Stimulus properties of venlafaxine in a conditioned taste aversion procedure.

Conditioned stimulus properties of venlafaxine are still unknown. In the present study, the discriminative stimulus properties of venlafaxine by using a conditioned taste aversion procedure were investigated. Swiss Webster mice were allowed to reach water from 2 pipettes for 20 min (09:00-11:30 h), plus 30 min (15:30-16:00 h), daily. During the 4 days, the test drugs [fluoxetine, escitalopram, tianeptine, reboxetine, and Nomega-nitro-L-arginine methyl ester (L-NAME)] were injected to mice at least 1 h after they had first water session. On day 5, they consumed glucose solution (5% w/v) and immediately injected with conditioning drug (venlafaxine 32 mg/kg). On day 8, mice were allowed to make a choice between water and glucose solution. The amount of glucose consumption as a percentage of total fluid intakes was calculated for each animal. Significant reduction in glucose choice was defined as conditioned taste aversion. Venlafaxine (32 mg/kg) induced a robust conditioned taste aversion in mice. Pre-exposure to tianeptine (2.5-10 mg/kg), fluoxetine (10 mg/kg), escitalopram (32 mg/kg), and reboxetine (5 mg/kg) substituted for venlafaxine by preventing the conditioned taste aversion induced by venlafaxine. L-NAME did not substitute for venlafaxine. Substitution of venlafaxine by fluoxetine, tianeptine, escitalopram, and reboxetine provides further evidence that both 5-HT and noradrenaline reuptake inhibition may play an important role in the stimulus effect of venlafaxine.

Lack of effect of Nomega-nitro-L-arginine methyl ester on bromocriptine-induced locomotor sensitization in mice.

The present study was designed to investigate the effects of Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitory agent, on bromocriptine-induced locomotor sensitization in mice. Adult male Swiss-Webster mice (26-32 g) were the subjects. Saline or L-NAME (15-60 mg/kg) was injected to mice intraperitoneally 30 min before bromocriptine (5 mg/kg), and locomotor activity was recorded for 240 min in an open field activity monitoring system. This procedure lasted for 2 weeks, once in 2 days from Monday to Friday, six sessions in total. After a 2-day drug-free period, a challenge injection of bromocriptine (5 mg/kg) or vehicle was administered by all groups of mice. Other groups of mice treated with bromocriptine according to the aforementioned procedure except L-NAME pretreatments were challenged with saline or L-NAME (15-60 mg/kg) plus bromocriptine (5 mg/kg) after a 2-day drug-free period. Bromocriptine produced a significant locomotor sensitization. L-NAME (15-60 mg/kg) did not have any significant effect on the development and expression of bromocriptine-induced locomotor sensitization in mice. Meanwhile, the data also imply that NO-related mechanisms may not be responsible for bromocriptine-induced locomotor sensitization in mice.

Effects of tianeptine on onset time of pentylenetetrazole-induced seizures in mice: possible role of adenosine A1 receptors.

Depression is a common psychiatric problem in epileptic patients. Thus, it is important that an antidepressant agent has anticonvulsant activity. This study was organized to investigate the effects of tianeptine, an atypical antidepressant, on pentylenetetrazole (PTZ)-induced seizure in mice. A possible contribution of adenosine receptors was also evaluated. Adult male Swiss-Webster mice (25-35 g) were subjects. PTZ (80 mg/kg, i.p.) was injected to mice 30 min after tianeptine (2.5-80 mg/kg, i.p.) or saline administration. The onset times of 'first myoclonic jerk' (FMJ) and 'generalized clonic seizures' (GCS) were recorded. Duration of 600 s was taken as a cutoff time in calculation of the onset time of the seizures. To evaluate the contribution of adenosine receptors in the effect of tianeptine, a nonspecific adenosine receptor antagonist caffeine, a specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A2A receptor antagonist 8-(3-chlorostyryl) caffeine (CSC) or their vehicles were administered to the mice 15 min before tianeptine (80 mg/kg) or saline treatments. Tianeptine (40 and 80 mg/kg) pretreatment significantly delayed the onset time of FMJ and GCS. Caffeine (10-60 mg/kg, i.p.) dose-dependently blocked the retarding effect of tianeptine (80 mg/kg) on the onset times of FMJ and GCS. DPCPX (20 mg/kg) but not CSC (1-8 mg/kg) blocked the effect of tianeptine (80 mg/kg) on FMJ. Our results suggest that tianeptine delayed the onset time of PTZ-induced seizures via adenosine A1 receptors in mice. Thus, this drug may be a useful choice for epileptic patients with depression.

LOAD limits for ambulatory pulse pressure and double product in normotensive and hypertensive subjects.

OBJECTIVE: The aim of this study was to to determine possible daytime (awake hours) and nighttime (sleeping hours) LOAD limits for ambulatory pulse pressure (PP) and double product (DP) in hypertensive (HT) subjects and secondly to assess whether there were significant differences in the LOAD values between hypertensive (HT) and normotensive (NT) subjects. METHODS: Seventy-eight untreated essential HT (46 female, 32 male; mean age 51.9+/-1.4 years) and 115 NT (89 female, 26 male; mean age 40.8+/-1.1 years) subjects participated in this study. Ambulatory blood pressure monitoring (ABPM) devices were applied to these subjects for 48 hours. Different possible ambulatory PP LOAD limits between 40 and 55 mmHg with 5 mmHg increments and ambulatory DP LOAD limits between 6000 and 12,000 mmHg x beats/min with 1000 mmHg x beats/min increments were used. Then according to these limits, LOAD values of NT and HT subjects have been assessed for daytime, nighttime and 48 hours. RESULTS: There were significant differences between NT and HT subjects in all the values for both ambulatory PP and DP. Although mean (total, day and night mean) values of HT subjects were higher approximately by 20% than of NT subjects, LOAD values for ambulatory PP in HTs were 33%-415% higher than in NTs (p<0.001). Hypertensive subjects' mean (total, day and night mean) values of DP were by 23%-33% higher than NTs values, but LOAD values for ambulatory DP in hypertensives were approximately 43%-673% higher than in NT subjects (p<0.001). CONCLUSIONS: We showed that although there were significant differences in the 48-hour, daytime and nighttime PP and DP means between NT and HT subjects, these differences became more prominent when possible LOAD limits were used for ambulatory PP and DP, One of these possible ambulatory PP and DP LOAD limits can be used in the clinical settings if a relationship with the end-organ damage will be showed by further studies.

Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats.

The effects of tianeptine and fluoxetine on pentylenetetrazole (PTZ)-induced seizures in rats were investigated. Female Wistar rats (172-278 g) were used in the study. Tianeptine (1.25, 2.5, 5, 10 and 20 mg/kg) and fluoxetine (2.5, 5, 10 and 20 mg/kg) or saline were injected to rats intraperitoneally 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ administrations, latency and intensity of the PTZ-induced seizures was recorded and scored, respectively. Fluoxetine (2.5-20 mg/kg) did not produce any significant difference in latency and intensity of the PTZ-induced seizures. Although tianeptine (1.25-20 mg/kg) also did not affect the latency time, it produced significant attenuations in the intensity of the seizures. Tianeptine did not cause any significant change in the locomotor activity of the rats. The results of this preliminary study suggest that tianeptine but not fluoxetine has some inhibitory effects on PTZ-induced seizures in rats.

CPP and amlodipine alter the decrease in basal acetylcholine and choline release by audiogenic stimulus in hippocampus of ethanol-withdrawn rats in vivo.

Effects of N-methyl-D-aspartate (NMDA) receptor and Ca2+ channel antagonists on extracellular acetylcholine and choline release in the hippocampus of ethanol-withdrawn rats were investigated by in vivo microdialysis. Ethanol was administered to Wistar rats in a liquid diet for 28 days. Basal acetylcholine and choline levels significantly increased at the 24th hour of ethanol withdrawal syndrome (EWS). Either an NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or a calcium channel antagonist amlodipine was administered, and 15 min later, an audiogenic stimulus (100 dB, 1 min) was applied to rats. While audiogenic stimulus increased acetylcholine and had no effect on choline release in control rats, it decreased acetylcholine and increased choline release in ethanol-withdrawn rats. CPP (15 mg/kg) and amlodipine (20 mg/kg) reversed the decrement in acetylcholine and increment in choline release in EW rats. Their effects on acetylcholine and choline release were not different from saline in control rats. Therefore, our findings suggest that, (a) because of adaptive changes in EWS, decrease of the acetylcholine release following audiogenic stimulus may play a role in the triggering of seizures, (b) hippocampal glutamatergic pathway may play a role in the audiogenic stimulus induced decrement of acetylcholine release in EWS, (c) inhibition of this pathway by NMDA receptor and calcium channel antagonists may prevent triggering of the seizures.

Comparison of circadian rhythm characteristics of blood pressure and heart rate in patients before and after elective coronary artery bypass surgery.

Coronary artery bypass grafting surgery (CABGS) is done to reperfuse the ischemic myocardium of coronary disease patients. This study was designed to analyze the circadian rhythm characteristics of blood pressure (BP) and heart rate (HR) of patients before and after CABGS. Fifty-one patients undergoing elective CABGS were studied; 21 patients received one, 12 two and 18 three or more grafts. BP was monitored for 24h before and after CABGS while patients were recumbent in the hospital. Systolic (S) and diastolic (D) BP and HR were assessed every 30 min. Of the 51 patients, 37 (73%) had nondipper 24h BP patterns (nocturnal decline in BP < 10% of daytime mean level) in the preoperative baseline assessment. The peak and MESOR (rhythm-adjusted 24h mean) values of the circadian rhythm in SBP, DBP, and pulse pressure (PP) significantly declined following surgery, while HR and rate-pressure product (RPP = SBP x HR) markedly increased. The double amplitude (peak-to-trough variation) of the circadian rhythm in SBP and DBP was significantly reduced postoperatively, and that of the rhythm in HR and RPP significantly increased. The slopes of the morning rise and evening dip in the 24h SBP profile were reduced significantly after bypass grafting. The corresponding slopes of the HR profile, in contrast, were markedly increased.