European Neuropsychopharmacology (v.15, #6)

These experiments aimed to assess whether enhanced activity at the cannabinoid CB1 receptor elicits antidepressant-like effects. To examine this we administered 1 and 5 mg/kg doses of the endocannabinoid uptake inhibitor AM404; 5 and 25 μg/kg doses of HU-210, a potent CB1 receptor agonist; 1, 2.5 and 5 mg/kg of oleamide, which elicits cannabinoidergic actions; 1 and 5 mg/kg doses of AM 251, a selective CB1 receptor antagonist, as well as 10 mg/kg desipramine (a positive antidepressant control) and measured the duration of immobility, during a 5-min test session of the rat Porsolt forced swim test. Results demonstrated that administration of desipramine reduced immobility duration by about 50% and that all of AM404, oleamide and HU-210 administration induced comparable decreases in immobility that were blocked by pretreatment with AM 251. Administration of the antagonist AM 251 alone had no effect on immobility at either dose. These data suggest that enhancement of CB1 receptor signaling results in antidepressant effects in the forced swim test similar to that seen following conventional antidepressant administration.
Keywords: Cannabinoid; Antidepressant; Forced swim test; Oleamide; Rat;

Clozapine improves working memory updating in schizophrenia by Cherrie A. Galletly; C. Richard Clark; Alexander C. McFarlane (601-608).
This study investigated the effect of clozapine on working memory in 15 subjects with schizophrenia, using an event related potential paradigm designed to separate components reflecting working memory updating from components related to target detection and response. Compared to matched controls and prior to treatment with clozapine, subjects with schizophrenia had N1, P3 and Late Slow Wave abnormalities indicating impairment in early stimulus evaluation and subsequent working memory functions. Treatment with clozapine was associated with normalization of the P3 and Late Slow Waves, indicating improvement in working memory updating and executive processing. There was also a partial normalization of N1 amplitude, suggesting improvement in early stimulus evaluation.
Keywords: Schizophrenia; Cognition; Memory; Clozapine; Event related potential; P3;

Levetiracetam selectively potentiates the acute neurotoxic effects of topiramate and carbamazepine in the rotarod test in mice by Jarogniew J. Luszczki; Marta M. Andres; Piotr Czuczwar; Anna Cioczek-Czuczwar; Joanna Wojcik-Cwikla; Neville Ratnaraj; Philip N. Patsalos; Stanislaw J. Czuczwar (609-616).
The effect of levetiracetam (LEV) on the acute neurotoxic profiles of various antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], phenobarbital [PB], valproate [VPA], lamotrigine [LTG], topiramate [TPM], oxcarbazepine [OXC], and felbamate [FBM]) was evaluated in the rotarod test, allowing the determination of median toxic doses (TD50 values) with respect to impairment of motor coordination in mice. The TD50 of LEV administered singly was 1601 mg/kg. Whilst LEV at 150 mg/kg, being its TID50 (a dose increasing the electroconvulsive threshold by 50%), was without effect with regards to motor coordination impairment associated with PHT, PB, VPA, LTG, OXC, and FBM, it significantly enhanced that associated with CBZ and TPM co-administration. Thus LEV (150 mg/kg) significantly decreased the TD50 of CBZ from 53.6 to 37.3 mg/kg (P  < 0.01) and that of TPM from 423 to 246 mg/kg (P  < 0.01). In addition LEV (75 mg/kg) significantly decreased the TD50 of TPM from 423 to 278 (P  < 0.01). That concurrent measurement of total brain LEV, CBZ, and TPM concentrations showed that concentrations were not significantly different when AEDs were administered singly compared to when they were administered in combination would suggest that there is no pharmacokinetic interaction between these AEDs. Thus, the observed potentialization of the acute neurotoxic effects of CBZ and TPM by LEV is the consequence of a pharmacodynamic interaction. These data support both experimental and clinical published data advocating that LEV may interact with some AEDs by pharmacodynamic mechanisms.
Keywords: Levetiracetam; Antiepileptic drugs; Acute neurotoxicity; Rotarod test; Pharmacodynamic interaction;

Deramciclane in the treatment of generalized anxiety disorder: A placebo-controlled, double-blind, dose-finding study by Hannu Naukkarinen; Roope Raassina; Jukka Penttinen; Antti Ahokas; Riitta Jokinen; Hannu Koponen; Ulla Lepola; Harri Kanerva; Leena Lehtonen; Tiina Pohjalainen; Auli Partanen; Outi Mäki-Ikola; Juha Rouru (617-623).
Deramciclane, a camphor derivative, is a novel anxiolytic agent with a unique mechanism of action. It acts as a potent and specific antagonist at serotonin 5-HT2A/2C receptors, and exhibits anxiolytic efficacy in animal models. The aim of this double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of a range of doses of deramciclane in patients with generalized anxiety disorder (GAD). Adult patients with a diagnosis of GAD (DSM-IV) and a Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 18; a score ≥ 2 for the HAM-A items ‘Anxious Mood’ and ‘Tension’; a score ≥ 4 on the Clinical Global Impression of Severity of Illness (CGI-S) Scale; and a score ≤ 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS) were enrolled in the study. Following a 1–2 week placebo run-in period, patients were randomized to receive deramciclane (10, 30, or 60 mg/day in two divided doses) or placebo for 8 weeks, followed by a 2-week placebo wash-out period. The primary efficacy measure was change in HAM-A score from baseline to week 8. Adverse events were monitored throughout the study. Withdrawal reactions were assessed at the end of the study (week 8) and during the placebo wash-out period using the Physician's Withdrawal Checklist (34 items). In the intent-to-treat population (n  = 208), both the deramciclane 30 mg/day and 60 mg/day doses provided clinically relevant improvements in HAM-A total score after 8 weeks of treatment, reaching statistical significance compared with placebo in the 60 mg/day dose group (p  = 0.024) and a clear trend in the 30 mg/day group (p  = 0.059). On the HAM-A psychic anxiety factor, significant improvements were seen in patients in the deramciclane 30 mg/day and 60 mg/day treatment groups compared with those in the placebo group (p  < 0.05). Adverse events were reported at a similar frequency across all four treatment groups; the most commonly reported adverse event was headache. No withdrawal reactions were observed on abrupt discontinuation of deramciclane. In conclusion, deramciclane 60 mg/day showed significant evidence of efficacy for the treatment of GAD in adult patients. The efficacy for the 30 mg/day dose was close to the larger dose although not significant in the primary analysis, and there was no significant evidence of efficacy for the 10 mg/day dose. Deramciclane was safe and well-tolerated up to the 60 mg/day dose over an 8-week period.
Keywords: Deramciclane; Generalized anxiety disorder; Withdrawal; Anxiolytic;

The action of nicotine on the nicotinic receptor-mediated release of inhibitory and excitatory acids in the nucleus accumbens, NAC, of freely moving rats was studied in order to clarify their effects' on reinforcing behavior as estimated by conditioned place preference (CPP). Using the technique of microdialysis, intraperitoneal (i.p.) injections of nicotine (0.15-0.3-0.6 mg/kg), significantly increased aspartate, glutamate, arginine, taurine, and alanine microdialysate content in the nucleus accumbens. The same doses of nicotine were able to elicit a reinforcing effect in a CPP paradigm which was probably associated with the increased brain levels of excitatory acids triggering additional dopamine release in the mesolimbic system.
Keywords: Nicotine; Nucleus accumbens; Microdialysis; Conditioned place preference;

Valproate attenuates dextroamphetamine-induced subjective changes more than lithium by Morgan C. Willson; Emily C. Bell; Sanjay Dave; Sheila J. Asghar; Brent M. McGrath; Peter H. Silverstone (633-639).
Dextroamphetamine administration in healthy controls produces a range of subjective and physiological effects, which have been likened to those occurring during mania. However, it is uncertain if these can be attenuated by lithium since conflicting results have been reported. To date there have been no previous studies examining the effects of valproate on dextroamphetamine-induced mood and physiological changes. The current study was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n  = 12), 900 mg lithium (n  = 9), or placebo (n  = 12) pre-treatment for 14 days. Subjective and physiological measures were then obtained prior to administration of a 25 mg dose of dextroamphetamine, and at two time points after administration. Differences in the response to dextroamphetamine were assessed between the three treatment groups. The results of this study show that pre-treatment with lithium only significantly attenuated dextroamphetamine-induced change in happiness, while valproate pre-treatment significantly attenuated the effects of dextroamphetamine on happiness, energy, alertness and on the diastolic blood pressure. These results suggest that lithium and valproate do not have the same mechanism of action on dextroamphetamine-induced changes, and this finding may relate to differences in their mechanism of action in mood disorders.
Keywords: Lithium; Sodium valproate; Dextroamphetamine; Human volunteers;

No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes by Klaus Lieb; Bernd L. Fiebich; Inga Herpfer; Michela Mantovani; Marlene Löffler; Thomas J. Feuerstein (641-646).
Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC50  = 10− 7.96 M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 μM. Furthermore, substance P as well as Sar9Met(O2)11SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.
Keywords: Affective disorders; Depression; Therapy; Etiology; 5-HT; Reuptake;

Circulatory neurosteroid levels in underweight female adolescent anorexia nervosa inpatients and following weight restoration by D. Stein; R. Maayan; A. Ram; R. Loewenthal; A. Achiron; D. Modan-Moses; M. Feigin; A. Weizman; A. Valevski (647-653).
Nineteen female adolescent inpatients diagnosed with anorexia nervosa, restricting type (AN-R) and 16 non-eating disordered (ED) controls were assessed for plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulphate (DHEA-S), and cortisol levels, and for eating-related and non-eating-related psychopathology. AN-R patients were assessed at admission, 1 month and 4 months following hospitalization. The non-ED controls were assessed once. No baseline between-group differences were found in plasma cortisol, DHEA, and DHEA-S levels, whereas the patient group had a significantly lower Cortisol/DHEA-S ratio and elevated scores on most psychopathological parameters. A significant increase was found in the body mass index of the AN-R patients at 4 months post-hospitalization, accompanied by a decrease in plasma cortisol levels and a trend towards decreased Cortisol/DHEA and Cortisol/DHEA-S ratios, whereas no change occurred in psychopathology. The difference in Cortisol/DHEA-S ratio between AN-R patients and non-ED controls, and the different patterns of change in cortisol vs. DHEA(-S) levels following weight restoration, may in part account for the feeding difficulties in AN, particularly during refeeding.
Keywords: Anorexia nervosa; Neurosteroids; Dehydroepiandrosterone; Dehydroepiandrosterone-sulphate; Cortisol; Refeeding;

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects of the acute administration of acetaldehyde. In particular, the role of this metabolite in ethanol-induced anxiolytic effects has never been extensively tested. The aim of the present study was to characterize the anxiolytic effects of acetaldehyde in two strains of mice, C57BL/6J and CD1 mice with the elevated plus-maze procedure. The results show that acute injections of ethanol (1–2 g/kg) induced significant dose-dependent anxiolytic effects in both strains of mice. In contrast, acetaldehyde failed to produce any anxiolytic effect, although it induced a significant hypolocomotor effect at the highest doses. In an independent experiment, cyanamide, an aldehyde dehydrogenase inhibitor, prevented the locomotor stimulant effects of ethanol, although it failed to alter its anxiolytic effects. Together, the results of the present study indicate that acetaldehyde is not involved in ethanol-induced anxiolytic effects, although it may be involved in its sedative/hypolocomotor effects.
Keywords: Ethanol; Acetaldehyde; Cyanamide; Elevated plus-maze; Anxiolysis;

Subjective and neurovegetative changes in healthy volunteers and panic patients performing simulated public speaking by Alexandre C.B.V. Parente; Cybele Garcia-Leal; Cristina M. Del-Ben; Francisco S. Guimarães; Frederico G. Graeff (663-671).
Drug-free symptomatic panic patients, drug-treated nonsymptomatic patients and healthy controls were submitted to simulated public speaking. Subjective anxiety, cognitive impairment and discomfort measured by the visual analog mood scale as well as skin conductance level were higher in symptomatic patients than in controls at the beginning of the experimental session, nonsymptomatic patients lying in between. Subjective sedation, spontaneous fluctuations of skin conductance, heart rate and blood pressure were similar in the three groups. Preparation and performance of speech decreased sedation while increasing anxiety, cognitive impairment, level and fluctuations of skin conductance, heart rate and blood pressure. Anxiety, cognitive impairment and conductance level were less increased in symptomatic patients than in controls. Electrodermal activity, but not cardiovascular measures of sympathetic arousal correlated with anticipatory anxiety. Chronic treatment with serotonin uptake inhibitors attenuated the differences between panic patients and controls, supporting the participation of serotonin in panic disorder.
Keywords: Experimental anxiety; Panic disorder; Skin conductance; Heart rate; Blood pressure; Serotonin uptake inhibitors;

Due to the electrochemical nature of the communication structure of the brain an intimate relationship between neurotransmitter activity on one side and field potentials (EEG) on the other side can be suspected. In order to learn more about this relationship pharmacological manipulation of the cholinergic transmitter system by means of agonistic and antagonistic receptor active drugs was used. Continuous recording of electrical activity from four selected brain areas (frontal cortex, hippocampus, striatum and reticular formation) in freely moving day–night converted Fisher rats was used (Tele-Stereo-EEG). Frequency analysis of telemetrically transmitted data and special definitions of frequency ranges were used to analyse the data from 45 min pre-drug and 180 min postdrug periods. Pharmacological modulation of brain activity by the selective nicotinic agonist metanicotine as well as the alpha 7 selective nicotinic antagonist methyllycaconitine revealed major changes in delta (1–4.5 Hz) and alpha2 (9–12.5 Hz) frequencies. In general blockade of the cholinergic system resulted in electrical power increases and activation in decreases. Unspecific modulation of cholinergic activity by using the cholinesterase inhibitors physostigmine, tacrine and galantamine led to alpha1 frequency (7–9.5 Hz) changes in addition to the delta and alpha2 changes. These three drugs produced a nearly identical pattern of frequency changes. Theta (4.75–6.75 Hz) and beta1 frequencies (12.75–18.5 Hz) changed to a lesser degree. A peculiar finding arose with respect to the effects of the antagonistic drugs scopolamine and biperiden since biperiden–besides the massive increase of delta and alpha1 power in common–induced a general decrease of alpha2 frequencies within all brain areas opposite to the effect of scopolamine. This special property of biperiden gives a plausible explanation for its efficacy in Parkinsonian patients since decreases of alpha2 waves in this model indicate enhancement of dopaminergic transmission [Dimpfel, W., Spüler, M., Koch, R., Schatton, W., 1987. Radioelectroencephalographic comparison of memantine with receptor-specific drugs acting on dopaminergic transmission in freely moving rats. Neuropsychobiology 18, 212–218]. Except for the effects of methyllycaconitine (p  < 10%) all results were statistically significant at least at the p  < 5% level. The results are best explained by assuming that electrical delta activity reflects cholinergic transmitter control followed by and closely linked to changes in dopaminergic transmission as indicated by additional concomitant changes in alpha2 electrical power.
Keywords: Acetylcholin; Drugs; Tele-Stereo-EEG; Rat; Electroencephalography;