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Purpose To investigate the hypothesis that paracetamol is absorbed faster from a hot drink than from a standard tablet using simultaneous scintigraphic imaging and pharmacokinetic sampling. Methods Twenty-five healthy male volunteers received both paracetamol formulations in a randomised manner. The formulation administered in the first treatment arm was radiolabelled to allow scintigraphic monitoring. In both treatment arms, blood samples were taken for assessing paracetamol absorption. Results Following the hot drink, paracetamol absorption was both significantly faster and greater over the first 60 min post-dose compared with the tablet, as evidenced by the median time to reach t0.25 μg/mL of 4.6 and 23.1 min, respectively, and AUC0-60 of 4668.00 and 1331.17 h*ng/mL, respectively. In addition, tmax was significantly shorter for the hot drink (median time = 1.50 h) compared with the tablet (1.99 h). However, Cmax was significantly greater following the tablet (9,077 ng/mL) compared with the hot drink (8,062 ng/mL). Onset of gastric emptying after the hot drink was significantly faster than after the standard tablet (7.9 versus 54.2 min), as confirmed scintigraphically. Conclusions Compared with a standard tablet, a hot drink provides faster absorption of paracetamol potentially due to more rapid gastric emptying.

A comparison of the 21-mg NiQuitin patch with other marketed nicotine patches reported significant differences in pharmacokinetic profiles, even among patches of the identical labeled dose strength. The 25-mg Nicorette Invisi patch became available in the United Kingdom at the end of 2008. No published studies have directly compared the pharmacokinetic profile of this new patch with that of the 21-mg NiQuitin patch.This study was conducted to compare the single-dose pharmacokinetics of the 21-mg/24-hour patch and the 25-mg/16-hour patch. To determine whether any pharmacokinetic differences might be related to differences in wear time, a post hoc exploratory analysis evaluated the nicotine delivery profiles of the patches under the assumption that the 21-mg patch was removed after 16 rather than 24 hours.This was a single-center, randomized, open-label, single-dose, 2-way crossover study in healthy adults who smoked10 cigarettes per day in the 6 months before the study. Eligible subjects were housed at the study center for 2 baseline and 2 treatment sessions; no smoking was permitted during the baseline or treatment sessions. Subjects were allocated to receive either the 21-mg patch (removed after 24 hours) or the 25-mg patch (removed after 16 hours) during the first treatment session, after which they crossed over to the alternative sequence in the second treatment session. Blood samples were obtained at predetermined time points before and after patch application. The primary pharmacokinetic parameter was the AUC(0-infinity), an indication of total nicotine exposure. Secondary pharmacokinetic parameters included AUC(0-t), C(max), and T(max). Post hoc exploratory parameters were the AUC(0-16) and the AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch. The differences in AUC(0-infinity), AUC(0-t), Cmax, AUC(0-16), and AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch were considered significant if the lower limit of the 90% CI for the geometric mean ratio (21 mg:25 mg) was100%. T(max) values were compared using a signed-rank test. Adverse events were elicited using a standard open-ended question on each day of confinement; spontaneously reported events were also captured. The topical effects of the patch (erythema; edema; extent of erythema/papules/pustules; self-reported pruritus) were assessed by study staff before patch application and 1 and 8 hours after patch application using a 4-point rating scale; any topical effects were recorded as adverse events.Fifty otherwise healthy smokers (29 men, 21 women) were enrolled; 47 (94%) were white. Their mean (SD) age was 31.5 (9.57) years (range, 20-53 years), mean weight was 70.24 (9.56) kg (range, 51.0-95.9 kg), and mean height was 173.0 (8.02) cm (range, 156-194 cm). Subjects reported smoking between 11 and 40 cigarettes per day before the study. The AUC(0-infinity) was significantly higher for the 21-mg patch worn for 24 hours than for the 25-mg patch worn for 16 hours (382.36 vs 243.69 ng/mL . h, respectively; geometric mean ratio: 156.90%; 90% CI, 148.10%-166.23%; P0.001). T(max) was reached significantly sooner with the 21-mg patch than with the 25-mg patch (6.0 vs 12.0 hours; P0.001). C(max) was significantly higher for the 21-mg patch compared with the 25-mg patch (18.34 vs 16.56 ng/mL; geometric mean ratio: 110.72%; 90% CI, 104.82%-116.94%; P0.01). The exploratory analyses suggested that the 21-mg patch applied for 16 hours may provide greater total nicotine exposure than the 25-mg patch applied for 16 hours. Although most subjects reported adverse events (75.0% with the 21-mg patch, 89.8% with the 25-mg patch), the majority of these events were mild.In this single-dose study in adult smokers, the 21-mg patch was associated with significantly greater nicotine exposure compared with the 25-mg patch. The 21-mg patch provided a maximal nicotine concentration faster than did the 25-mg patch.

Objective: Controversy exists over the effect of tobacco deprivation in nicotine-dependent individuals and the efficacy of nicotine in reversing performance decrements. This study's aim was to assess the efficacy of nicotine (4-mg lozenge) versus placebo on aspects of cognitive and psychomotor performance, mood, and withdrawal symptoms in male and female established smokers. Methods: Male and female smokers (N = 22; mean age, 28.8 years), with a smoking history of more than 1 year and time to first cigarette of less than 30 minutes upon waking, were enrolled. Baseline measures were obtained at 17 hours of abstinence. At 18-hour abstinence, nicotine or placebo was administered every 2 hours over an 8-hour period. Cognitive and psychomotor performance measurements were taken 30 minutes after dose. Cognitive test battery included Rapid Visual Information Processing, Continuous Tracking Task, Critical Flicker Fusion, Choice Reaction Time, Stroop Test, and Sternberg's Short-term Memory Scanning Task. Withdrawal (Modified Minnesota Withdrawal Scale) and mood (Positive and Negative Affect Schedule) were also assessed. A mixed-models analysis of covariance was performed. Results: Compared with placebo nicotine (4 mg) significantly improved vigilance, divided attention, executive functioning, working memory, and sensorimotor performance in abstinent volunteers (P ≤ 0.05). Withdrawal symptoms including craving, difficulty concentrating, irritability, and restlessness were also attenuated, and affective state was improved after nicotine 4 mg administration. Conclusions: Compared with placebo, nicotine (4 mg) improved measures of vigilance, memory, and attention; improved mood; and reduced withdrawal symptoms. These findings suggest that repeated nicotine replacement therapy over a period of 8 hours can improve cognitive deficits associated with nicotine withdrawal.

The aim of this study was to identify predictors of successful relapse prevention in smokers receiving long-term sustained-release bupropion. Smokers (N=784) who were interested in stopping smoking were enrolled in a 7-week, open-label bupropion phase. Abstinent subjects at the end of treatment and eligible to proceed (N=429) were randomized to active bupropion or placebo through Week 52 and then followed for an additional year. The best overall predictor of less relapse to smoking was assignment to active bupropion. In aggregate, the results indicate that bupropion can be prescribed to diverse populations of smokers with expected comparable results. There was a medication effect that was independent of any predictor except older age and those who gained no or minimal weight during the open-label phase. Predictors of successful relapse prevention included lower baseline smoking rates, a Fagerstrom Tolerance Questionnaire score of

Objective To examine previous use of nicotine replacement therapy (NRT) on the smoking-cessation efficacy of bupropion sustained release (SR). Methods Secondary analysis of a parallel-group, randomized, double-blind, placebo-controlled study. Smokers who had, based on self-report, no previous history of NRT (N = 453) or who had used NRT at least once (N = 440) were randomized to receive placebo, bupropion SR, nicotine transdermal system (NTS), or a combination of bupropion SR and NTS. Results Bupropion SR showed similar efficacy in participants with or without previous use of NRT. Conclusion Bupropion SR is effective in promoting smoking abstinence regardless of prior NRT use.

Background: Recent data suggest that women smokers respond differently than men to cessation pharmacotherapies, particularly nicotine replacement therapy (NRT). Lower abstinence and higher relapse rates are often reported for women treated with NRT. Gender effects for those treated with non-nicotinic, bupropion-hydrochloride sustained release for relapse prevention have not been studied. Methods: Data from a multicenter relapse-prevention (RP) trial of bupropion (November 1995–June 1998) were analyzed for gender differences. Men and women smokers (N=784) were treated with open-label bupropion for 7 weeks. Those abstinent at Week 7 ( n =432) were enrolled in the double-blind relapse-prevention phase and randomized to placebo or continued bupropion for 45 additional weeks. Results: Differences in point-prevalence abstinence rates between men (61.8%) and women (55.6%) in open-label bupropion (Week 7) were not significant. In the RP-phase Week 52, continuous abstinence rates for men and women were 37.8% and 36.4% (bupropion) and 36.6% and 29.9% (placebo), respectively; point-prevalence abstinence rates for men and women were 54.1% and 55.9% (bupropion) and 42.9% and 41.3% (placebo), respectively. Abstinence rates and time to relapse were superior for both men and women who received longer treatment. Gender differences within treatment groups were not significant. Median time to relapse was equal for men and women within each treatment group: Week 32 for bupropion and Week 20 for placebo. Conclusions: Our data suggest that bupropion is a promising pharmacotherapy for preventing relapse, particularly for women.

Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.

Binding of 3H-spiperone and 3H-raclopride to membranes of cells stably-transfected with a human dopamine D2 receptor clone was investigated, as was that of 3H-spiperone to those stably-transfected with a human D4 receptor clone. 3H-spiperone and 3H-raclopride labeled the same number of sites in the D2 receptor preparation. The inhibition of binding by clozapine, spiperone, (-) eticlopride, haloperidol and the novel substituted benzamide 1192U90 was also investigated. Clozapine and 1192U90 showed greater inhibition of 3H-raclopride binding than 3H-spiperone binding to the D2 receptor. Comparison with inhibition of 3H-spiperone binding to the D4 receptor revealed that clozapine and 1192U90 displayed apparent selectivity (as assessed by Ki ratios) for the D4 receptor when compared with binding of 3H-spiperone, but not 3H-raclopride, to the D2 receptor.

1. Administration of the irreversible antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, (EEDQ, 2 mg kg-1, i.p.) to mice reduced binding of [3H]-RX 821002 (2-methoxy-idazoxan) to alpha 2-adrenoceptors in whole mouse brain by 75% 24 h later. The receptor binding returned over time only being reduced by 25% by 16 days post administration; the time taken for binding to return to 50% of control levels was estimated to be 5.25 days. 2. EEDQ administration also resulted in the loss of the sedative effect of the alpha 2-adrenoceptor agonist, medetomidine, measured by the holeboard test of directed exploration and locomotor activity. Agonist-induced sedation returned to control values by 8 days post EEDQ administration. 3. EEDQ administration also resulted in the loss of the hypothermic response to medetomidine (0.1 mg kg-1, i.p.). Medetomidine-induced hypothermia returned to control values by 12 days post EEDQ administration. 4. Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 821002 (0.1-3.0 mg kg-1, i.p.) 45 min before EEDQ prevented the loss of alpha 2-adrenoceptors as well as the blockade of medetomide-induced sedation and hypothermia by EEDQ. 5. The results of these experiments indicate that there is significant receptor reserve for alpha 2-adrenoceptor-mediated behavioural and physiological responses.

Impaired attention ('difficulty concentrating') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG α power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the α-correlated activation across these regions. We also found that EEG α power was negatively correlated with RVIP-induced deactivation in regions comprising the 'default mode' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These α-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and α EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks.

In recent years it has become apparent that the parental origin of genetic material has an impact on gene expression and this effect has become known as genomic imprinting. The evidence for the influence of genomic imprinting on behavior and in the etiology of certain neurobehavioral disorders is discussed. The possibilities for a role for genomic imprinting in the inheritance of behaviors related to alcohol abuse and alcoholism and in the paternal alcohol syndrome are also explored.

The gene for tryptophan 2,3-dioxygenase (TDO) heretofore was believed to be expressed only in liver. The data presented here demonstrate that RNA encoding TDO is present in rodent brain. Oligonucleotide primers based on the rat liver TDO cDNA sequence were synthesized and used to amplify RNA derived from mouse whole brain and liver and rat brain regions by the RNA-PCR. Reaction products were purified and subjected to DNA sequencing. Identical sequences were obtained when mouse whole brain and liver RNAs were amplified, and these sequences were shown to be 96% identical to the published rat liver tryptophan TDO cDNA sequence. In addition, TDO sequences were found in RNA derived from rat brainstem, cerebellum, cortex, hypothalamus, and the remainder of the brain.

The effect of alcohol on aggressive behavior was studied in the highly aggressive transgenic TGF alpha male mouse. In contrast to findings obtained in other aggressive animals, low and moderate doses of alcohol failed to reduce this behavior in the TGF alpha mice; only a high dose reduced aggression. The plasma levels of alcohol were similar in the TGF alpha mice and non-transgenic control mice. However, the loss of righting reflex following an alcohol administration was significantly lengthened in the TGF alpha mice. These results suggest that the male TGF alpha mice can be used to investigate the mechanisms determining the physiological sensitivity to alcohol. Furthermore, these mice represent the first animal model supporting the findings obtained in humans that alcohol maintains pathological aggression.

Caffeine and other methylxanthines induce a dose-dependent reduction in core body temperature in mice. These experiments investigated the effects of neurotransmitter and neuromodulator antagonists on caffeine-induced hypothermia. Pretreatment with the α 2 -adrenoceptor antagonist, atipamezole; the β-adrenoceptor antagonist, propranolol; the dopamine antagonist, haloperidol; or the benzodiazepine receptor antagonist, flumazenil had no intrinsic effects on core body temperature nor did they interact significantly with the hypothermic effects of caffeine. The α 1 -adrenoceptor antagonist, prazosin and the 5-HT receptor antagonist, metergoline significantly enhanced the hypothermic effects of caffeine, probably involving a combined effect with their intrinsic hypothermic actions. Pretreatment with the opiate receptor antagonist, naloxone (3 mg/kg i.p.), had no intrinsic effect on core body temperature but attenuated the hypothermic effect of caffeine reflected in a parallel shift to the right in the caffeine dose-effect curve. The naloxone-induced attenuation of the hypothermic effects of caffeine was also seen to be dose-dependent. The results reveal that opiate receptors (but not adrenoceptors, 5-HT, dopamine or benzodiazepine receptors) may play a role in modulating the hypothermic action of caffeine and possibly other methylxanthines.

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Caffeine induces a dose-dependent decrease in core body temperature in mice and the hypothermia induced by a 100 mg/kg dose of caffeine was seen to persist for greater than 160 min. Other alkylxanthines including theophylline, enprophylline, isbutylmethylxanthine and 1,3-dipropyl-7-methylxanthine also showed dose-dependent reductions in body temperature. The dose of these drugs required to reduce body temperature by 2 degrees C was calculated and correlated with the affinities for the compounds at adenosine A1 and A2 receptors and their activities in inhibiting calcium dependent and independent phosphodiesterases. Significant relationships were found between the 2 degrees C hypothermic dose (HD2) and soluble and membrane calcium-independent phosphodiesterase inhibiting activity (r2s = 0.950 and 0.940, respectively). No significant relationship was seen between HD2 and soluble calcium-dependent phosphodiesterase inhibiting activity or with A2 adenosine receptor affinity. The relationship between HD2 and A1 adenosine receptor affinity (r2 = 0.739) did however almost reach statistical significance. These results would suggest that phosphodiesterase inhibition, instead of or in addition to adenosine receptor blockade, may play an important role in the effects of alkylxanthines on body temperature.

The putative 5-HT 1A receptor antagonist properties of 1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)butyl] piperazine (NAN-190) were studied in mice. The responses studied were hypothermia- and hyperglycemia-induced by the 5-HT 1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT). NAN-190 (0.3–3 mg/kg) did not antagonize either response, but rather appeared to be additive with the effect produced by 8-OH-DPAT (0.25 mg/kg) alone, at least with respect to temperature. NAN-190, given alone in similar doses, caused hypothermia and hyperglycemia. These results suggest that NAN-190 has similar properties to 8-OH-DPAT with regard to temperature and glucose effects. Therefore, it does not appear to be a effective antagonist for all 5-HT 1A -mediated responses.

1. The effects of pretreatment with two novel and relatively specific alpha 2-adrenoceptor antagonists on the hypothermic and hyperglycaemic responses induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in mice. The alpha 2-adrenoceptor antagonists used were, atipamezole, which occupies both central and peripheral receptors, and L 659,066, which poorly penetrates the blood brain barrier. 2. Atipamezole (1 and 3 mg kg-1) alone had no effect on body temperature but significantly attenuated the 8-OH-DPAT-induced hypothermic response. The hyperglycaemic effect of 8-OH-DPAT was also attenuated by pretreatment with atipamezole; however, 3 mg kg-1 atipamezole did cause some hypoglycaemia when administered alone. 3. Pretreatment with L 659,066 (3-30 mg kg-1) failed to alter the hypothermic effects of 8-OH-DPAT. All doses of L 659,066 tested attenuated 8-OH-DPAT-induced hyperglycaemia, but the highest dose (30 mg kg-1) produced hypoglycaemia when administered alone. 4. The results suggest that the attenuation of 8-OH-DPAT-induced hypothermia by alpha 2-adrenoceptor antagonist may be centrally mediated whereas the blockade of 8-OH-DPAT-induced hyperglycaemia may involve peripheral mechanisms.

The effect of tryptophan on immobility in Porsolt's swim test was studied in male NIH Swiss mice. Preexposure to a swim or fight-stressor was included in the design. Doses of tryptophan (0, 12.5, 50, 75, 100, 125 and 200 mg/kg) were administered intraperitoneally 60 min prior to the swim test. In the nonstressed mice tryptophan had an U-shaped dose-response relationship: immobility in the water was dose-dependently shortened after doses from 0 to 100 mg/kg, whereas after 125 and 200 mg/kg tryptophan the immobility times did not differ from the values obtained after a saline injection. Preexposure to a swim- or fight-stressor did not make mice more sensitive to the effects of tryptophan. Tryptophan (0-300 mg/kg) had no effect on exploratory behavior or locomotor activity in the holeboard, suggesting that sedation was not a factor in the swim test results. The findings suggest that tryptophan has antidepressant -like properties in Porsolt's swim test.

Psychological Medicine / Volume 20 / Issue 03 / August 1990, pp 475 486 DOI: 10.1017/S0033291700016986, Published online: 09 July 2009 Link to this article: http://journals.cambridge.org/abstract_S0033291700016986 How to cite this article: Michael J. Durcan and Philip F. Morgan (1990). Prospective role for adenosine and adenosinergic systems in psychiatric disorders. Psychological Medicine, 20, pp 475-486 doi:10.1017/ S0033291700016986 Request Permissions : Click here

The effect of adenosine agonist pretreatment on the seizure activity of caffeine was investigated in NIH Swiss mice. The seizure ED 50 of caffeine alone was determined to be 223 mg/kg and this was reduced to 68 mg/kg following pretreatment with 0.30 mg/kg N-ethyl carboxamidoadenosine (NECA). Additionally, NECA dose-dependently increased the seizure potency of 100 mg/kg caffeine (a dose which is normally subconvulsant). A proconvulsant effect of NECA was also detected following intracerebroventricular administration of 2.5 ug NECA, however the same doses of N 6 -cyclohexyladenosine (CHA) and 2-chloroadenosine (2 Cl-ADO) did not precipitate seizures. The data reveal proconvulsant actions of both peripherally and centrally administered NECA towards caffeine-induced seizures. Such actions need to be reconciled with the general anticonvulsant action of adenosine and adenosine agonists.

To assess the efficacy of bupropion SR on smoking abstinence using a "slips allowed" analysis.Retrospective analysis, which did not consider brief episodic "slips" as a return to regular smoking, of data from a multicenter, randomized, doubleblind, placebo-controlled relapse prevention study.Using a slips-allowed analysis, median time to relapse on bupropion SR was 65 weeks versus 30 weeks on placebo. This is compared to 32 and 20 weeks, respectively, using a traditional analysis not allowing for slips.Bupropion SR is efficacious for the prevention of smoking relapse. A slips-allowed analysis may provide a more clinically relevant assessment of efficacy.

Objective To assess the efficacy of bupropion SR on smoking abstinence using a "slips allowed" analysis. Methods Retrospective analysis, which did not consider brief episodic "slips" as a return to regular smoking, of data from a multicenter, randomized, doubleblind, placebo-controlled relapse prevention study. Results Using a slips-allowed analysis, median time to relapse on bupropion SR was 65 weeks versus 30 weeks on placebo. This is compared to 32 and 20 weeks, respectively, using a traditional analysis not allowing for slips. Conclusion Bupropion SR is efficacious for the prevention of smoking relapse. A slips-allowed analysis may provide a more clinically relevant assessment of efficacy.

The aim of this study was to identify predictors of successful relapse prevention in smokers receiving long-term sustained-release bupropion. Smokers (N= 784) who were interested in stopping smoking were enrolled in a 7-week, open-label bupropion phase. Abstinent subjects at the end of treatment and eligible to proceed (N= 429) were randomized to active bupropion or placebo through Week 52 and then followed for an additional year. The best overall predictor of less relapse to smoking was assignment to active bupropion. In aggregate, the results indicate that bupropion can be prescribed to diverse populations of smokers with expected comparable results. There was a medication effect that was independent of any predictor except older age and those who gained no or minimal weight during the open-label phase. Predictors of successful relapse prevention included lower baseline smoking rates, a Fagerström Tolerance Questionnaire score of6, and initiation of smoking at an older age. These data should encourage others to perform similar pharmacologic relapse prevention studies with this or other pharmacotherapies.

We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.

11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.

The effects of two structurally different inhibitors of phenylethanolamine-N-methyltransferase, LY 134046 and CGS 19281A were investigated in a holeboard test of directed exploration and locomotor activity. Both compounds dose-dependently reduced exploratory head-dipping without affecting locomotor activity. The interaction of each drug with ethanol was also studied by testing the ataxia. Administration of these compounds had differential effects in a test of ethanol-induced ataxia. LY 134046 significantly attenuated ethanol-induced ataxia whereas CGS 19281A was without effect or (at 50 mg kg-1) potentiated ethanol's effect. These results suggest that the ethanol attenuating properties of LY 134046 may not solely be due the inhibition of PNMT and that its alpha 2-adrenoceptor blocking properties may be playing a role.

The effect of pretreatment with pertussis toxin on N-methyl-D-aspartate (NMDA)-induced seizures was investigated in mice. In animals treated with pertussis toxin (0.5 micrograms/animal i.c.v) five days prior to testing the convulsant ED50 of NMDA was calculated to be 18 mg/kg whereas it was calculated to be 107 mg/kg in sham-treated animals. These results suggest the pertussis toxin enhances sensitivity to NMDA, possibly via its actions on inhibitory G-proteins.

The present study examined behavior of streptozotocin-diabetic mice in Porsolt's swim test, a putative animal model of depression, in the holeboard test of exploration and locomotor activity, in the plus maze test of anxiety, and in the resident-intruder paradigm of aggression. Two weeks after an IP injection of 200 mg/kg streptozotocin, which caused a 20% weight loss and increased fluid consumption and urination, male NIH Swiss mice were found to show lengthened duration of immobility in the swim test. One week of insulin treatment (0.1 IU/g/day) partially antagonized this change. The locomotor activity scores in the streptozotocin-treated mice were lower in the holeboard but higher in the plus maze than in the controls; therefore, the lengthened immobility was not likely to be due to a general motor impairment. No significant changes in the time spent in social interaction or aggressive behavior were found in the streptozotocin-treated mice. The results indicate that streptozotocin-treated mice show lengthened immobility in the swim test.

The centrally active inhibitors of phenylethanolamine-N-methyltransferase (PNMT), LY 78335 and LY 134046, were investigated both alone and in combination with ethanol (2 g/kg) in a holeboard test of directed exploration and locomotor activity. Both PNMT inhibitors showed dose-related reductions in exploratory head-dipping but were without effect on locomotor activity. In combination with ethanol both PNMT inhibitors tended to attenuate the ethanol-induced reductions in exploratory head-dipping but did not effect ethanol's locomotor stimulant properties. LY 134046 showed neither an anxiolytic nor an anxiogenic profile in the plus-maze test of anxiety, nor did it alter the anxiolytic effects of either 1.2 g/kg or 2 g/kg ethanol. LY 134046 did, however, attenuate the ataxic effects of a 2.4 g/kg dose of ethanol. These results may suggest a role for adrenaline synthesis in some, but not all, of the behavioral effects of ethanol.

This paper demonstrates the application of an assay design that is particularly valuable for estimating receptor number (B max values) and affinity (K d values) in many small samples of tissue. It is illustrated by its application to a study of possible circadian rhythms in the number of 5HT 2 receptors in the rat cerebral cortex. The assay design involves the use of only two radioligand concentrations, the lower one being close to K d (estimated from pilot studies) and the upper one close to 4 times this concentration. The results show that chronic clorgyline (1mg/kg/day/28 days) administration to rats results in an 18% decrease in the number of cortical 5HT 2 receptors (as measured by specific [ 3 H]ketanserin binding). There is no significant circadian rhythm in receptor number in either the control or the MAOI-treated group. There is however, evidence of co-variation between the pairs of control animals housed in the same cage, and interestingly, that this effect is abolished by treatment with the MAOI.

The 5HT uptake inhibitor fluoxetine had no effect on motor activity or directed exploration (head-dipping) in a holeboard test or in an elevated plusmaze test of anxiety. Fluoxetine (20 mg/kg) attenuated the anxiolytic effect of a 2.4 g/kg dose of ethanol in the plusmaze but failed to alter ethanol's effects on exploratory head-dipping or locomotion. This interaction did not seem directly related to fluoxetine's 5HT uptake inhibiting properties because it was not observed with other 5HT uptake inhibitors (fluvoxamine and citalopram). Desipramine, which predominantly inhibits noradrenaline uptake, also failed to show effects similar to those of fluoxetine.

The effects of two selective alpha 2 -adrenoceptor agonists (clonidine and medetomidine) and antagonists (atipamezole and idazoxan) were examined in the holeboard test. The interactions of the two antagonists with ethanol were also investigated. Atipamezole (0.1–3.0 mg/kg) and idazoxan (0.01–0.3 mg/kg) were without effect on either directed exploration or locomotor activity in the holeboard test, whereas clonidine (0.003–0.1 mg/kg) and medetomedine (0.003–0.1 mg/kg) were sedative. Atipamezole (1–3 mg/kg) and idazoxan (0.3–1.0 mg/kg) reversed the behavioral effects of 0.1 mg/kg of medetomidine. When administered with ethanol (2 g/kg), atipamezole (1–3 mg/kg) showed a significant antagonism of the ethanol-induced reduction in exploratory head-dipping: no change in the locomotor stimulant properties of ethanol was seen. A similar trend was seen for exploration after a combination of idazoxan (1–3 mg/kg) with 2 g/kg ethanol; however, the 3 mg/kg dose attenuated the locomotor stimulant effect. Both antagonists caused a dose-related reduction in the increase in head-dipping seen after administration of 1 g/kg of ethanol, without any effect on the locomotor stimulant effect of this dose. These results suggest mediation of alpha 2 -adrenoceptors in some of the behavioral effects of ethanol.

The interaction of a highly potent and selective alpha-2 adrenoceptor antagonist, atipamezole with ethanol was investigated in tests assessing a number of ethanol's behavioral effects. Atipamezole antagonized ethanol's effects on directed exploration in a holeboard test, reduced observer-rated intoxication and also reduced the duration of loss of righting reflex caused by ethanol. Similar effects were produced by another alpha-2 adrenoceptor antagonist idazoxan. The magnitude of the effects was comparable to that produced in the same animal models by the imidazodiazepine Ro 15-4513, which antagonizes ethanol by an action at central benzodiazepine receptors. Whereas Ro 15-4513 possesses marked behavioral effects on its own, atipamezole is comparatively inactive in all paradigms so far tested. The data suggest that alpha-2 adrenoceptors can play an important role in modulating the intoxicating effects of ethanol.

The effects of the imidazothienodiazepinone Ro 19-4603 were investigated in mice. Ro 19-4603 (0.03–0.3 mg/kg) caused a dose-related reduction in seizure threshold to i.v. bicuculline. Doses of 0.1–3 mg/kg induced seizures in some but not all mice, consistent with its suggested action as a partial benzodiazepine receptor inverse agonist. Ro 19-4603 (0.01–0.3 mg/kg) attenuated the intoxicating effects of ethanol (2.4 g/kg) and was as effective as Ro 15-4513 in this respect.

Treatment with 5HT reuptake inhibitors has been shown to attenuate ethanol consumption in both animals and humans. These experiments investigate in mice the interactions of the 5HT reuptake inhibitors fluoxetine, citalopram and fluvoxamine and the NA uptake inhibitor desipramine with ethanol in the holeboard test and the elevated plusmaze test of anxiety. Ethanol (2.4 g/kg) increased activity both in the holeboard and on the plusmaze, decreased both the number and duration of head-dips in the holeboard, and increased both the percentage time and percentage entries on to the open-arm of the plusmaze (reflecting its anxiolytic properties). On their own, the selective 5HT uptake inhibitors fluoxetine, fluvoxamine, and citalopram and the NA uptake inhibitor desipramine (10-20 mg/kg) did not significantly alter any of the behavioral measures. The only consistent interaction was seen with fluoxetine which reduced ethanol's anxiolytic effects at the 20 mg/kg dose without altering ethanol's effects on exploration or locomotion. The results suggest that the attenuation of ethanol's anxiolytic properties by fluoxetine may not be serotonin related since other 5HT reuptake inhibitors did not show this effect at the doses used.

The distribution of specific binding of [ 3 H]dihydroalprenolol( 3 H]DHA) in sucrose gradients (0.2–1.75 M), containing homogenates of the cortex of rat brain, centrifuged to equilibrium (110,000 g /16 hr), was examined in controls and after treatment with antidepressant drugs. There were no significant changes in the specific binding of[ 3 H]DHA after acute administration of desipramine (DMI, 50 mg/kg) or clorgyline (20 mg/kg), either in terms of the number of receptors or distribution in the sucrose gradient. There was a significant decrease (29%) in the number of β-adrenoceptors after the chronic regimen with DMI, but again no apparent alteration in the density of the receptor-containing membranes, both samples having a maximum distribution at approximately 1.1 M sucrose. Non-specific binding was maximal at 0.65 M sucrose. Electron microscopy showed that the non-specific binding was largely to myelin and the fraction containing most specific binding was composed of membrane fragments. The activity of Na + K + ATPase had a single broad peak (maximum at 1.1 M sucrose). Thus, at the times studied, in vivo desensitisation/intemalisation of cortical β-adrenoceptors did not apparently occur following large acute doses of antidepressant drugs and furthermore the down-regulation which followed the chronic regimen with DMI did not involve migration of receptors into “light density fractions” which are reported to be present after acute exposure to agonists in vitro .

The time-course of the hypomotility effects of the adenosine analogues 5'-N- ethylcarboxamidoadenosine (NECA) and N6-cyclohexyladenosine (CHA) was investigated in a holeboard test. Behaviourally equipotent doses of both compounds given to independent groups of animals showed significant depression of both exploratory head-dipping and locomotor activity at the 9, 18 and 36 min time points after drug administration. No significant differences from control group values were detected at 72 or 144 min post-administration. Additionally, the effects of both analogues administered immediately before a holeboard test were examined by investigating four 2 min time bins over the 8 min test session. Significant drug x time bin interactions were detected: NECA and CHA both showed faster reductions in locomotor activity, and NECA more reduction in head-dipping, over the test as compared to control. However, no differences between NECA and CHA on test habituation were detected. The results of these experiments support the view that pharmacodynamic rather than phar macokinetic factors may be responsible for the different behavioural potencies of NECA and CHA.

The hypomobility induced by a series of adenosine analogues was investigated using a holeboard test and their behavioral potencies correlated to their reported adenosine A1 and A2 receptor affinities. All of the adenosine analogues dose dependently inhibited both exploratory behavior (head dipping) and locomotor activity. The rank order of potency 5'-ethylcarboxamido adenosine (NECA) greater than 5'-methylcarboxamido adenosine (MECA) greater than N6-[(R)-1-methyl-2-phenylethyl]adenosine (R-PIA) greater than N6-cyclohexyladenosine (CHA) = N6-cyclopentyladenosine (CPA) greater than N6-[(S)-1-methyl-2-phenylethylladenosine (S-PIA) greater than N6-(2-hydroxyethyl)adenosine (2-OH-ethyl) was observed for inhibiting both activities. The behavioral potency of these adenosine analogues correlates extremely well with their reported A2 receptor affinity (r2 = 0.93, P less than 0.01 and r2 = 0.86, P less than 0.05 for locomotor and head dipping activity respectively), but very poorly with their reported A1 receptor affinity (r2 less than 0.02, P greater than 0.50 for both activities). These results suggest that adenosine A2 receptors, but not A1 receptors, may be involved in the hypomobility induced by adenosine analogues.

The effects of monoamine oxidase inhibiting antidepressant drugs on behavioral and biochemical measures of dopamine receptor status were measured in the rat. Male Wistar rats received clorgyline (1 mg/kg/day for 21–28 days), pargyline (1 mg/kg/day for 21–28 days) or a combination of these regimens. They were then either tested for stereotypy induced by 1 mg/kg SC injection of apomorphine or were sacrificed and their striata used to measure specific [ 3 H]spiroperidol binding. All three chronic treatment regimens produced statistically significant increases in apomorphine induced stereotypy: there was, however, no significant difference between the three drug regimens. None of the antidepressant drug treatments significantly affected [ 3 H]spiroperidol binding in the corpus striatum. This study demonstrates that behavioral and biochemical measures of dopamine function may not always be closely correlated. It is proposed that the behavioral changes may be related to alterations in other monoaminergic systems, which are known to have fibres running into the nigrostriatal pathway.

The effects of three drugs, chosen for their differential effects on directed exploration and locomotion (ethanol, caffeine, and FG 7142), were examined on the locomotor activity of mice in a holeboard apparatus containing either a solid floor or one with four holes in it. The dose-related effect of all three drugs on locomotor activity was not changed by the presence of the holes, although activity was slightly higher when a solid floor was used. The results indicated that the two measures can vary independently and that the directed exploration component (head-dipping) of the holeboard test does not significantly influence the locomotor activity component.

Effects of selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, on ethanol-induced hypothermia were investigated in mice. Ethanol significantly reduced (P less than 0.001) core temperature whilst both alpha 2-adrenoceptor antagonists were without effect when administered alone. However, both the 1 and 3 mg/kg doses of atipamezole significantly (P less than 0.05) attenuated the ethanol-induced reduction in body temperature 20 and 40 min after administration. The 3 mg/kg dose of idazoxan (but not the 1 mg/kg dose) also significantly (P less than 0.05) attenuated ethanol's hypothermic effect 20 min after administration but this effect was not statistically significant at 40 min. In a subsequent experiment using lower doses of atipamezole (0.03-1.0 mg/kg) the attenuation of ethanol-induced hypothermia caused by atipamezole was found to be dose-related. The effect of the benzodiazepine inverse agonist Ro 15-4513 on ethanol-induced hypothermia was also investigated. This compound possessed an intrinsic hypothermic action but neither attenuated nor enhanced the hypothermic effect of ethanol. These results suggest that alpha 2-adrenoceptor can, at least partially, modulate the hypothermic effects of ethanol.

Experiments are described which assess the behavioral status of two sublines of the Roman High and Low Avoidance strains which have been maintained by brother x sister mating without selection at the Institute of Psychiatry, University of London. The strains demonstrate significant differences in the avoidance behavior for which they were originally selected. However, the Low Avoiding strain did show some high-scoring individuals and a degree of selection pressure was consequently applied to this line. The results of this selection and the performance of these strains in an open field are reported. The data are discussed in the light of a recent report that other sublines no longer display differences in avoidance conditioning.

The effects of caffeine and its interaction with ethanol were examined in a test of social behavior and a holeboard test of exploration and locomotion. Male mice were injected i.p. with 15, 30 or 60 mg/kg caffeine alone or in combination with 2 g/kg ethanol. The animals were then put in pairs into a familiar arena, or examined individually in the holeboard. Only the highest dose of caffeine (60 mg/kg) had a significant effect on the time spent in social interaction and motor activity in the social behavior test: both measures were reduced. The duration and frequency of avoidance-irritability behavior was dose-dependently increased by caffeine. In the holeboard, caffeine caused a dose-dependent increase in locomotor activity. 30 mg/kg caffeine reversed the ethanol-induced reduction of time spent in social interaction, and 60 mg/kg caffeine antagonized the ethanol-induced increase in locomotor activity in both the social behavior and holeboard tests. Caffeine's effects on ethanol-induced behavioral changes are compared with those of other drugs.

1. Real and computer-simulated data were used to examine the efficiency of designs for receptor binding assays. 2. Initially, several different concentrations of [3H]-ketanserin were used in receptor binding studies, using membrane preparations from rat cerebral cortex to establish the form of the binding curves and to investigate the relationship between the variance of the binding measurements and their means. 3. The data showed that the specific binding could be modelled by a simple rectangular hyperbola, and were consistent with the assumption that the binding measurements have a constant coefficient of variation (0.1). 4. Computer-simulated data, with a coefficient of variation of 0.1, were then used to look at the precision of estimates of KD and Bmax obtained through the use of assay designs based on replicate incubations at two radioligand concentrations, or through the use of a geometric sequence of 5-7 radioligand concentrations. In each case, the influence of varying amounts (3.8-50%) of non-specific binding at KD on the precision of these estimates was monitored. 5. The results (a) illustrate the problems which arise in the analysis of receptor binding data when there are relatively high amounts of non-specific binding in combination with a constant coefficient of variation, (b) calculate the errors involved and (c) quantitate the relative merits of 2, 5, 6 and 7 point saturation curves in the estimation of Bmax and KD.

An hypothesis that repeated stress results in central changes in alpha 2-adrenoceptor sensitivity was investigated using a behavioural test. Stressed (immobilisation for 2 h/day for 7 days) and unstressed rats from the RHA/iop and RLA/iop strains were tested for the sedative effects of the alpha 2-adrenoceptor agonist clonidine on Y-maze behaviour. The measures used were number of lines crossed, arm entries and rearing. The stressed animals showed higher scores for line crossings and rearing; but the only significant difference between the strains was for rearing, which was higher for RHA/iop. Clonidine significantly depressed all the measures of activity. However, there was no evidence of an interaction of the drug with stress for any of the measures. It is concluded that neither repeated stress nor genetic differences in the ability to cope with stress influence the behavioural effects of clonidine. This suggests that stress responses are not related to the central alpha 2-adrenoceptor system.