorded. Chronic (21 days), but not acute injections of desipramine (DMI; 10 mg/kg) and amitriptyline (AMI; 10 mg/kg) significantly reduced the latency to begin eating compared to controls, but the percentage decrease was not as great as that seen with either acute or chronic treatment with diazepam (2 mg/kg) or adinazolam (20 mg/kg). A time course study indicated that at least 2 weeks of treatment was necessary to observe a significant anxiolytic effect of antidepressants. The anxiolytic effect of the antidepressants was specific to the novel environment, as 2 weeks of treatment with either diazepam or DMI did not influence the latency to begin eating in the home cage. Finally, a single dose of the central benzodiazepine receptor antagonist, Ro15-1788 (20 mg/kg), given 15 min prior to testing, did not block the anxiolytic effects of chronic DMI, while it completely eliminated the effect of chronic diazepam treatment. These data suggest that antidepressants acquire anxiolytic properties following chronic administration and that this effect appears to be independent of the benzodiazepine receptor system.

Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens

Abstract: Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2,5-dimethoxyphenylisopropylamine; DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT2, 5-HT1A, 5-HT1B, and 5-HT1C receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT2 receptor was labelled with the agonist/hallucinogen radioligand 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT1A, 5-HT1B, and 5-HT1C receptors were labelled with 3H-OH-DPAT, 3H-5-HT, and 3H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10–100 fold higher affinities for the 5-HT2 receptor than for the 5-HT1C receptor and 100–1000 fold higher affinities for the 5-HT2 receptor than for the 5-HT1A or 5-HT1B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT2 receptor affinities of the phenylisopropylamines (r=0.90); the correlation coefficients for the 5-HT1A, 5-HT1B, and 5-HT1C were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT1A-selective or 5-HT1B-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT2 receptor interaction is implicated and supports our previous suggestions to this effect. A secondary role for 5-HT1C receptors cannot be discounted at this time. These results, when integrated with other receptor pharmacological information, indicate that an important component of the mechanism of action of LSD and the phenylisopropylamine hallucinogens is through stimulation of brain 5-HT2 receptors.

Intravenous nicotine in Alzheimer's disease: a pilot study

Abstract: In the first study to examine direct nicotinic augmentation of central cholinergic functioning in Alzheimer's disease, six patients were studied in an intensive pilot study with three doses (0.125, 0.25, and 0.5 μg/kg/min) of intravenous nicotine and placebo. Cognitive tests showed a decrease in intrusion errors on the middle (0.25 μg) dose. Prominent behavioral effects were noted, with significant dose-related increases in anxiety and depressive affect. These results suggest that central nicotinic cholinergic stimulation deserves further investigation as a treatment in Alzheimer's disease and that nicotine may also be a useful investigative tool in other populations as a probe of central cholinergic function, especially in regard to the modulation of affect.

Caffeine physical dependence: a review of human and laboratory animal studies.

Abstract: Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been poorly characterized in laboratory animals and only moderately well characterized in humans. In humans, a review of 37 clinical reports and experimental studies dating back to 1833 shows that headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving). When caffeine withdrawal occurs, severity can vary from mild to extreme (i.e. incapacitating). The withdrawal syndrome has an onset at 12–24 h, peak at 20–48 h, and duration of about 1 week. The pharmacological specificity of caffeine withdrawal has been established. The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%. Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6–15 days of ≥600 mg/day). Although animal and human studies suggest that physical dependence may potentiate the reinforcing effects of caffeine, human studies also demonstrate that a history of substantial caffeine intake is not a necessary condition for caffeine to function as a reinforcer. The similarities and differences between caffeine and classic drugs of abuse are discussed.

Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors.

Abstract: Male Sprague-Dawley rats deprived of food for 18 h were injected with the 5-HT agonists RU 24969, 1-(3-chlorophenyl)piperazine (mCPP) or 1-[3-(trifluoromethyl)phenyl)]piperazine (TFMPP) and 20 min later presented with their normal diet. Food intake was determined 1, 2 and 4 h later. All three drugs reduced intake over 1 and 2 h. Three out of four drugs with high affinity for 5-HT1C receptors (metergoline, mianserin, and mesulergine but not cyproheptadine) opposed hypophagia caused bymCPP. Another drug reported to have high affinity for the 5-HT1C site, 1-naphthyl-piperazine (1-NP), also blocked the hypophagic response tomCPP at doses which attenuatedmCPP-induced hypolocomotion. Only one of the above drugs (metergoline) which also has high affinity for other 5-HT sites opposed hypophagia caused by RU 24969. Two out of three 5-HT1B receptor antagonists [(±) cyanopindolol, (−) propranolol, but not (−) pindolol)] which oppose hypophagia caused by RU 24969 (Kennett et al. 1987) also opposed hypophagia caused bymCPP. The 5-HT2 antagonists ketanserin and ritanserin, the 5-HT3 antagonist ICS 205-930 and the α2 adrenoceptor antagonist idazoxan did not oppose the hypophagic effect ofmCPP. In agreement with results formCPP, hypophagia caused by TFMPP was opposed by both, mianserin and (±) cyanopindolol. Given alone, mianserin 1-NP and cyproheptadine but not ICS 205-930 increased food consumption of normally fed rats. The results suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors but not on 5-HT1C receptors, whilemCPP (and TFMPP)-induced hypophagia may depend on both receptors. Thus, 5-HT1C and 5-HT1B receptors may evoke hypophagia via a common pathway but the effect of antagonists implies that at the doses usedmCPP and TFMPP act predominantly at 5-HT1C receptors. Since only the hypophagic response tomCPP is blocked by cyanopindolol and (−) propranolol (Kennett and Curzon 1988) it is unlikely to be secondary to hypoactivity induced by the drug.

Induction of oral stereotypy following amphetamine microinjection into a discrete subregion of the striatum.

Abstract: Amphetamine and other psychostimulant drugs induce perseverative motor behavior in rodents, such as compulsive sniffing, licking and biting. Although it is known that this behavior, termed stereotypy, is a consequence of dopaminergic stimulation of the striatum, the precise localization of the site of activation is unclear. It is reported here that microinjection of amphetamine (20 micrograms/0.5 microliter) into a circumscribed subregion of the striatum specifically produces intense oral stereotypy. It is proposed that this region, which corresponds to a small area within the ventrolateral striatum, contains motor circuitry critical to oral behavior, including feeding. The behavior elicited by amphetamine-induced stimulation of this area may represent a simple animal model in which to study certain orofacial dyskinesias.

Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder.

Abstract: Normal controls (NC) (n=15), patients with panic disorder (PD) (n=13) and patients with major depression (MD) (n=17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.

Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol.

Abstract: The present experiment explored whether delta 9-tetrahydrocannabinol (delta 9-THC), the psychoactive ingredient in marijuana, shares with other drugs of abuse the ability to facilitate brain stimulation reward acutely, as measured by electrical intracranial self-stimulation (ICSS). Laboratory rats were implanted with stimulation electrodes in the medial forebrain bundle, and trained to stable performance on a self-titrating threshold ICSS paradigm. delta 9-THC, at a dose believed pharmacologically relevant to moderate human use of marijuana, acutely lowered ICSS thresholds, suggesting that marijuana acts on similar CNS hedonic systems to most other drugs of abuse.

Stereoselective binding of 11C-raclopride in living human brain ― a search for extrastriatal central D2-dopamine receptors by PET

Abstract: The selective D2-dopamine receptor antagonist raclopride and its pharmacologically inactive (R)-enantiomer FLB472 were labelled with 11C and used in a study with positron emission tomography to examine the stereoselectivity of 11C-raclopride binding to central D2-dopamine receptors in three healthy men. After the injection of 11C-raclopride, there was a high accumulation of radioactivity in the dopamine-rich basal ganglia, whereas after the injection of 11C-FLB472 there was no such accumulation of radioactivity. Thus, the binding of 11C-raclopride is stereoselective. Distribution ratios [radioactivity in a brain region/“free” (not protein-bound) radioactivity in plasma] were calculated for the two enantiomers to study regional differences in the accumulation of radioactivity. The distribution ratios in white matter were similar for the two enantiomers. In the putamen, a three to four-fold higher distribution ratio was found for 11C-raclopride than for 11C-FLB472, reflecting the presence of specific binding of 11C-raclopride binding to D2-dopamine receptors in the basal ganglia. In the temporal and frontal cortices the distribution ratios were, however, only a few per cent higher for 11C-raclopride than for 11C-FLB472, indicating that if D2-dopamine receptors are present in the human neocortex, then their density is indeed very low.

Delay-dependent short-term memory deficits in aged rats

Abstract: Separate groups of rats of three ages (6 month, 15 month or 24 month) were trained in a two-lever operant chamber on one of two versions of a paired-trial delayed response task involving either matching or non-matching of the choice response to a sample lever. The older rats were unimpaired in learning either version of the task during initial training with no (0 s) delay between the sample and choice responses. However, when variable 0–24 s delay intervals were introduced, the 24-month group was impaired on acquisition of the delayed non-matching task, and both the 15- and 24-month groups were impaired on acquisition of the delayed matching task compared to the 6-month group. Deficits in the older groups in asymptotic performance were attributable to an impairment at longer delay intervals whilst maintaining near perfect performance at the shorter delay intervals, suggesting a selective short-term memory impairment. The delay-dependent deficits of the older groups were not ameliorated by the muscarinic agonist arecoline or the cholinesterase inhibitor physostig-mine, and so failed to corroborate a cholinergic interpretation of the observed age-related impairment in short-term memory.

Intra-amygdala injections of corticotropin releasing factor facilitate inhibitory avoidance learning and reduce exploratory behavior in rats

Abstract: The effects of intra-amygdala injections of corticotropin-releasing factor (CRF) on memory and exploratory behavior in rats were examined in the present study. Rats with chronically implanted cannulae received intra-amygdala injections of vehicle or CRF at a dose of 0.01, 0.1 or 1.0 μg, either immediately after the inhibitory avoidance training or prior to the open field activity test. Results indicated that while CRF at low (0.01 μg) and high (1.0 μg) doses produced no significant effect on retention or exploration, immediate post-training intra-amygdala injections of CRF at the medium dose (0.1 μg) significantly improved retention of the inhibitory avoidance response. The same dose of CRF, given shortly prior to the open field activity test, decreased locomotor activity, rearing and hole-poke responses in rats. These results suggest that the amygdala is one of the anatomical loci involved in CRF modulation of memory processing and exploration in rats. The implication of CRF in mediating the influences of stress on behavior is discussed.

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat.

Abstract: The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025–2.0 mg/kg) and bromocriptine (0.25–6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05–0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects.

Cocaine-induced place conditioning: importance of route of administration and other procedural variables.

Abstract: It has been shown that pretreatment with dopamine (DA) receptor blockers disrupts the effect of intravenously (IV) and intracerebrally (ICV), but not intraperitoneally (IP) administered cocaine on place preference conditioning (PPC). The present study was undertaken to further evaluate possible differences between IV and IP cocaine PPC. To this end, several factors which may differentially influence IV and IP cocaine PPC were examined. Firstly, dose-response effects were studied. Intravenous cocaine produced PPC within a narrow dose range (0.5–2.5 mg/kg). Animals receiving IV injections of 5 and 10 mg/kg cocaine experienced convulsions and did not show PPC. For IP cocaine a 10-fold increase in dose (10 mg/kg) and twice the number of training trials was required in order to obtain PPC equal in magnitude to that with IV cocaine (0.5 mg/kg; two trials). Cocaine PPC was retained at least 1 month. Following IV cocaine preference developed for the side associated with the drug regardless of whether the conditioning was to the least or most preferred side. After IP cocaine, preference developed for the drug side only when the drug was paired with the least preferred side. Rats trained with IV, but not IP, cocaine significantly preferred the drug familiar side to a novel compartment. Preference for the IV or IP cocaine side developed regardless of whether testing was carried out in the drugged or undrugged state, excluding possible state-dependent effects as an explanation of the cocaine PPC. The results show PPC procedure to be a valid test for evaluating rewarding properties of IV cocaine. However, they fail to show rewarding effects of IP cocaine.

Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions of d-amphetamine and apomorphine.

Abstract: Lesion studies employing 6-hydroxydopamine (6-OHDA) suggest that locomotor hyperactivity induced by certain stimulant drugs is dependent on dopaminergic neurotransmission in the nucleus accumbens (NACC). However, studies to date have not adequately controlled for the reported effects of 6-OHDA on baseline (non-drug) activity and on DA levels in other terminal regions. Slow bilateral infusions of 6-OHDA into the NACC, but not into olfactory tubercle (OT) or medial prefrontal cortex (mPFCx), reducedd-amphetamine (0.5 mg/kg SC) hyperactivity and resulted in a “supersensitive” (hyperactive) response to a low dose of apomorphine (0.1 mg/kg SC) in photocell cages. Direct observation revealed no behavioral changes in OT lesioned rats challenged with apomorphine which might correspond to a “denervation supersensitivity” syndrome. Assays of DA and 5-hydroxytryptamine (5-HT) in mPFCx, OT, NACC, and caudate-putamen revealed that 6-OHDA infusion into NACC caused substantial DA loss in NACC, OT and mPFCx, whereas infusion at mPFCx or OT sites depleted DA locally (>85% loss) with little or no remote change. Concentrations of 5-HT were little altered by 6-OHDA, except for a local depletion in mPFCx. The present results confirm the importance of nucleus accumbens DA in the expression of locomotor stimulation induced by apomorphine andd-amphetamine, and suggest that the mPFCx and OT do not make an important contribution.

Drug discrimination studies with MDMA and amphetamine.

Abstract: The term entactogen has recently been introduced to describe a new pharmacological class of compounds best represented by 3,4-methylenedioxymethamphetamine, MDMA, and its alpha-ethyl homologue MBDB. The present study was designed to test the similarities of the discriminative stimulus properties produced by MDMA and MBDB, as well as to elaborate further the distinction between entactogens, hallucinogens and stimulants. Two groups of rats were trained to discriminate saline from either racemic MDMA hydrochloride (1.75 mg/kg) or S-(+)-amphetamine sulfate (1.0 mg/kg) in a two-lever drug discrimination task. The (±)-MDMA cue completely generalized to S-(+)-MDMA, S-(+)-amphetamine, (±)-MDA, S-(+)-MBDB, (±)-MBDB, R-(-)-MDMA, and R-(-)-MBDB, but not to LSD or DOM. The S-(+)-amphetamine cue generalized to (±)-methamphetamine, but not to racemic MDMA or MBDB, nor to their optical isomers. The S-(+)-isomers of both MDMA and MBDB were more potent than the R-(-)-isomers. The results indicate that MDMA and MBDB may share a component of their discriminative stimulus properties which is different from both stimulants and hallucinogens. Although MDA and MDMA have been shown to be amphetamine-like, the lack of stimulant effects for MBDB suggests that amphetamine-like stimulant activity is not necessary for a compound to share discriminative stimulus properties with MDMA.

Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal.

Abstract: Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 μg/μl) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.

Post-training administration of GABAergic antagonists enhances retention of aversively motivated tasks

Abstract: The effect of sub-convulsive doses of GABAergic antagonists on the retention of two aversively motivated tasks, inhibitory avoidance (IA) and Y-maze discrimination (YMD), was investigated in CFW mice. In the IA task, post-training intraperitoneal injections of picrotoxin and bicuculline induced a dose-dependent enhancement of retention measured 24 h after the training, while retention was not affected by bicuculline methiodide (a GABA receptor antagonist that does not readily cross the blood-brain barrier). In the absence of footshock on the training day, post-training administration of picrotoxin and bicuculline did not affect retention test latencies. In the YMD task, the discrimination was reversed on the retention test and errors made on the reversal trials served as the index of retention of the original training. The reversal error scores of mice given post-training injections of picrotoxin or bicuculline, but not bicuculline methiodide, were significantly higher than those of saline-treated controls. These findings extend previous observations that GABAergic antagonists enhance retention of aversively motivated tasks and suggest the involvement of central GABAergic processes on memory consolidation.

Effects of trazodone on the sleep of depressed subjects--a polygraphic study.

Abstract: The effects of 400–600 mg trazodone on the sleep patterns of ten depressed in-patients treated for 5 weeks were studied during the initial (days 1–3) and terminal (days 26–28) treatment periods. The sleep parameters were compared to those obtained from three sleep recordings performed just prior to the initiation of the treatment and after 2 adaptation nights at the end of a 2-week drug-free period. At the same time, the clinical evolution of patients was evaluated weekly using MADRS and Hamilton-Anxiety scales for anxiety-depression symptomatology and Spiegel and Norris sleep scales. Weekly blood samples were collected to measure plasma levels of trazodone and, at the end of the study, the elimination half-life at steady state was calculated by repeated measurements of plasma levels. Clinical improvement, as assessed by a reduction of more than 60% in MADRS scale scores, was accompanied by evidence of the definitely beneficial effects of trazodone on the disturbed sleep of these depressed patients. From the beginning of treatment, there was a hypnotic-like effect (increase in total duration of sleep and stage II, decrease in sleep latency and intrasleep awakenings). In addition, records at the end of the study showed an increase in delta sleep and an increase in REM latency, an effect classically associated with an antidepressant action. These particularly valuable effects of trazodone on sleep would suggest that this drug should especially be given in cases of depression with major insomnia.

The effects of scopolamine on working memory in healthy young volunteers

Abstract: Twenty healthy young adults completed a series of nonverbal and problem solving tasks in a repeated measures design involving placebo and 0.6 mg scopolamine, administered by subcutaneous injection. Subjects completed the test battery under standard presentation conditions and with concurrent articulation, which precludes verbal recoding of test material. Under standard presentation conditions, scopolamine significantly impaired performance on the problem solving task and on tasks of visuo-spatial and spatial memory; memory for abstract shapes was not impaired. Concurrent articulation impaired performance on the shape recognition and interacted with drug treatment on the problem solving task. The results suggest that scopolamine impairs working memory, and that the decrement is at the level of the central executive mechanism rather than the subsystems which it controls.

Behavioural effects of histamine and its antagonists: a review.

Abstract: This review focusses on the behavioural effects of histamine and drugs which affect histaminergic function, particularly the H1- and H2-receptors antagonists. Research in this area has assumed considerable importance with increasing interest in the role of brain histamine, the clinical use of both H1 and H2 antagonists and evidence of nonmedical use of H1 antagonists. Results from a number of studies show that H1 and H2 antagonists have clear, but distinct subjective effects and that H1 antagonists have discriminative effects in animals. While H1 antagonists are reinforcers in certain conditions, histamine itself is a punisher. Moderate doses of H1 antagonists affect psychomotor performance in some situations, but the results are variable. The exceptions are terfenadine and astemizole, which do not seem to penetrate the blood-brain barrier readily. In studies of schedule-controlled behaviour, marked changes in response rate have been observed following administration of H1 antagonists, with the magnitude and direction dependent on the dose and the baseline behaviour. Histamine reduces avoidance responding, an effect mediated via H1-receptors. Changes in drinking and aggressive behaviour have also been observed following histamine administration and distinct roles for H1- and H2-receptors have been delineated. Separate H1- and H2-receptor mechanisms have also been suggested to account for changes in activity level. While the H2 antagonists do not always have strong behavioural effects when administered peripherally, there is evidence that cimetidine has a depressant effect on sexual function. These and other findings reveal an important role for histaminergic systems in a wide range of behaviour.

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

Abstract: Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were “very much” or “much” improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Anxiolytic effects of buspirone and gepirone in the fear-potentiated startle paradigm

Abstract: Fear potentiation of the acoustic startle reflex was produced by eliciting startle responses in the presence of a light that had been previously paired with a shock Buspirone (06–50 mg/kg) and gepirone (125–100 mg/kg), but not their common metabolite, 1-PP (05–40 mg/kg), produced a dose-dependent reduction of fear-potentiated startle These doses of buspirone and gepirone slightly increased baseline startle levels Reduction of fear-potentiated startle appears to involve supraspinal sites of action, since intraventricular but not intrathecal administration of buspirone (200 μ;g) reduced fear-enhanced startle Both buspirone and gepirone were highly efficacious in this model compared to other animal tests that are used to study anxiolytic compounds

The effects of age on the response to caffeine.

Abstract: Twelve healthy subjects, six young and six elderly, of either sex, took part in this two-period crossover study. In each session, a dose of trial drug--either 200 mg caffeine or a matching placebo--was given orally at 0900 hours. A battery of psychomotor tests and visual analogue scales was administered before treatment and at 1, 2 and 3 h post-treatment. The objective tests showed a significant increase in tapping rate in the young, while the elderly showed improved attention, faster choice-reaction time, and greater body sway on caffeine. The visual analogue scales showed that the young subjects felt more alert, calmer, more interested, and steadier on caffeine, while no significant changes were seen in the elderly. These results show that caffeine produces changes predominantly in the direction of improved performance and feeling of well-being, and suggest that the elderly are more sensitive to the objective effects of the drug, while reporting less subjective effect than the young.

α1- and α2-Adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced byd-amphetamine and apomorphine in the rat

Abstract: The importance of dopamine (DA) in mediating locomotor, exploratory and stereotyped behaviour in rodents is well established. Evidence also indicates a modulatory role for noradrenaline (NA) although, due to non-specificity of previously available agents, a precise role remains undefined. The effects of the specific and selective α-adrenoreceptor antagonists idazoxan (α2) and prazosin (α1) on behaviour induced by amphetamine and apomorphine have been investigated in the rat.d-Amphetamine (2 mg/kg) induced hyperactive locomotion and exploration. Pretreatment with prazosin (1 mg/kg) markedly reduced these responses. In contrast, pretreatment with idazoxan (20 mg/kg) only marginally alteredd-amphetamine hyperactivity. Apomorphine (0.5 mg/kg) induced biphasic locomotor and exploratory activity. Neither α-antagonist affected the initial burst of activity (60 min), although prazosin inhibited whereas idazoxan potentiated the secondary phase (90–180 min). At higher dosage, amphetamine (6 mg/kg) and apomorphine (2 mg/kg) induced stereotyped behaviours. Prazosin pretreatment enhanced stereotyped gnawing and decreased sniffing and locomotion, whereas idazoxan increased locomotion and decreased amphetamine-induced mouth movements. These data indicate that DA-induced locomotor and stereotyped behaviours are differentially influenced (in opposite directions) by both α1- and α2-adrenoreceptor antagonists. NA may thus modulate the expression and character of behaviour by influencing DA function in certain brain areas.

Potential anxiolytic properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin 1A receptor agonist.

Abstract: The effects of a selective serotonin 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were studied in two animal models of anxiety. Peripherally injected 8-OH-DPAT in doses ranging from 0.125 to 2.0 mg/kg did not increase black-white transitions (BWT) and black square entries (BSE) in a two-compartment exploratory test or punished responding in a test of conditioned suppression of drinking. With 2.0 mg/kg 8-OH-DPAT BSE and unpunished responding were reduced. In an investigation of the drinking time of water-deprived rats, naive or habituated to the test environment, 1.0 and 2.0 mg/kg 8-OH-DPAT increased the drinking time of naive rats but 2.0 mg/kg 8-OH-DPAT reduced that of habituated animals. In animals deprived of water for 48 h or subjected to immobilization stress for 2 h, 1.0 mg/kg 8-OH-DPAT increased BWT and BSE values in the two-compartment exploratory test. Infusions of 5 micrograms/0.5 microliter 8-OH-DPAT in the nucleus raphe medianus increased BWT and BSE values in the exploratory test and punished responding in the test of conditioned suppression of drinking, whereas the same dose of 8-OH-DPAT injected in the nucleus raphe dorsalis had no effect on punished but suppressed unpunished responding. The effects of 8-OH-DPAT are only detectable in the appropriate experimental conditions. When injected systemically, the effects are evident when a state of arousal of the animals contributes to the overall behavioural output. 8-OH-DPAT shows effects comparable to those of established anxiolytics such as benzodiazepines and barbiturates when it is injected in the nucleus raphe medianus, but not in the dorsalis.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased food intake in satiated rats induced by the 5-HT antagonists methysergide, metergoline and ritanserin.

Abstract: Two series of experiments examined whether 5-hydroxytryptamine (5-HT) antagonists induce feeding in rats. In the first series of experiments separate groups of rats were injected with various doses of methysergide, cyproheptadine, metergoline or ritanserin prior to a 2 h period of access to a wet mash diet which induced vigorous feeding under control conditions. None of the antagonists increased food intake in this paradigm. Rather, at certain doses, methysergide, cyproheptadine and ritanserin induced slight decreases in food intake. Since 5-HT may be involved in controlling satiety, it may be that a more appropriate test of the efficacy of these compounds involves administering them to maximally satiated rats. Consequently, the effects of these drugs were investigated in groups of rats which had fed to satiety immediately prior to drug treatment. In this paradigm methysergide, metergoline and ritanserin, but not cyproheptadine, induced definite increases in food intake. It is suggested that this effect occurs via a dissipation of satiety signals, and that these results further support the hypothesis that 5-HT is involved in controlling satiety. The possibility that these antagonists act on peripheral 5-HT systems is discussed.

Anxiogenic properties of beta-CCE and FG 7142: a review of promises and pitfalls.

Abstract: The behavioral effects of the benzodiazepine (BZP)-receptor partial inverse agonists, beta-CCE and FG 7142, are reviewed and the claim that these compounds possess “anxiogenic” properties is examined. Results obtained from human studies and global observations in animals, as well as those from experiments on aggression in animals or from studies of pentylenetetrazole discrimination cannot be considered conclusive. Contradictory findings have been obtained in studies using animal testing procedures derived from BZP-sensitive models of anxiety and in newer experimental situations and these are discussed from various theoretical perspectives: (1) the ability of the models to measure increased anxiety; (2) the possible ability of the drugs to reveal latent anxiety which generalizes from a punished to an otherwise non-fearful component of a testing procedure (“spreading anxiety”); (3) anxiety produced by a pro- or pre-convulsant state. Finally, several hypotheses are considered to account for the behavioral effects of beta-CCE and FG 7142 without assuming anxiogenic properties. These include the possible existence of different forms of anxiety, rate dependency, and drug-induced motivational changes. It is concluded that available data are insufficient to strongly support the notion that FG7142 and beta-CCE are the anxiogenic drugs “par excellence” they are often claimed to be.