Journal of Psychopharmacology

Zuurman, L. ;Roy, C. ;Schoemaker, RC ;Hazekamp, A. ;Hartigh, J. den;Bender, JCME ;Verpoorte, R. ;Pinquier, JL ;Cohen, AF ;van Gerven, JMA

doi: 10.1177/0269881108089581pmid: 18515447

This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano® vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano® vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano® vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of 'alertness' (8 mg: -33.6 mm: 95% CI -41.6, -25.7), 'feeling high' (8 mg: 1.09 U: 95% CI 0.85, 1.33), 'external perception' (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4 - 84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.

Strougo, A. ;Zuurman, L. ;Roy, C. ;Pinquier, JL ;van Gerven, JMA ;Cohen, AF ;Schoemaker, RC

doi: 10.1177/0269881108089870pmid: 18583433

Pharmacokinetics after pulmonary administration of δ-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic—pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration—effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.

Fisk, JE ;Montgomery, C.

doi: 10.1177/0269881107084000pmid: 18208908

The relationships between executive processes, associative learning and different aspects of real world memory functioning were explored in a sample of cannabis users and nonusers. Measures of executive component processes, associative learning, everyday memory, prospective memory, and cognitive failures were administered. Relative to nonusers, cannabis users were found to be impaired in several aspects of real world memory functioning. No other group differences were apparent. The absence of cannabis related deficits in those executive component processes and aspects of learning that are believed to support real world memory processes is surprising given that cannabis related deficits were obtained in real world memory. The present results are discussed within the context of neuroimaging evidence which suggests that cannabis users may exhibit different patterns of neural activation when performing executive tasks while not always exhibiting deficits on these tasks.

Bradley, BP ;Field, M. ;Healy, H. ;Mogg, K.

doi: 10.1177/0269881107083844pmid: 18208922

Research indicates that drug-related cues elicit attention and approach biases in drug users. However, attentional biases are not unique to addiction (e.g., they are also found for emotional information). This study examined whether attentional and approach biases in cigarette smokers are mediated by the motivational salience of cues (relevance to drug-taking), rather than by their affective properties (subjective liking of the cues). Cues included pleasant and unpleasant smoking-related pictures. Attentional biases, approach tendencies and subjective evaluation of the cues were assessed on visual probe, stimulus—response compatibility and rating tasks, respectively. Compared with non-smokers, smokers showed a greater attentional bias for both pleasant and unpleasant smoking-related cues presented for 2000 ms, but not for 200 ms. Smokers showed a greater approach bias for unpleasant cues, although the groups did not differ significantly in approach bias for pleasant smoking-related cues. Smokers rated both pleasant and unpleasant smoking pictures more positively than did non-smokers. Results suggest that a bias to maintain attention on smoking-related cues in young adult smokers is primarily a function of drug-relevance, rather than affective properties, of the cues. In contrast, approach tendencies and pleasantness judgements were influenced by drug use, drug-relevance and the affective properties of the cues.

Hartley, JE ;Montgomery, AMJ

doi: 10.1177/0269881107082903pmid: 18308782

The effects of 8-OH-DPAT treatment on rat grooming behaviour, elicited either prandially or in response to spraying with water were investigated. Dose (≤0.1 mg/kg s.c.) response studies employed momentary time sampling over 30 or 60 min with behaviour being scored in one of 6 or 7 (depending on food availability) mutually exclusive categories (feeding, active, scratching, face-grooming, body grooming, genital-grooming and resting) at 15 s intervals. In non-deprived rats, tested with wet mash available, feeding and activity frequencies were increased, but resting and total grooming were inhibited by 8-OH-DPAT. Face-, body- and genital-grooming occurred at higher levels than scratching, but all categories were reduced with reductions in scratching occurring at a lower dose (0.01 mg/kg). Misting rats with a fine water spray selectively increased body grooming and decreased activity without altering feeding, while 8-OH-DPAT increased feeding and reduced face-, body- and genital-grooming, without affecting already low levels of scratching. In misted rats, tested without food, 8-OH-DPAT reduced face-, body- and genital-grooming and increased resting. These results confirm i) that the water spray technique is a useful method for increasing grooming and ii) that 8-OH-DPAT has a suppressant effect on grooming independent of response competition from enhanced feeding.

Tsao, C-W. ;Lin, Y-S. ;Cheng, J-T. ;Lin, C-F. ;Wu, H-T. ;Wu, S-R. ;Tsai, W-H.

doi: 10.1177/0269881107082951pmid: 18308792

Interferon (IFN)-α upregulates serotonin (5-HT) uptake and serotonin transporter (5-HTT) messenger ribonucleic acid (mRNA) expression in immune cells, which implies the mechanism underlying IFN-α-induced depression. However, the signal transduction of this effect remains unclear. We investigated whether the effects of IFN-α on the functions of 5-HTT were related to mitogen-activated protein kinase (MAPK). By performing Western blotting, real-time reverse transcriptase—polymerase chain reaction and [3H]5-HT labelling, we examined MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake in Jurkat T cells. The cells had been cultured for different time periods (1) with IFN-α alone and (2) preincubated with either MAPK inhibitors or with the selective serotonin reuptake inhibitor, fluoxetine, and subsequently cultured along with IFN-α. The levels of MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake all increased in the IFN-α-treated cells but were blocked in those that were pretreated with MAPK inhibitors and fluoxetine. These results appear to clarify the association of depression with IFN-α-induced 5-HT uptake that reduces the 5-HT levels and IFN-α-regulated transcription of 5-HTT; further, the results suggest the involvement of MAPK in this process.

Erkinjuntti, T. ;Gauthier, S. ;Bullock, R. ;Kurz, A. ;Hammond, G. ;Schwalen, S. ;Zhu, Y. ;Brashear, R.

doi: 10.1177/0269881107083028pmid: 18308781

Alzheimer's disease combined with cerebrovascular disease (AD with CVD) is associated with progressive decline, with CVD impacting AD onset and severity of progression. Subjects with confirmed diagnosis of AD with CVD were treated with galantamine during a six-month, randomized, placebo-controlled trial (N = 285). Responder analyses were performed for cognitive, behavioural and functional outcome measures. Galantamine treatment resulted in significantly greater cognitive and functional improvements compared with placebo at six months, and a significantly higher percentage of treatment responders. The proportion of responders demonstrating improved or maintained cognition on the 11-item AD assessment scale-cognitive subscale (ADAS-cog/11) was 60.5% for galantamine versus 46.0% for placebo (P = 0.013). The proportion of patients responding by at least four-points on the ADAS-cog/11 was significantly greater for the galantamine group compared with placebo (33.6% versus 17.2%; P = 0.003). Seventy-five percent of galantamine-treated subjects improved or remained stable as assessed by CIBIC-plus compared with 53.6% on placebo (P = 0.0006). Significantly higher responder rates were observed with galantamine for behaviour (64.9% versus 56.6%; P = 0.024), and numerically favourable responder rates were seen with galantamine for activities of daily living. Treatment-emergent adverse events were generally related with the gastrointestinal system (nausea 20% versus 10%; vomiting 12% versus 5%; galantamine and placebo groups, respectively). Three deaths occurred during double-blind treatment: 2 of 188 subjects receiving galantamine, and 1 of 97 subjects receiving placebo. These findings are consistent with a broad range of cognitive, functional and behavioural benefits with galantamine across the spectrum of AD and AD with CVD.

Reich, CG ;Mohammadi, MH ;Alger, BE

doi: 10.1177/0269881107083999pmid: 18308796

Recently, disruption of the endogenous cannabinoid (endocannabinoid, eCB) system was found to impair extinction in delay and contextual fear conditioning models. However, conditioning procedures used in that work precluded investigation of possible eCB effects on acquisition of learned fear. We therefore examined the role of eCBs in modulating fear responses using multiple-trial versions of trace (hippocampal-dependent) and delay (amygdala—dependent) Pavlovian fear conditioning. By administering the CB1 receptor antagonist AM251 (5 mg/kg, i.p) to C57/Bl/6 mice at various times, we systematically identified the stages of learning and memory (i.e. acquisition, consolidation, recall and extinction) that are modulated by eCB signaling. During tone (CS) — footshock (US) conditioning, AM251 enhanced acquisition of freezing behavior for both trace- and delay-conditioning protocols. CB1 antagonism also enhanced generalized fear (baseline freezing) and cued (CS) freezing during memory recall tests in a state-dependent manner for both trace and delay conditioned animals. Furthermore, in trace-conditioned animals, AM251 impaired extinction performance of both cued and generalized fear. CB1 antagonism did not affect short-term memory (STM) or long-term memory (LTM) consolidation processes. Together, these results suggest that during acquisition and recall of aversive learning, eCBs prevent the expression and retention of inappropriate generalized and learned responses. These findings have important implications for the therapeutic use of CB1 antagonists.

Shajahan, P. ;MacRae, A. ;Bashir, M. ;Taylor, M.

doi: 10.1177/0269881107083483pmid: 18308790

We aimed to study aripiprazole, as monotherapy and combined with other antipsychotics, in routine clinical practice, to identify patients who had a favourable clinical response. We retrospectively identified all secondary care psychiatric patient records started on aripiprazole (n = 85). We assigned Clinical Global Impression scores to measure effectiveness. We examined demographic and clinical correlates of patients who improved (CGI Improvement scores < 5) versus those who did not improve (CGI ≥ 5). 56 patients (66%) received aripiprazole as monotherapy, 29 patients (34%) in combination with other antipsychotics. 52 patients (62%) received a CGI 1-4 (minimally to very much improved), 32 patients (38%) a CGI ≥ 5 (no change to very much worse). Patients who improved were less likely to have had previous or subsequent treatment with clozapine (p = 0.04). Discontinuation was due to agitation (35%), inefficacy (21%), nausea (18%) and worsening psychosis (12%). Combination with other antipsychotics resulted in less discontinuation and a lower maximum dose of aripiprazole. Aripiprazole was combined with other regular additional antipsychotics in 1/3rd of patients. Combination and monotherapy were clinically effective in around 60% of patients. Favourable response was associated with lack of treatment resistance. Agitation was the commonest reason for discontinuation.

Feng, P. ;Vurbic, D. ;Wu, Z. ;Hu, Y. ;Strohl, KP

doi: 10.1177/0269881106082899pmid: 18753273

Depression is associated with a deficiency of serotonergic neurons that have been found to suppress orexinergic neurons, which in turn activate these neurons in a feedback loop. This evidence suggests that orexins may be involved in the pathology of depression. Long Evans rats were treated with clomipramine (CLI) and saline (SAL) from postnatal days 8 through 21. One set of rats from both groups was sacrificed at 35 days of age for quantification of orexins in multiple brain regions. At 3—4 months of age a second set of rats was tested for immobility in a forced swim procedure, a common test for depressive signs in rats, and a third set was sacrificed for the quantification of orexins. Compared with the control rats, adult rats with neonatal CLI treatment had (1) increased forced swim immobility and (2) increased orexins A and B in the hypothalamus. However, both orexins A and B levels were decreased in multiple brain regions in the juvenile CLI rats compared with same-age controls. We concluded that although orexin levels were decreased in juvenile CLI rats, adult CLI rats with features of depression had significantly higher levels of hypothalamic orexins compared with adult controls. These results imply that orexins are likely to be involved in the pathological regulation of depression.