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PubMed1990

Actions of baclofen and phaclofen upon ON- and OFF-ganglion cells in the cat retina.

The effects of the GABAB (gamma-amino butyric acidB) receptor agonist, baclofen and its antagonist, phaclofen on physiologically identified retinal ganglion cells were studied in the optically intact eye of pentobarbitone-anaesthetized cats. These results were compared with the effects of the GABAA receptor agonist, muscimol and its antagonist, bicuculline. Baclofen inhibited the total visually driven firing of both ON- and OFF-cells more effectively upon OFF- than ON-cells; this action was weaker and slower than that of muscimol. Whilst bicuculline raised the firing level of only ON-cells in the area centralis together with all peripheral cells, phaclofen raised that of all OFF-cells. Paradoxically, in OFF-cells, baclofen enhanced the driven transient component and suppressed the sustained component, whilst phaclofen raised the sustained component. Thus, GABAB receptors activated by tonically released GABA may modulate the sustained and transient excitatory inputs to OFF-cells.

Animals↗
PubMed1991

Dopamine modulates the inhibition induced by GABA in rat cerebral cortex: an iontophoretic study.

Effects of iontophoresed gamma-aminobutyric acid (GABA) and two GABA agonists, 4,5,6,7-tetrahydroisooxazolo-[5,4-c]pyridine-3-ol (THIP) and baclofen were quantitatively compared in the anterior cingulate, frontal, and parietal cortex of urethane-anesthetized intact rats after catecholamine (CA) depletion with alpha-methyl-p-tyrosine (alpha-MPT) or selective dopamine (DA) denervation with 6-hydroxydopamine (6-OHDA). As assessed with to the IT50 index, the postsynaptic sensitivity to GABA was significantly higher in anterior cingulate than in frontal and parietal cortex. The responsiveness to GABA was also greater in frontal than in parietal cortex. Sensitivity to GABA was significantly reduced in both anterior cingulate and frontal cortex after CA depletion, and similarly, after DA denervation with 6-OHDA. The difference in the sensitivity to GABA between the three cortical regions in intact rats as well as after CA depletion did not seem to be correlated with either GABAA or GABAB receptors since the responsiveness to both GABA agonists in every region examined was comparable in intact rats, and remained unchanged after alpha-MPT treatment. This finding raises the possibility that some GABA receptors in the cerebral cortex may be pharmacologically distinct from the two main subtypes of GABA receptors, GABAA and GABAB. When GABA was administered by iontophoresis in the anterior cingulate cortex during continuous applications of subthreshold currents of DA, the inhibition induced by GABA was either increased or decreased. As DA innervation density is nearly two-fold greater in anterior cingulate than in frontal cortex, and 30-fold greater in anterior cingulate than in parietal cortex, these results suggest that responsiveness to GABA may be correlated with the regional density of DA innervation and that elevated levels of DA may enhance the sensitivity to GABA.

Animals↗
PubMed1992

Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors.

Continuous infusion of the dopamine D2 receptor agonist quinpirole into mice with unilateral striatal 6-hydroxydopamine lesions initially produces a supersensitive rotational behavior. This is followed by reductions of dopamine D2-mediated behavior and dopamine D2 receptors. In this study we attempted to determine if it is possible to inhibit the acute increase in D2-mediated behavior while still allowing the reduction of D2-mediated behavioral responses and dopamine D2 receptors to occur. Mice were implanted with Alzet minipumps containing either quinpirole alone or quinpirole combined with the GABA receptor modulator triazolam or the dopamine D2 receptor antagonist sulpiride, and rotational behavior was monitored for the 6 days of infusion. The pumps were then removed, and D2 receptors in striatal membranes were determined. Triazolam completely blocked the initial rotational behavior normally induced by implanting quinpirole. However, the quinpirole-induced reduction of D2-mediated behavioral responses and D2 receptors still occurred. Continuous infusion of sulpiride also inhibited the rotational behavior produced by quinpirole, but it prevented the reduction of dopamine D2 receptors. We conclude that up-regulated dopamine receptors and dopaminergic behaviors can be reversed by the continuous administration of a dopamine receptor agonist and that this reversal can occur without producing an initial exacerbation of dopaminergic responses. These results suggest that this type of treatment regimen might be useful for treating clinical conditions associated with dopaminergic supersensitivity.

Analysis of Variance↗
PubMed1995

Blockade of morphine-induced place preference by diazepam in mice.

The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Flumazenil blocks the anxiolytic action of allopregnanolone.

In the burying behaviour test allopregnanolone (0.5 mg/rat) reduced the cumulative time of burying, interpreted as a reduction in anxiety. The selective benzodiazepine antagonist, flumazenil (5 and 10 mg/kg), did not affect the burying behaviour when administered alone but effectively prevented the reduction produced by allopregnanolone. No scheme modified the ambulatory behaviour, thus suggesting that the effect of these treatments was selective on experimental anxiety. These results indicate that the anxiolytic actions of neurosteroids are most likely mediated via the stimulation of GABAA receptors. Data are discussed on the basis of such relationships.

Animals↗
PubMed1995

Effects of site-selective NMDA receptor antagonists in an elevated plus-maze model of anxiety in mice.

NMDA receptor antagonists have been shown to be anxiolytic in animal models of anxiety, although they have not been tested extensively. These compounds bind to several specific sites within the NMDA-receptor complex, including the NMDA site itself, the phencyclidine site, and the strychnine-insensitive glycine site. The purpose of the present study was to examine potential anxiolytic effects of site-selective NMDA receptor antagonists in the elevated plus-maze. Drug-naive albino mice were placed in the center of an elevated maze shaped like a plus sign. Two opposing arms were enclosed by high walls; the crossing arms were open. Following injection with drug or vehicle, the number of entries and time spent in each type of arm were measured during 5-min tests. Analysis of results showed that the benzodiazepine, diazepam, and the competitive NMDA receptor antagonist, NPC 17742 (2R,4R,5S 2-amino-4,5-(1,2-cyclohexyl)-7-phosphono-heptanoic acid), increased number of open arm entries and open arm time. N-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor which may interfere with the transduction of NMDA receptor activation, also increased open arm entries and time; however, the magnitude of these increases was small. The phencyclidine-site NMDA receptor antagonist, phencyclidine, increased open arm entries, but failed to significantly increase open arm time. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione), a putative glycine-site antagonist, had significant effects only on open arm entries at the highest dose tested. These results suggest that NMDA receptor antagonists show promise as potential anxiolytic agents, but that differences among antagonists acting at different cellular sites may be expected.

Amino Acids↗
PubMed1996

Chronic ethanol exposure selectively increases diazepam-insensitive [3H]RO15-4513 binding in mouse cerebellum.

The effect of chronic ethanol exposure and withdrawal on [3H]RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4] benzodiazepine-3-carboxylate) binding to diazepam-sensitive and diazepam-insensitive binding sites was determined in mouse brain. Neither chronic ethanol treatment nor withdrawal significantly altered total [3H]RO15-4513 binding in mouse cortex or cerebellum. However, diazepam-insensitive [3H]RO15-4513 binding density (Bmax) in cerebellum was significantly increased immediately following chronic ethanol treatment (60%) and at 8 h following withdrawal (75%). [3H]RO15-4513 binding affinity was not significantly influenced by chronic ethanol exposure or withdrawal. These results indicate that chronic ethanol treatment and withdrawal can selectively up-regulate diazepam-insensitive [3H]RO15-4513 binding sites and suggest that this unique GABAA receptor subtype may play some role in ethanol dependence and withdrawal.

Administration, Inhalation↗
PubMed1996

Hyperphagia induced by direct administration of midazolam into the parabrachial nucleus of the rat.

Benzodiazepine receptor agonists increase food intake in many different species, yet there has been little investigation of the central site of actions of these drugs on ingestive behaviour. In the present experiments, direct administration of the benzodiazepine receptor agonist midazolam (3-30 micrograms/microliter) into the parabrachial nucleus of the pons significantly increased the consumption of a wet mash diet and a 3% sucrose solution in adult non-deprived rats. The hyperphagic response was blocked by pre-treatment with the selective benzodiazepine receptor antagonist flumazenil. Injection of midazolam into the parabrachial nucleus had no effect on locomotor activity, despite the fact that in the same animals an increase in mash intake was observed following intra-parabrachial midazolam. These data suggest that benzodiazepine receptors located in the parabrachial nucleus may be an important site of action for the effects of benzodiazepines specifically on ingestive behaviour.

Analysis of Variance↗
PubMed1996

Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem.

The BZ1 (omega 1)-selective compound, zolpidem, is a clinically effective hypnotic drug with a pharmacological profile which differs from those of benzodiazepine anxiolytics and hypnotics. Zaleplon (CL 284,846) has recently been described as a hypnotic agent which also has BZ1 (omega 1) receptor selectivity. The pharmacological effects of zolpidem and zaleplon were therefore compared in mice and rats. Both drugs blocked tonic convulsions induced in mice by pentylenetetrazole and electroconvulsive shock and clonic convulsions induced by isoniazid. Zaleplon was more potent than zolpidem but the maximal effect of zolpidem for increasing the latency to isoniazid-induced convulsions was greater than that of zaleplon. Little tolerance developed to the anticonvulsant effect of zaleplon against isoniazid-induced seizures following twice daily administration of 10 or 30 mg/kg for 10 days. Both compounds reduced locomotor activity and produced motor deficits in the rotarod and loaded grid tests in mice. However, while zaleplon produced all three effects at similar doses, zolpidem showed the greatest potency for reducing locomotion. Zaleplon and zolpidem also decreased locomotion and produced a rotarod deficit in rats. Again, the difference between the doses giving rise to these two effects was greater for zolpidem than for zaleplon. In a drug discrimination procedure using rats trained to discriminate a dose (5 mg/kg) of chlordiazepoxide, zaleplon produced partial substitution for chlordiazepoxide at doses which greatly reduced response rates. These results show that zaleplon and zolpidem have similar pharmacological profiles, presumably related to their BZ1 (omega 1) receptor selectivity. However, the difference between doses producing motor deficits (rotarod, loaded grid) and those giving rise to other effects (anticonvulsant, decreased locomotion) was greater for zolpidem than for zaleplon. This difference may be related to a greater in vivo intrinsic activity of zolpidem as indicated by the different efficacies of the two drugs to antagonise isoniazid-induced convulsions.

Acetamides↗
PubMed1995

Behavioral effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI) in the elevated plus-maze test.

The serotonin (5-hydroxytryptamine, 5-HT) system has consistently been implicated in the actions of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and other hallucinogens. Recent evidence suggest that the 5-HT2A/2C receptor subtypes may be major targets for such drugs in the CNS. DOI-treated hooded rats (0.1-5.0 mg/kg) and DOI treated ICR mice (0.1-2.0 mg/kg), displayed aversions at lower doses and anti-aversions at higher doses to the open arms of the plus-maze. Mianserin (0.5 mg/kg) and ketanserin (0.1 mg/kg) blocked the anti-aversive behavior, but only mianserin was effective at reversing the aversions produced by the higher doses of DOI in the ICR mice. DOI produced an intense aversion in the DBA/2 and anti-aversion in the C57/BL6 mice to the open arms of the plus-maze. These opposing actions of DOI in the plus-maze may be exploited in studying the neurobehavioral effects of hallucinogens. Since flumazenil was ineffective at blocking the DOI induced changes, it was concluded that the mechanism of DOI induced anxiolysis or anxiogenesis may not involve an action at the benzodiazepine receptors.

Amphetamines↗
PubMed1996

Interaction of 2,4,4'-trichloro-2'-hydroxydiphenyl ether with microsomal cytochrome P450-dependent monooxygenases in rat liver.

We studied the effects of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on the kinetics of the cytochrome P450 (P450)-dependent monooxygenases in rat liver microsomes. The activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) in rat liver microsomes exposed to 3-methylcholanthrene (MC) and phenobarbital (PB) respectively, were substantially inhibited by Irgasan DP300. The inhibition profile of EROD was competitive, whereas that of PROD was noncompetitive; the Ki values from Hanes plots were 0.24 and 1.48 microM for EROD and PROD, respectively. Phenacetin O-deethylase (PCOD) and 4-nitrophenol hydroxylase (4NPH) activities in rats exposed to PB were also inhibited by Irgasan DP300, at Ki values lower than those for other microsomes. Irgasan DP300 slightly inhibited testosterone 6 beta-hydroxylase (TS6BH) activities in some microsomes. No effect of Irgasan DP300 on lauric acid omega-hydroxylase (LAOH) activity was evident in any microsomal preparations. These results indicated that Irgasan DP300 inhibits MC- and PB-inducible P450-dependent monoxygenase in vitro competitively or noncompetitively, and that the P450 enzymes of the CYP1A or CYP2B subfamily may contribute to Irgasan DP300 toxicity.

Animals↗
PubMed1980

Studies on the involvement of GABA in the aggression directed by groups of intact or gonadectomized male and female mice towards lactating intruders.

The aims of the present studies were (a) to determine the effects of pharmacological elevation of GABA by treatment with DPA (competitive inhibitor of GABA transaminase) on a form of aggression displayed by grouped female mice towards lactating and non-lactating intruders; (b) to estimate GABA levels in six different brain areas of intact and gonadectomized male and female mice. The results revealed that DPA treatment considerably reduced this form of aggression. Increased GABA levels, modulated by the hormonal state of the animals, were observed in most brain areas studied.

Aggression↗
PubMed1995

Antagonism of isoniazid-induced convulsions by abecarnil in mice tolerant to diazepam.

The ability of the benzodiazepine receptor full agonist diazepam, the selective agonist abecarnil, and the partial agonist imidazenil to antagonize convulsions induced by isoniazid (200 mg/kg, S.C.) was studied in mice chronically treated with diazepam (3 mg/kg, i.p., three times daily) or abecarnil (0.1 or 1 mg/kg, i.p., three times daily or 6 mg/kg, S.C., daily). Diazepam induced tolerance to its own anticonvulsant effect. In contrast, chronic treatment with abecarnil failed to induce tolerance to its own anticonvulsant activity. Animals treated with abecarnil at 0.1 mg/kg developed cross-tolerance to imidazenil, whereas those treated with 1 mg/kg became less sensitive to diazepam. Mice chronically treated with abecarnil at 6 mg/kg showed almost complete tolerance to diazepam. Abecarnil was able to antagonize the convulsions elicited by isoniazid in diazepam-tolerant mice. These data indicate that chronic administration of abecarnil, unlike that of classical benzodiazepines, does not induce tolerance to its anticonvulsant effect, and that abecarnil overcomes tolerance induced by long-term treatment with the full agonist diazepam.

Animals↗
PubMed1996

Effects of triazolam and diazepam on learning and memory as assessed using a water maze.

One of the reported adverse side effects of the frequently prescribed benzodiazepines diazepam (Valium) and triazolam (Halcion) is an impairment of anterograde memory in humans. The experiments described in this article compared the effects of triazolam and diazepam on performance in a water maze task that is sensitive to drugs that affect learning and memory. The water maze utilized is a traditional type of maze with alleyways and door choices, unlike the Morris open water maze. Time required to find an out-of-the-water platform and errors committed during the swim are used as performance measures. Rats were tested on a previously learned maze configuration and on the acquisition of new maze configurations. Neither diazepam (0.25, 1.0, or 2.0 mg/kg) nor triazolam (0.05, 0.2, or 0.3 mg/kg) injected 30 min prior to testing on the previously learned maze affected swim time or errors committed. Administration of diazepam (0.5, 1.0, or 2.0 mg/kg, IP) prior to daily training on three different new maze configurations did not affect swim time, but did increase swim errors. Triazolam administered at 0.1, 0.2, or 0.3 mg/kg markedly impaired performance as assessed by either swim time or errors. There were no differences in performance of rats previously treated with triazolam, diazepam, or vehicle in learning another new maze after drug treatment was terminated. These data demonstrate that both diazepam and triazolam affect acquisition but not recall of maze configurations and support similar conclusions reached using other types of tasks in humans and animals.

Animals↗
PubMed1996

Serotonergic activation reduces defensive freezing in the conditioned fear paradigm.

Our previous study showed that conditioned fear stress (CFS) increased serotonin (5-HT) metabolism in the medial prefrontal cortex and induced freezing behavior. Although these results could support the 5-HT hypothesis of anxiety, the functional significance of the 5-HT response to stress is unclear. In this study, the effects of 5-HT reuptake inhibitors, agonists, antagonists, and diazepam on freezing behavior induced by CFS were examined using a time-sampling procedure. Various doses of test compounds were administered subcutaneously to rats 24 h after the last session of repeated foot-shock for 5 days. Rats were again placed in the shock chamber without shocks 20 min after injections of drugs, and observed. Diazepam (1 mg/kg) and the 5-HT1A agonist ipsapirone (0.5-10 mg/kg) significantly inhibited freezing behavior. L-5-Hydroxytryptophan (with benserazide) and the selective 5-HT reuptake inhibitor citalopram (10 mg/kg) reduced freezing behavior. The 5-HT2 antagonists ICI169,369 and ketanserin failed to change freezing behavior. p-Chlorophenylalanine (200 mg/kg) administered 15 h before the test did not affect freezing. The effect of ipsapirone was not modified in rats with lesions of 5-HT neurons, produced by p-chloroamphetamine (2 x 10 mg/kg). In conclusion, these results suggest the anxiolytic potential of ipsapirone and citalopram, and support the hypothesis that the facilitation of 5-HT neurotransmission decreases anxiety.

Animals↗
PubMed1996

Effects of psychotropic drugs on rat responding in an operant paradigm involving choice between delayed reinforcers.

Preference for immediate reward, taken as an index of impulsiveness, has been suggested to be under the preferential control of central serotonin (5-HT) function. The present study examined the effects of the acute administration of drugs which directly or indirectly alter 5-HT transmission on tolerance to delay of reward in rats subjected to a procedure of discrete-trial choice in an operant chamber. Different groups of rats were trained to choose between two levers giving access to reinforcers differing in both magnitude and delay: one food pellet, delayed by 0 or 5 s, vs. five pellets delivered after a prereinforcer interval fixed at either 15, 30, 45, or 60 s, depending on the experiments. The learning curves indicated that rats were able to adjust their choice strategy precisely according to various factors: the respective duration of the delays before the small and large rewards, the immediacy of the small reward delivery, and the lengthening of the trials by a postreinforcer delay (or intertrial interval). Whatever the experimental parameters and stage of the learning, an acute administration of drugs able to reduce 5-HT neuronal activity (benzodiazepines; 5-HT1A receptor partial agonists: buspirone and MDL 73005EF) or enhance 5-HT transmission (5-HT reuptake inhibitors: indalpine and zimelidine; 5-HT1A receptor full agonist: 8-OH-DPAT) failed significantly to alter choice strategy (decreased or increased preference for the large but delayed reward, respectively), as they did in other situations such as a T-maze procedure. Only d-amphetamine (0.5 mg/kg), on one occasion, significantly reduced preference for the larger reward. The choice strategy was also insensitive to acute changes in experimental parameters such as a reduction in delay or increase in the magnitude of the large reinforcement. These results indicate that the present operant paradigm is not sensitive to acute modifications in the internal state of the animals and in the reward contingencies, and therefore is not useful to evaluate tolerance to delay and variations in impulsiveness in rats.

Animals↗
PubMed1996

Expression of Fos protein in various rat brain areas following acute nicotine and diazepam.

We studied the effects of an acute dose of (-)-nicotine (1 mg/kg) on Fos-like immunostaining (IS) in rat brain areas. Nicotine increased Fos IS significantly in the medial terminal nucleus of accessory optic tract (MT), and tended to increase it in the interpeduncular nucleus (i.p.), as well as in the stress-related areas, the paraventricular hypothalamic nucleus (PVN) and the supraoptic nucleus (SON). Previously nicotine was reported to increase Fos IS also in another stress-related area, the central nucleus of amygdala (ACe). This led us to study the interaction of nicotine with diazepam (10 mg/kg). Diazepam alone increased Fos IS in PVN and in SON as well as in ACe. In diazepam- and nicotine-treated rats Fos IS was increased in PVN and SON as well as in MT and i.p.. In MT and i.p. of diazepam and nicotine-treated rats Fos IS was similar to that induced by nicotine alone, and in PVN and SON of these rats Fos IS in ACe. Taken together, diazepam induced Fos IS in all stress-related areas studied (PVN, SON, ACe), but not in central visual structures, where nicotine induces Fos IS (MT, i.p.). No significant interactions on Fos expression were found between acute effects of diazepam and nicotine suggesting that these drugs activate different sets of neurons within the stress-related brain areas.

Amino Acid Sequence↗
PubMed1996

Neuroendocrine effects of diazepam and flesinoxan in the stress-induced hyperthermia test in mice.

In the stress-induced hyperthermia (SIH) paradigm in mice, both a benzodiazepine receptor agonist, diazepam, and a 5-HT1A receptor agonist, flesinoxan, reduced the stress-induced increase in rectal temperature. The SIH procedure itself enhanced plasma ACTH and corticosterone levels but not plasma glucose levels. Diazepam (3, 6, and 12 mg/kg p.o.) did neither affect basal plasma ACTH, corticosterone, or glucose levels, nor did it suppress the stress-induced rises in these parameters. Flesinoxan (1, 3, and 10 mg/kg p.o.) enhanced plasma ACTH and corticosterone concentrations under nonstress conditions but did not affect the stress-induced increases in ACTH and corticosterone secretion. No clear effects of flesinoxan on plasma glucose levels were found. Our results indicate that in mice the anxiolytic effects of diazepam and flesinoxan in the SIH paradigm are not paralleled by a blockade of stress-induced increases in plasma ACTH, corticosterone, and glucose levels.

Adrenocorticotropic Hormone↗