Differential modulatory actions of GABAA agonists on susceptibility to GABAA antagonists-induced seizures in morphine dependent rats: possible mechanisms in seizure propensity

In order to clarify the mechanisms involved in the susceptibility to GABA_A antagonists-induced seizures in morphine dependent rats, we investigated how GABA_A agonists modulate this vulnerability. Seizures were induced to animals by infusion of GABA_A antagonists: pentylenetetrazole (PTZ), picrotoxin (PIC) and bicuculline (BIC). GABA_A agonists, muscimol (MUS) and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP), were administered intravenous (i.v.) before antagonists. Morphine-dependence significantly decreased the PTZ threshold dose (19.16 ± 1.89 versus 25.74 ± 1.25 mg/kg) while, it had no effect on PIC induced seizures. BIC doses for both threshold and tonic-clonic seizures induction were significantly lower in morphine dependent rats (0.10 ± 0.01 and 0.12 ± 0.02 versus 0.25 ± 0.02 and 0.39 ± 0.07 mg/kg respectively). In morphine-dependence, although pre-treatment with MUS significantly increased the required dose of PTZ for seizures threshold, THIP significantly decreased the required dose of PTZ for tonic-clonic convulsion. Moreover, MUS pretreatment completely recovered the effect of morphine dependency on BIC seizure activity.The results suggest that the capability of GABA_A agonists on modulation of propensity to seizures induced by different antagonists in morphine-dependence is dissimilar. Therefore, it seems that long-term morphine alters some properties of GABA system so that the responsive rate of GABA_A receptors not only to its antagonists, but also to its agonists will change differently.     

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

Deficits in N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA_B receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC-EC in freely moving rats. Infusion of the GABA_B receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA_B agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABA_B receptors on DA terminals, with both GABA_B ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.     

Correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics,biapenem, imipenem/cilastatin and meropenem

The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the carbapenems were tested for their ability to inhibit [³H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1–10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [³H]muscimol binding to the GABA_A receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABA_A binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.     

MELATONIN REDUCES BLOOD PRESSURE IN RATS WITH STRESS-INDUCED HYPERTENSION VIA GABAA RECEPTORS

• 1 Several groups have reported that melatonin produces a significant decrease in blood pressure in mammals and that pinealectomy in rats causes hypertension. The purpose of the present study was to investigate the effects of melatonin and bicuculline methiodide on the blood pressure of rats, both in the developing and fully developed stage of stress‐induced hypertension (SIH).
• 2 Rats with SIH were generated by mild electric foot shocks for 15 days, after which tail arterial systolic pressure and plasma angiotensin (Ang) II levels were measured. The effects of melatonin injections (i.p. or i.c.v.) on mean arterial pressure (MAP) in rats with SIH were also determined.
• 3 Pretreatment with 1 mg/kg, i.p., melatonin significantly diminished the elevated tail arterial systolic pressure and plasma AngII levels caused by 15 days stress. The suppressive effects of melatonin were blocked by i.p. injection of 1 mg/kg bicuculline methiodide, an antagonist of the GABA_A receptor.
• 4 Intraperitoneal (0.2, 0.5 and 1 mg/kg) or i.c.v. (0.15 and 1.5 µg/3 µL) injection of melatonin produced a dose‐dependent lowering of MAP in rats with SIH. The antihypertensive response induced by melatonin was blocked by injection of both 1 mg/kg, i.p., and 1.5 × 10⁶ µg/3 µL, i.c.v., bicuculline methiodide.
• 5 In conclusion, melatonin not only prevents increases in blood pressure during the developing stage of SIH, but can also reduce the blood pressure of rats that have already developed SIH. The antihypertensive effect of melatonin may be mediated by GABA_A receptors through inhibition of plasma AngII levels.

     

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

Rationale

Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABA_A receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence.

Objective

The present study used this approach to investigate the role of GABA_A receptor subtypes in mediating dependence-like effects following benzodiazepine administration.

Methods

Squirrel monkeys (n?=?6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABA_A receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABA_A subtype-preferring agonist), and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABA_A receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABA_A receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABA_A receptor antagonists).

Results

Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem.

Conclusions

These data raise the possibility that α1 subunit-containing GABA_A receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.     

Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: Comparison with diazepam

Zolpidem and diazepam are widely used drugs acting via benzodiazepine binding sites on GABA_A receptors. While diazepam is non-selective, zolpidem has a high affinity for α1-, and no affinity for α5-containing receptors. Several studies suggested that behavioral effects of zolpidem might be more similar to classical benzodiazepines than previously thought. To compare the sedative and anticonvulsant properties of these drugs and to evaluate the importance of GABA_A receptor subunits for development of tolerance during chronic treatment, we tested the effects of acute and repeated administration of zolpidem and diazepam on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ). Both drugs given acutely in doses 0.3, 1 and 3 mg/kg reduced locomotion, and in doses 1 and 3 mg/kg elevated the threshold for PTZ-induced seizures. The effects of zolpidem and diazepam on the tonic seizure threshold were greater than on myoclonus and clonic seizure threshold. Diazepam and zolpidem (3 mg/kg), given 18 or 42 h after repeated drug treatment (10 days, 5 mg/kg, twice daily), decreased the PTZ seizure threshold and increased the locomotor activity as compared to control mice, indicating development of tolerance to their anticonvulsant and sedative effects. After repeated treatment the PTZ seizure threshold was not different between the two drugs, while differences in sedation became larger than after the acute treatment. The results suggest that α5-containing GABA_A receptors are not crucial for the development of sedative and anticonvulsant tolerance.     

过量表达GABA转运蛋白-1的转基因小鼠对药物诱发癫痫易感

目的：应用过量表达GABA转运蛋白Ⅰ(GAT-1)的转基因小鼠研究GAT-1在癫痫发生中的作用。方法：采用腹腔注射戊四唑(PTZ),印防己毒素(PIC)或红藻氨酸(KA)诱导的癫痫发作为模型,比较GAT-1转基因小鼠和C57BL／6J对照小鼠阵挛性发作和强直性痉挛发生的百分率及潜伏期．结果：GAT-1转基因小鼠不但对不同剂量GABAA受体抑制剂PTZ,PIC,也对谷氨酸受体激动剂KA诱导的癫痫易感．GAT-1抑制剂ethyl nipecotate可明显减轻PTZ诱导的癫痫发作。结论：GAT-1转基因小鼠对癫痫易感证明GABA系统参与了癫痫发生,并且该转基因小鼠模型可作为研究癫痫发生的有用动物模型。     

Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.     

The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane

The plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC50: MAC--the end-tidal concentration at which half the dogs moved in response to clamping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group 1, four dogs in Group 2 received ketamine as a continuous infusion of 300 micrograms.kg-1.min-1 for 5 hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 micrograms/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2 beta = 122 +/- 9 vs. 141 +/- 40 min (mean +/- SD) and CL = 18.1 +/- 5.9 vs. 13.9 +/- 2.5 ml.kg-1.min-1, respectively. When administered as a continuous infusion (Group 2), KET remained relatively stable at 22.1 +/- 4.6 micrograms/ml for 5 hr. The degree of MAC reduction remained relatively stable at 73% during the continuous infusion. Finally, the enflurane MAC reduction vs. KET was established over a wide range of plasma concentrations in 4 additional dogs (Group 3). This study determined that the pharmacokinetics of ketamine were consistent under two different experimental conditions and demonstrated the relationship between plasma concentration and anesthetic effect in the dog.     

Anticonvulsant activity of MK-801 and nimodipine alone and in combination against pentylenetetrazole and strychnine

The effects of the N-methyl-D-aspartate receptor antagonist MK-801 and the dihydropyridine calcium channel antagonist nimodipine were assessed for their anticonvulsant activity alone and in combination against clonic convulsions to pentylenetetrazole (PTZ) and strychnine (STR) in mice. Nimodipine (2-20 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) did not affect the number of mice displaying clonic convulsions to PTZ. However, nimodipine in a dose-dependent manner increased (100%) the latency to clonic convulsions and lethality (mortality from tonic extension convulsions and respiratory failure) following PTZ. In contrast, MK-801 did not increase the latency to PTZ convulsions, but prevented the lethal effects of PTZ. When combined, MK-801 and nimodipine produced a significant reduction in the number of animals (40-60%) displaying PTZ convulsions and a greater increase in the latency to PTZ convulsions than did nimodipine alone. In contrast, MK-801 decreased the onset time, and increased the severity of STR convulsions. A combination of MK-801 and nimodipine which afforded significant protection against PTZ convulsions did not affect STR convulsions. These findings suggest that MK-801 and nimodipine, while possessing significant anticonvulsant activity on their own, produce a potent anticonvulsant synergism against PTZ but not STR.     

The modulatory effects of high affinity GABAB receptor antagonists in an active avoidance learning paradigm in rats

It has been reported that selective GABA_B receptor antagonists can enhance cognitive performance in a variety of learning paradigms. This prompted us to examine the effects of some more potent and newly synthesised GABA_B antagonists CGP 71982, CGP 62349 and CGP 55845A in an active avoidance test in rats. A two-way active avoidance test with negative reinforcement was performed for the first 5 of 12 days of antagonist administration. CGP 71982 and CGP 55845A at all doses applied (0.01–1.0 mg/kg) had an improving effect on learning, and memory retention on day 12; the rats made more avoidances in both sessions compared to controls. CGP 62349 was only active at the lowest dose tested (0.01 mg/kg). The present study confirms that GABA_B receptor antagonists can enhance cognitive performance but provides no insight into the mechanism of action of these novel antagonists. Received: 4 August 1997/Final version: 28 November 1997     

Baclofen does not block interoceptive discriminative stimulus produced by pentylenetetrazol

Baclofen was compared with diazepam for ability to block the interoceptive discriminative stimulus produced by the anxiogenic drug pentylenetetrazol (PTZ). Male hooded rats of the Long Evans strain were trained in two-lever operant chambers to respond for food reward. Presses on one lever were reinforced after intraperitoneal injections of PTZ (20 mg/kg), and on the other lever after saline. After rats had acquired the PTZ discrimination, it was shown that pretreatment with baclofen failed to block the interoceptive stimulus produced by PTZ, whereas pretreatment with diazepam was effective. As baclofen is ineffective in a conflict procedure as well as in antagonizing the PTZ stimulus, but produces a diazepamlike interoceptive discriminative stimulus, it is concluded that elicitation of the diazepam stimulus may not be related to diazepam's anxiolytic efficacy and that diazepam discrimination may be an inappropriate model for studying anxiolytic properties of drugs. Furthermore, the difference between baclofen and diazepam with respect to anxiolytic efficacy is suggested to be related to receptor specificity. The binding of diazepam facilitates GABA_A receptor activity, whereas the binding of baclofen facilitates BABA_B receptors Hence, it is suggested that modulation of GABA_A receptors may be critical in diazepam's blockade of the PTZ stimulus.     

Acute exposure to trichloroethylene differentially alters the susceptibility to chemoconvulsants in mice

The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an anesthetic agent but its in vivo mechanism is still unknown, on convulsant-induced seizures in mice were examined. Pretreatment with TCE (250-2000 mg/kg, i.p.) significantly increased pentylenetetrazol (PTZ)-, picrotoxin (PIC)-, bicuculline (BIC)-, strychnine (STY)-, 4-aminopyridine (4-AP)- and N-methyl-D-aspartate (NMDA)-induced convulsion thresholds and lethal doses. However, the increase in convulsion thresholds and lethal doses was much greater for GABAergic antagonists (PIC, BIC, and PTZ) than non-GABAergic convulsants (STY, 4AP, and NMDA) following 2000 mg/kg TCE administration. Pre-treatment of mice with disulfiram (an inhibitor of CYP 4502E1) but not 4-methyl pyrazole (an inhibitor of alcohol dehydrogenase) significantly prolonged the time required for TCE (5000 mg/kg, i.p.) to induce the loss of righting reflex. These results suggest that acute exposure to TCE differentially alters the susceptibility to chemically induced convulsions in mice. The anticonvulsive effect of TCE may be predominantly mediated by GABA(A) receptors. In addition, TCE appears to exert a direct anesthetic effect.     

TACHYKININ RECEPTORS AND NON-CHOLINERGIC BRONCHOCONSTRICTION IN THE ANAESTHETIZED GUINEA-PIG

1. Bronchoconstriction can be evoked by electrical stimulation of the vagus nerves in the presence of atropine. We have used novel, highly selective tachykinin receptor antagonists, together with a procedure for on-line, breath-by-breath analysis of total lung resistance (Rl , subtractor method) and dynamic lung compliance (C_dyn), to investigate the role of tachykinins in this response in anaesthetized, paralysed guinea-pigs. 2. In the presence of 1 mg/kg phosphoramidon (a neutral endopeptidase inhibitor), CP 96345 (the non-peptide NK₁ selective antagonist) at 200 nmol/kg had no effect on the increase in Rl caused by vagal stimulation, but significantly inhibited the associated decrease in C_dyn. 3. The NK₂ selective antagonist, MDL 29913 (1 μmol/kg), significantly antagonized the changes in both Rl and C_dyn. In the absence of phosphoramidon, MDL 29913 again significantly inhibited the changes in Rl and C_dyn, although CP 96345 no longer had any effect. 4. The non-peptide NK₂ selective antagonist, SR 48968 (100 nmol/kg), also effectively inhibited the responses to vagal stimulation and was more potent than MDL 29913. 5. These results emphasize the importance of the NK₂ receptor system in mediating non-cholinergic bronchoconstriction evoked by vagal stimulation in the guinea-pig.     

Filicene obtained from Adiantumcuneatum interacts with the cholinergic, dopaminergic, glutamatergic, GABAergic, and tachykinergic systems to exert antinociceptive effect in mice

In the present study, we describe the antinociceptive effect of filicene, a triterpene isolated from Adiantumcuneatum (Adiantaceae) leaves, in several models of pain in mice. When evaluated against acetic acid-induced abdominal constrictions, filicene (10, 30 and 60 mg/kg, i.p.) produced dose-related inhibition of the number of constrictions, being several times more potent [ID₅₀ = 9.17 (6.27-13.18) mg/kg] than acetaminophen [ID₅₀ = 18.8 (15.7-22.6) mg/kg], diclofenac [ID₅₀ = 12.1(9.40-15.6) mg/kg] and acetylsalicylic acid [ID₅₀ = 24.0(13.1-43.8) mg/kg] in the same doses as those used for the standard drugs. Filicene also produced dose-related inhibition of the pain caused by capsaicin and glutamate, with mean ID₅₀ values of 11.7 (8.51-16.0) mg/kg and < 10 mg/kg, respectively. Its antinociceptive action was significantly reversed by atropine, haloperidol, GABA_A and GABA_B antagonists (bicuculline and phaclofen, respectively), but was not affected by L-arginine-nitric oxide, serotonin, adrenergic and the opioid systems. Together, these results indicate that the mechanisms involved in its action are not completely understood, but seem to involve interaction with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems.     

Participation of GABAA,GABAB receptors and neurosteroids in toluene-induced hypothermia: Evidence of concentration-dependent differences in the mechanism of action

Toluene is a misused substance that modifies γ-aminobutyric acid (GABA) release and shares behavioral and molecular effects with GABA_A and GABA_B receptor agonists. GABAergic compounds are involved in thermoregulation processes and volatile substance users have reported that one of the reasons to inhale is to avoid feeling cold. At present, no studies have analyzed the effects of inhalants on body temperature and the mechanism of action involved. Thus, the main purpose of this study was to evaluate the effects of a (60 min) acute toluene inhalation (2000, 4000 and 6000 ppm) in core temperature. In addition, we tried to prevent the changes of temperature induced by toluene with the specific GABA_A receptor blockers picrotoxin (0.01–0.1 mg/kg), bicuculline (0.1–0.3 mg/kg), and flumazenil (3–30 mg/kg); the GABA_B receptor antagonist phaclofen (10–30 mg/kg) and the neurosteroid synthesis inhibitor finasteride (10–30 mg/kg). Results show that toluene reduced core temperature in mice in a concentration-dependent manner. The hypothermia produced by 4000 ppm toluene was prevented by picrotoxin, bicuculline, phaclofen and finasteride but not by flumazenil. In contrast none of these antagonists tested blocked the effects of 6000 ppm toluene. In conclusion, toluene decreases core temperature, GABA receptors and neurosteroids participate in toluene’s action at 4000 ppm; but other mechanisms of action are involved in the hypothermic effects of 6000 ppm toluene.     

Antiepileptogenic effects of the novel synthetic neuroactive steroid,ganaxolone, against pentylenetetrazol-induced kindled seizures: Comparison with diazepam and valproate

Pharmacological treatment of epilepsy is often unsatisfactory due to side effects and the lack of drugs that control the progressive epileptogenic process. Modulation of inhibitory γ-aminobutyric acid (GABA)-ergic neurotransmission by synthetic agonists of the neuroactive steroid binding site on the GABA_A receptor complex is one approach toward the identification of improved antiepileptic agents. In this study, antiepileptogenic and anticonvulsive effects of the novel synthetic neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), were evaluated in comparison with diazepam and valproate against pentylenetetrazol (PTZ)-induced kindled seizures in mice. Kindled seizures provide a model of the progressive epileptogenic process. Successive administration of 45 mg/kg PTZ on days 1, 3, 5, 8, and 10 resulted in the rapid development of kindled seizures and significant reductions in thresholds for clonic convulsions, tonic convulsions, and lethality induced by PTZ on day 10. Ganaxolone, diazepam, and valproate dose-dependently protected against clonic convulsions induced by acute submaximal dose of PTZ (70 mg/kg). The compounds also dose-dependently suppressed fully kindled seizures and blocked the expression of kindled seizures over successive treatments with PTZ (45 mg/kg). Relative to acute anticonvulsive potencies against 70 mg/kg PTZ, however, ganaxolone was more potent than valproate or diazepam against fully kindled seizures and in blocking the expression of kindled seizures over successive treatments with PTZ. Importantly, only ganaxolone demonstrated antiepileptogenic activity by blocking the development of kindling, as evidenced when PTZ was administered in the absence of anticonvulsant treatments. Both diazepam and valproate failed to prevent development of kindled seizures even at doses that fully suppressed motor expression of seizures during kindling acquisition. Unlike diazepam and valproate, ganaxolone did not impair ambulatory activity within the dose range used in this study. These data, taken in conjunction with other findings on the unique pharmacological actions of ganaxolone, predict an improvement in the pharmacological management of epilepsy with this synthetic neuroactive steroid. Drug Dev. Res. 44:21–33, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane

The plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC₅₀: MAC-the endtidal concentration at which half the dogs moved in response to damping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group I, four dogs in Group 2 received ketamine as a continuous infusion of 300 g·kg^–1·min^–1 for 5hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 g/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group2: =122±9 vs. 141±40min ( ±SD) and CL±8.1±5.9 vs. 13.9±2.5ml·kg^–1min^–1, respectively. When administered as a continuous infusion (Group 2), KET remained relatively stable at 22.1±4.6 g/ml for 5hr. The degree of MAC reduction remained relatively stable at 73% during the continuous infusion. Finally, the enflurane MAC reduction vs. KET was established over a wide range of plasma concentrations in 4 additional dogs (Group 3). This study determined that the pharmacokinetics of ketamine were consistent under two different experimental conditions and demonstrated the relationship between plasma concentration and anesthetic effect in the dog.Supported in part by a grant from the Swiss National Fund.     

GABAergic influences on plus-maze behaviour in mice

Manipulations of GABA function have been found to produce highly variable effects in animal models of anxiety. In the present series, an ethological version of the murine elevated plus-maze was used to examine in detail the behavioural profiles of diazepam (1.5 mg/kg; positive control) and a range of GABA-related compounds: valproic acid (100–400 mg/kg), No-711 (1.25–10.0 mg/kg), muscimol (0.5–3.0 mg/ kg), (+)bicuculline (4.0–8.0 mg/kg), picrotoxin (0.25– 2.0 mg/kg), R(+)baclofen (0.375–3.0 mg/kg) and CGP 35348 (25–200 mg/kg). On both conventional and ethological indices, results confirmed the anxiolytic profile of diazepam under present test conditions, and revealed substantially similar effects for the GABA-T inhibitor, valproic acid (100–400 mg/kg), and the GABA_A receptor agonist, muscimol (2 mg/kg). The GABA reuptake inhibitor, No-711, produced weak anxiolytic-like effects at low doses (1.25–2.5 mg/kg) but disrupted behaviour at the highest dose tested (10 mg/ kg). Although the GABA_A receptor antagonists, (+)bicuculline and picrotoxin, produced changes indicative of anxiety enhancement, concomitant behavioural suppression was evident at high doses (8 mg/kg and 1–2 mg/kg, respectively). Further studies suggested that the effects observed with bicuculline may be mediated by an active metabolite, such as bicucine. In contrast to the effects of valproic acid and direct GABA_A receptor manipulations, the GABA_B receptor agonist, R(+) baclofen, non-specifically disrupted behaviour at the highest dose tested (3 mg/kg) while the GABA_B receptor antagonist, CGP 35348, was inactive over the dose range studied. Although present data confirm the sensitivity of the plus-maze to agents which modify GABA_A receptor function, further studies will be required in order more fully to characterize this relationship. Received: 8 March 1996/Final version: 28 July 1996     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.