The relationship between type of antidepressant and neurovegetative symptoms in adult unipolar nonpsychotic depression: an opinion survey.

The bi-directional nature of the neurovegetative symptoms of depression, as well as the differential response to antidepressant medications, underscore the existence of possible subtypes of this disorder. This study surveyed 56 physicians practicing psychiatry in Hawaii for opinions regarding the most effective antidepressant medication for the following symptoms: hypersomnia vs. insomnia, psychomotor agitation vs. retardation, and gain vs. loss of appetite or weight. Fluoxetine was found to be the drug of choice for weight and appetite gain, hypersomnia, and psychomotor retardation. Mirtazapine was viewed as most effective for weight and appetite loss. Trazodone was found most effective for insomnia and nefazodone for psychomotor agitation. It is concluded that subtyping of depression should be investigated at the symptom level and the generalizability of the effects of each specific compound should be tested.

Behavioural and pharmacological characterisation of the canopy stretched attend posture test as a model of anxiety in mice and rats.

The behavioural element, stretched attend posture (SAP), is an important component of the "risk-assessment" repertoire of defensive behaviour in rodents. The present experimental paradigm was devised as a novel and simple method of eliciting high levels of SAP in mice and rats. The SAP test apparatus comprised an elevated black Perspex circular platform. A smaller clear red Perspex circular "Canopy" was supported directly above the platform by a central pillar, thus dividing the platform into an inner, dimly lit covered zone and an outer, brightly lit exposed zone. In both the rat and mouse version of this model, vehicle-treated animals exhibited a marked preference for exploring the covered zone and also exhibited high baseline levels of SAP, particularly at the covered zone boundary whilst they investigated the exposed zone. In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg s.c.) and chlordiazepoxide (2 mg/kg s.c.), and the 5-HT1A receptor agonists, buspirone (1 and 3 mg/kg s.c.), ipsapirone (3 mg/kg s.c.) and 8-OH-DPAT (0.2 mg/kg s.c.), all significantly decreased the frequency of SAP without impairing motor activity. In the rat SAP test, diazepam (0.5 mg/kg s.c.) significantly decreased, whilst the anxiogenic 5-HT2C/1B receptor agonist, mCPP (0.25 and 0.5 mg/kg s.c.), significantly increased, the frequency of SAP. Ipsapirone (3 mg/kg s.c.) induced a non-specific behavioural inhibition. These data suggest that the "Canopy" SAP test is a useful paradigm to investigate risk assessment behaviour in both rats and mice, and may provide a sensitive novel rodent model of anxiety.

Blood-Brain Barrier Integrityin HIV Infection:Evaluation by Contrast-EnhancedMagnetic Resonance Imaging.

This study assesses the integrity of the blood-brain barrier (BBB) in human immunodeficiency virus (HIV) seropositive individuals to magnetic resonance imaging (MRI) contrast agent Gd-DTPA. Twelve HIV seropositive patients and six control subjects had T2-weighted and serial pre- and post-contrast TI-weighted MRI. Ten of the twelve seropositive patients demonstrated white matter hyperintensity with or without atrophy on T2-weighted MRI and 8/10 who underwent neurological examination demonstrated neurological abnormalities. No statistically significant differences of trends in white matter pixel values were observed between pre- and post-contrast scans in any of the patients or controls. Serial T1-weighted MRI does not demonstrate any change in the integrity of the BBB to Gd-DTPA in HIV seropositive patients, regardless of the presence or absence of white matter hyperintensity with or without atrophy on T2-weighted MRI or clinical signs of HIV-I associated with cognitive/motor complex.

Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety.

The elevated "zero-maze" is a modification of the elevated plus-maze model of anxiety in rats which incorporates both traditional and novel ethological measures in the analysis of drug effects. The novel design comprises an elevated annular platform with two opposite enclosed quadrants and two open, removing any ambiguity in interpretation of time spent on the central square of the traditional design and allowing uninterrupted exploration. Using this model, the reference benzodiazepine anxiolytics, diazepam (0.125-0.5 mg/kg) and chlordiazepoxide (0.5-2.0 mg/kg) significantly increased the percentage of time spent in the open quadrants (% TO) and the frequency of head dips over the edge of the platform (HDIPS), and reduced the frequency of stretched attend postures (SAP) from the closed to open quadrants. In contrast, the anxiogenic drug m-chlorophenyl-piperazine (mCPP; 0.25-1.0 mg/kg) induced the opposite effects, decreasing %TO and HDIPS, and increasing SAP. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.001-0.1 mg/kg) had no effects on either %TO or HDIPS, but did decrease SAP at 0.01 mg/kg although not at higher or lower doses. Similarly, the 5-HT3 receptor antagonist, ondansetron (0.0001-1.0 mg/kg) decreased SAP and increased %TO at 0.01 mg/kg, but not at other doses. The present data suggest that a combination of the novel "zero-maze" design and a detailed ethological analysis provides a sensitive model for the detection of anxiolytic/anxiogenic drug action.

Cerebrospinal fluid-intracranial volume ratio measurements in patients with HIV infection: CLASS image analysis technique.

PURPOSE: To prospectively study the cerebrospinal fluid volume-total intracranial volume ratio (CSF/ICV) in human immunodeficiency virus (HIV)-infected patients at various stages of disease. MATERIALS AND METHODS: A total of 258 volume measurements were obtained with use of a 1.5-T magnetic resonance (MR) imager and the cluster localized automated spherical segmentation technique (which reduces two-dimensional pixel data from dual spin-echo MR images to a one-dimensional histogram) in 69 control subjects and 189 HIV-infected patients. RESULTS: The CSF/ICV was statistically significantly increased in patients with late-stage (Centers for Disease Control and Prevention group IV) acquired immunodeficiency syndrome (AIDS) (0.16 +/- 0.05 [standard deviation]) compared with seronegative control subjects (0.12 +/- 0.03) and patients without symptoms (0.13 +/- 0.03). CONCLUSION: No substantial change in CSF/ICV occurs until development of late-stage AIDS.

Proton spectroscopy in HIV infection: relaxation times of cerebral metabolites.

In vivo proton spectroscopy has demonstrated abnormalities in the cerebral metabolite ratios from subjects with acquired immunodeficiency syndrome (AIDS). Some of the sequences employed are subject to T1 or T2 weighting, which may affect spectroscopic interpretation. The relaxation times of choline (Cho), creatine (Cr), and N-acetyl (NA) resonances have been estimated at 1.5 T in 21 patients infected with the human immunodeficiency virus (HIV) and 8 controls using gradient localised, spin-echo spectroscopic sequences of varying echo and repetition times. A statistically significant increase in the T2 of NA was found in the HIV seropositive patients who had diffuse abnormalities on MR imaging consistent with HIV encephalopathy (493 +/- 199 ms) when compared to controls (292 +/- 118 ms; p < .05). No other statistically significant differences were found in the relaxation times between patients and control subjects. These results demonstrate that signals from the NA resonance obtained using long echo time sequences in subjects who are HIV seropositive are not solely indicative of metabolite concentration.

The effects of CCKA and CCKB antagonists on activity in the black/white exploration model of anxiety in mice.

In view of evidence suggesting that cholecystokinin (CCK) may have a role in the mediation of human panic disorders, it was predicted that CCK receptor antagonists may have anxiolytic-like activity in an animal model of anxiety, the black/white exploration test. Data revealed that, in mice, the CCKA receptor antagonist, devazepide (formerly L-364,718, MK-329), produced a clear anxiolytic-like profile with an inverted U-shaped dose-response curve centered around 5 micrograms/kg. Similarly, L-365,031, a specific, but less potent, CCKA antagonist, also produced a profile consistent with weak anxiolysis but only at 5 micrograms/kg. By direct contrast, the potent and specific CCKB antagonist L-365,260 had no robust anxiolytic-like effects in this test. Therefore, these data suggest that devazepide has the greatest effects in this model, that L-365,031 is only marginally active, and that L-365,260 is without influence. These results suggest that CCKA receptor mechanisms are involved in the mediation of anxiolytic-like effects in the black/white model of exploration in mice.

An ethopharmacological analysis of the behavioral effects of 8-OH-DPAT.

Several behaviors associated with the serotonin syndrome have been reported in rats following administration of the 5-HT1A receptor agonist 8-OH-DPAT. The present investigation approached this phenomenon from an ethopharmacological perspective, and provided a detailed temporal analysis of the behavioral effects of this compound over a 2-h period, in both male and female rats in the home cage. In addition, in order to further characterize the nature of the forepaw-treading and locomotor elements, and assess the extent of influence of the physical characteristics of the test arena, this study provided a detailed analysis of these behaviors in both the home cage and a large oval runway. In the initial analysis, the data indicate a distinct chronological sequence of effects following 8-OH-DPAT treatment. For example, "flat back" activity and lower lip retraction were apparent within a few minutes post-injection, the former dissipating after about 30 min and being replaced as the prepotent response by a more general (curved back) locomotor enhancement, while the latter effect remained throughout the 2-h test period. Interestingly, there were reliable gender differences in terms of the onset and disappearance of several behavioral components, with females generally being more rapidly affected, but recovering earlier than males. The detailed analysis of locomotor activity and forepaw treading would suggest that the locomotor syndrome primarily involves forward movement, heavily guided by the physical environment. Furthermore, forepaw-treading would seem only to occur when an animal reaches a barrier and forward movement is briefly interrupted, as no reliable incidence of this behavior was observed in the open area of the test area. Together, these findings provide further characterization of the behavioral syndrome induced by 8-OH-DPAT, and indicate the importance of time post-administration, gender of the subject, and the physical characteristics of the test environment, when considering stereotypical drug effects.

Influence of prior maze experience on behaviour and response to diazepam in the elevated plus-maze and light/dark tests of anxiety in mice.

A single prior undrugged exposure to the elevated plus-maze has been reported to reduce open arm activity on retest and to attenuate/abolish the anxiolytic response to benzodiazepines at retest intervals ranging from 48 h to 14 days. The present study was designed to examine the generality of these findings by comparing the effects of prior maze experience on baseline behaviour and response to diazepam in two murine models of anxiety. Parallel experiments were conducted in which DBA/2 mice were exposed/not exposed to the plus-maze, treated daily with saline or diazepam (2-4 mg/kg daily for 8 days) and then tested on either the elevated plus-maze or in the light/dark test of exploration. Results show that, in both tests, diazepam reduced behavioural indices of anxiety in maze-naive mice only. However, interpretation of this apparent loss of diazepam efficacy is at least partially confounded by the observation that maze experience per se altered baseline behaviour in both procedures, reducing open arm activity in the plus-maze and increasing light compartment activity in the light/dark test. The apparent elimination of an anxiolytic response to diazepam in two animal models of anxiety by prior plus-maze experience is discussed in relation to experience-related baseline shifts in behaviour.

Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine.

The anxiety/defense test battery has been developed to assess defensive reactions in rats to situations associated with a natural predator, the domestic cat. This comprises three paradigms designed to study the effects of cat exposure on general activity and location with respect to the cat (proxemic avoidance), the effects of cat exposure on non-defensive consummatory behavior, and the behavioral response to cat odor. In the present study subjects were exposed to 21 days pretreatment with imipramine (0, 5, and 15 mg/kg), before being assessed in the three experimental paradigms (carried out over a total period of 7 days). Imipramine treatment was maintained on a daily basis during the 7 days taken to complete the series of tests. The data indicated a behaviorally specific profile consistent with anxiety/fear reduction, but not with sedation, in three different paradigms, following treatment with 15 mg/kg imipramine. These behavioral changes included a reduction in freezing, proxemic avoidance and a disinhibition of suppressed feeding in response to cat presentation. Similarly, imipramine treatment (15 mg/kg) significantly reduced behaviors associated with risk assessment (e.g. flat back approach, stretch attend) during presentation of a cat odor stimulus. This behavioral profile suggests that chronic pretreatment with imipramine produces an attenuation of antipredator defensive behavior.

Ondansetron, gender and antipredator defensive behaviour.

The 5-HT(3) 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.

Attenuation of defensive analgesia in male mice by 5-HT3 receptor antagonists, ICS 205-930, MDL 72222, MDL 73147EF and MDL 72699.

Recent studies have shown that non-opioid defensive analgesia in male mice is potently inhibited by the 5-HT3 receptor antagonist, ondansetron. The present series of experiments was conducted to further explore the involvement of 5-HT3 receptor mechanisms in this particular form of adaptive inhibition of pain. The drug ICS 205-930 significantly attenuated the reaction at 1.25-2.5 micrograms/kg, with smaller and larger doses being ineffective. Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively. Although MDL 72699, the quaternary salt of MDL 72222, also inhibited the reaction, this effect was seen at comparatively large doses (0.5-1.0 mg/kg) only. None of the compounds tested had significant intrinsic effects of tail-flick latencies, over the dose ranges tested. These findings indicate that 5-HT3 receptor mechanisms may have an important modulatory role in certain forms of "stress" analgesia. Data are discussed in relation to the consistent profile of partial inhibition produced by 5-HT3 receptor antagonists in this model.

Morphine attenuates antipredator ultrasonic vocalizations in mixed-sex rat colonies.

Mixed-sex groups of laboratory rats living in a visible burrow system (VBS) emit 18-27 kHz ultrasound and retreat to the burrow when a cat is placed in the open area of the VBS. The total duration of ultrasonic vocalizations was reliably reduced by pretreatment with 5 mg/kg morphine. In a subsequent study using male-female colony pairs, presentation of a cat to individual rats in the absence of their colony mate indicated significant gender differences in base frequency, degree of emission, and characteristics of pulses elicited. Specifically, females showed a greater number and duration of vocalizations, of higher frequency (kHz), and with shorter individual pulse durations than males. In the same study, morphine (5 mg/kg) produced a general decrease in the level of ultrasonic emissions in both sexes, reduced the mean base frequency (kHz), and increased the mean duration of individual pulses. These data suggest that endogenous opioid mechanisms may be involved in the mediation of ultrasonic vocalization in response to a predator, and are discussed with reference to known involvement of such systems in defensive responding.

The anxiety/defense test battery: influence of gender and ritanserin treatment on antipredator defensive behavior.

The anxiety/defense test battery has been developed to measure defensive reactions in laboratory rats to both direct exposure to, and stimuli associated with, a natural predator, the domestic cat. The present investigation confirmed earlier findings with each test providing a distinct behavioral profile following exposure to predator stimuli. In addition, the data showed a consistent gender difference in a number of these behavioral measures, indicating that females are more defensive than males. These effects included reliability higher levels of cat avoidance and crouching, with lower levels of transits, lying and drinking for cat-exposed females. Similarly, females exposed to a cat odor stimulus showed a reliably higher level of stretch attend and flat back approach behaviors (risk assessment) towards the stimulus block. The 5-HT2 antagonist, ritanserin, failed to provide significant indication of anxiolytic activity, and had minimal influence on antipredator defensive behavior. An important exception to this profile was a reliable decrease in stretch attend behavior to a cat odor stimulus in females but not males. Overall, these findings suggest a complex relationship between gender, antipredator defensive behavior, and anxiolytic drug treatment.

MK-801 produces a reduction in anxiety-related antipredator defensiveness in male and female rats and a gender-dependent increase in locomotor behavior.

The present study investigated the effects of the non-competitive NMDA antagonist MK-801 (0.04-0.16 mg/kg), on antipredator defensive reactions of male and female rats in three paradigms comprising the Anxiety/Defense Test Battery (A/DTB). In order to facilitate interpretation of data from the above study, the behavioral effects of the compound were also assessed in the non-threatening environment of the home cage. The data indicate a marked gender difference in the locomotor effects of the compound with females, but not males, showing a dose-dependent increase in general locomotor activity, a decrease in freezing, and a loss of balance at the highest dose, in both non-threatening and threatening contexts. The behavioral profile for males in the A/DTB included decreased orientation to and proxemic avoidance of the cat stimulus or stimulus site, and increased transits and eating in the cat situation. Contacts with the cat odor stimulus were increased, as was normal, curved back, locomotion in this test. In the absence of non-specific locomotor effects for males, this profile for the A/DTB provides convincing evidence for anxiety/fear reduction with MK-801. While locomotor effects tended to mask the putative anxiolytic properties of the compound in females, evidence remains from behavioral changes not attributable to a locomotor influence to indicate anxiety/fear reduction in this sex.

Evidence for differential effects of 8-OH-DPAT on male and female rats in the Anxiety/Defense Test Battery.

The Proxemics/Activity test and the Eat/Drink test, two components of the Anxiety/Defense Test Battery, were developed to measure defensive reactions to situations associated with a natural predator (cat). In the present studies the behavioral effects of 8-OH-DPAT treatment (0.01-1.0 mg/kg, SC) were entirely consistent with anxiety/fear reduction. These effects included an increase in time spent near the cat compartment, and a complimentary decrease in time spent farthest from this compartment, together with an increase in transits and locomote behavior. 8-OH-DPAT (1.0 mg/kg) also increased eat frequencies and durations (highly preferred food) both during and following cat presentation, without influencing drinking. This finding is discussed with reference to previous findings with 8-OH-DPAT in studies assessing both food intake and anxiolysis. Interestingly, 8-OH-DPAT was more potent in a majority of its effects in female subjects, a finding consistent with recent neurochemical data. These findings provide important behavioral evidence for a sexual differentiation in 5-HT function, and support the case for greater emphasis on female subjects in animal models of anxiety.

Effects of diazepam on behavioural and antinociceptive responses to the elevated plus-maze in male mice depend upon treatment regimen and prior maze experience.

Recent studies have shown that brief exposure to an elevated plus-maze (EPM) produces non-opioid antinociception in male mice. The present experiments were designed to assess the effects of diazepam on this phenomenon. When acutely administered, low doses (0.5-1.0 mg/kg) of diazepam failed to produce an anxiolytic profile and exerted rather inconsistent effects on EPM-induced elevations in tail-flick latencies. In EPM-experienced mice, chronic treatment with higher doses of diazepam (2-4 mg/kg, 8 days) produced a weak anxiolytic action and inhibited the early phase of EPM antinociception only. However, in EPM-naive mice, 8-day diazepam pretreatment exerted a marked anxiolytic effect and completely eliminated the antinociceptive response to the maze. Together, these data support the view that anxiety is a key factor in certain forms of adaptive pain inhibition and suggest a possible mediational role for benzodiazepine receptors. Our findings also show that prior exposure to the EPM, rather than chronic handling/injection, greatly reduces the anti-anxiety effect of diazepam. Furthermore, since re-exposure to the maze, per se, decreased time spent on the open arms and central platform, a shift in behavioural baseline ("retest anxiogenesis") may have contributed to the weak behavioural effects of diazepam in test-experienced animals. Importantly, as chronic treatment with diazepam did not influence this anxiogenic-like retest profile, our data suggest that a single prior experience of the EPM may radically alter the nature of the anxiety reaction provoked by this test.

Differential effects of novel ligands for 5-HT receptor subtypes on nonopioid defensive analgesia in male mice.

The effects of a number of 5-HT receptor ligands were examined on nonopioid defensive analgesia in male DBA/2 mice. MDL 73005EF (0.05-1.0 mg/kg), a selective 5-HT1A receptor agonist, potently and dose-dependently inhibited the analgesic consequences of social defeat. CGS 12066B (0.5-10.0 mg/kg) and MK-212 (0.3-10.0 mg/kg), selective agonists for 5-HT1B and 5-HT1C sites, respectively, failed to influence this particular form of adaptive pain inhibition. Two 5-HT2/1C receptor antagonists, ritanserin (0.05-10.0 mg/kg) and ICI 169.369 (0.3-10.0 mg/kg), were also devoid of specific effects upon defensive analgesia. Both ritanserin and ICI 169,369 were found to have intrinsic analgetic efficacy and to induce behavioural changes indicative of increased defensiveness. These data, together with previous findings, confirm the specific involvement of 5-HT1A receptor mechanisms in the analgesic consequences of social defeat in male mice. Results are discussed in relation to the role of anxiety in adaptive pain inhibition.

Sex effects in defensive behavior: baseline differences and drug interactions.

Female rats consistently show a pattern of differences in defensive behaviors compared to males which parallel the effects of exposure to a nonpainful threat stimulus (cat or cat odor) in the same tests and measures. These indications of greater defensiveness for females are particularly common in situations involving potential, as opposed to actual and present, threat, a factor which probably also reflects ceiling or floor effects in situations involving very intense defensiveness. In addition, pharmacological studies indicate sex differences in the effects of selective serotonin (5-HT) receptor agonists and antagonists on defensive responding. These findings indicate that sex effects must be considered in studies of the pharmacological control of defensive behaviors, and suggest that responsivity to sex effects may be an additional criterion for the suitability of animal models of anxiety.