Interactions of metergoline with diazepam,quipazine, and hallucinogenic drugs on a conflict behavior in the rat

The effects of diazepam quipazine, lysergic acid diethylamide (LSD), and 2,5-dimethoxy-4-methylamphetamine (DOM) were examined on a conditioned suppression paradigm. Food-deprived rats were trained to drink a liquid diet from a tube. Subsequently, intermittent 7-s tones were presented during the daily 10-min sessions, the tube being electrified during the last 5 s of each tone. The subject gradually learned to suppress contact with the tube during the tone periods to a low stable level (punished responding) and consumed stable volumes of the liquid diet during the silent periods (unpunished responding). Treatment with diazepam caused large increases (1,000% of control) in punished responding. The hallucinogens produced only modest increases (200–300%), while quipazine did not significantly increase punished responding. Metergoline pretreatment (0.1–2.0 mg/kg, 180 min) had no effect on punished responding itself, and there was no significant alteration of the diazepam dose-response pattern. The weak increase in punished responding by LSD was antagonized by metergoline, but the interaction between metergoline and DOM was variable and inconsistent. Diazepam, quipazine, LSD, and DOM caused dose-dependent decreases in unpunished responding (fluid intake). Metergoline alone decreased unpunished responding only at 2.0 mg/kg. Metergoline pretreatment (1.0 mg/kg) only slightly antagonized the LSD effect on unpunished behavior, but shifted the dose-response curves of DOM and quipazine for decrease in fluid intake to the right approximately eight fold. On the contrary, the dose-response curve of diazepam to decrease fluid intake was shifted to the left by metergoline pretreatment. These data suggest that altered activity of brain serotonin (5-HT) neurons is not responsible for the dramatic increase in punished responding by diazepam. The hallucinogens, quipazine, and diazepam all produce a decrease in unpunished responding, but they appear to do so by different neuropharmacological mechanisms. In addition, there may be at least slight differences in the mechanism by which LSD produces its effects as compared with that of quipazine and DOM.     

Anticonflict action of tandospirone in a modified Geller-Seifter conflict test in rats.

Tandospirone is a novel non-benzodiazepine compound possessing potent anxiolytic properties in a water lick conflict paradigm in rats and a high affinity for central 5-HT1A receptors. In the present study, tandospirone was evaluated for anxiolytic activity in a modified Geller-Seifter conflict paradigm in rats. Tandospirone produced significant increases in the punished responding at doses of 1.25, 2.5 and 5.0 mg/kg, i.p. or 20 mg/kg, p.o., although it decreased unpunished responding at doses of 2.5 and 5.0 mg/kg, i.p. or 20 mg/kg, p.o. Likewise, diazepam was also effective after i.p.-administration in this test, and its minimum effective dose was slightly higher than that of tandospirone. This suggests that tandospirone might be as effective in the treatment of anxiety as diazepam. The anticonflict action of tandospirone was not inhibited by Ro-15-1788, a benzodiazepine antagonist, although that of diazepam was completely inhibited. 8-OH-DPAT, a full agonist of 5-HT1A receptors, was also effective in this test with a high potency. Therefore, the possibility exists that the anticonflict action of tandospirone is related to its agonist action on 5-HT1A receptors, not on benzodiazepine receptors.     

Antagonism of the anti-conflict effects of phenobarbital,but not diazepam,by the A-1 adenosine agonistl-PIA

The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 adenosine agonist N⁶-R-phenylisopropyladenosine (l-PIA), and the A-2 adenosine agonist 5-N-ethylcarboxamidoadenosine (NECA) on conflict behavior. Water-restricted rats were trained to drink from a tube that was electrified (0.5 mA intensity) on a FI-29s schedule, electrification being signaled by a tone. After 3 weeks of daily 10-min sessions, the animals accepted a stable number of shocks (punished responding) and consumed a consistent volume of water (unpunished responding) per session. Different doses ofl-PIA and NECA were then tested separately at weekly intervals. In addition, the effects of diazepam and phenobarbital were determined in animals pretreated with saline,l-PIA, or NECA. Neitherl-PIA (15–250 nmole/kg) nor NECA (2.5–20 nmole/kg) produced a significant anti-conflict effect when administered alone. Diazepam (1.25–10 mg/kg) or phenobarbital (10–40 mg/kg) administration to saline-pretreated rats resulted in a dose-dependent increase in punished responding (shocks received) with minimal effects on unpunished responding (water intake). Neitherl-PIA nor NECA pretreatment reliably altered the effects of diazepam on conflict behavior. Pretreatment withl-PIA, but not NECA, significantly reduced the anti-conflict effects of phenobarbital on conflict behavior. These data suggest that phenobarbital, but not diazepam, anti-conflict responses may involve interactions with A-1 adenosine receptors.     

Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1–3.0 mg/kg) and chlordiazepoxide (3.0–30 mg/kg) increased punished responding at doses that had little effect on unpunished responding;d-amphetamine (0.3–5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding. Changeover responses were increased only moderately by the anxiolytic drugs when the punishment schedule was added to a 3-min variable-interval schedule and the alternate schedule was a 1-min variable-interval schedule without punishment; the amount of time spent in the punishment component, however, increased two-fold at the higher doses of chlordiazepoxide. When these conditions were reversed and punishment was added to the variable-interval 1-min schedule, time spent in the punishment component increased and changeover responses out of the punishment component decreased, particularly following chlordiazepoxide. Anxiolytic drugs appear to attenuate the aversiveness of stimuli correlated with punishment, but the degree of attenuation is controlled by other conditions prevailing in the presence of those stimuli.     

Biphasic effect of l-5-HTP in the Vogel conflict model

The effect of l-5-HTP (25–400 mg/kg IP) following inhibition of the peripheral aromatic amino acid decarboxylase by means of benserazide (25 mg/kg IP) was investigated in a test modified from Vogel's drinking conflict model. At 50 mg/kg an anti-conflict action was detected, while higher doses (100–400 mg/kg) decreased punished responding. A lower dose (25 mg/kg) had no effect. Non-specific effects — such as alterations in muscle tone, in motivation to drink or in the sensitivity to electrical shock — could not explain the anxiolytic- and anxiogenic-like actions of 50 and 100 mg/kg, respectively. The bi-phasic effect of l-5-HTP is discussed in terms of different subpopulations of central serotoninergic receptors, possibly exerting opposing influences on conflict responding. The study emphasises the importance of 5-HT mechanisms in anxiety, and the possibility of finding novel anxiolytics among drugs selectively affecting central 5-HT neurotransmission.     

Olanzapine,an atypical antipsychotic,increases rates of punished responding in pigeons

The effects of olanzapine [LY 170053; 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2, 3b][1,5]benzodiazepine), a potential atypical antipsychotic, were determined in pigeons whose keypeck responding was punished. These effects were compared to the anxiolytic agents chlordiazepoxide and pentobarbital, and to other antipsychotic agents. Keypeck behavior was maintained under a multiple FR30 FR30 schedule, signalled by white and red stimulus lights, respectively. Each component of the schedule alternated every 3 min with a 30-s timeout. During the white keylight component, responding was maintained by food presentation. During the red keylight component, responding was maintained by food and simultaneously suppressed by electric shock presentation, with response rates being only about 5% of those during the white stimulus light. Olanzapine (0.01–1.0 mg/kg) increased punished responding at doses below those which had an effect on unpunished responding. Clozapine (0.01–1.0 mg/kg), ritanserin (0.1–3.0 mg/kg), and, to a lesser extent, risperidone (0.1–1.0 mg/kg) were also effective at increasing punished responding. Generally, the maximum effect seen with olanzapine was equal to that seen with ritanserin, and it exceeded that seen with clozapine. However, these effects were generally less than those seen with chlordiazepoxide and pentobarbital. Haloperidol (0.01–0.1 mg/kg) was completely without effect on punished responding, while it caused decreases in unpunished behavior. These results provide further evidence that olanzapine has a profile in behavioral tests unlike the typical antipsychotic haloperidol. Moreover, this profile is similar to clozapine, a clinically effective antipsychotic with an atypical profile.     

Antagonism of the anticonflict effects of chlordiazepoxide by β-carboline carboxylic acid ethyl ester,Ro 15-1788 and ACTH(4–10)

The antagonism of the anticonflict effect of chlordiazepoxide (CDP) by -carboline carboxylic acid ethyl ester (BCCE), Ro 15-1788 and ACTH(_4–10) has been evaluated in the Geller-Seifter rat conflict test in which CDP increases punished (conflict), but not unpunished responding. BCCE (0.5–10 g ICV) produced a dose-dependent reduction in the anticonflict activity of CDP. This was also significantly reduced by Ro 15-1788 (25 mg/kg IP) and a high dose of ACTH(_4–10) (5 g ICV). None of these test compounds had a marked direct effect on punished or unpunished responding in the doses used. These experiments provide further physiological support for the suggestion from binding studies that BCCE and Ro 15-1788 act on benzodiazepine receptors. However, the ability of ACTH(_4–10) to reduce the anticonflict effect of CDP may be by some other, possibly opioid, mechanism.     

Effects of chlordiazepoxide on comparable rates of punished and unpunished responding

Identical overall rates and patterns of key pecking by pigeons were maintained under a multiple fixed-interval schedule of food presentation. In one component, every thirtieth response produced an electric shock (punishment) whereas during the other component the response that produced food had to be preceded by a pause of a minimum (10 or 11 s) duration. Although chlordiazepoxide (1.0–17.0 mg/kg) increased both punished and unpunished responding, greater increases were uniformly obtained with punished responding.     

Attenuation of conflict-induced suppression by clonidine: Indication of anxiolytic activity

Clonidine was tested in a conflict-induced suppression paradigm (bar pressing for food reward suppressed by electric foot shock) in rats. This drug significantly and dose dependently (25–100 μg/kg) both increased punished responding and decreased unpunished responding. Clonidine at 200 μg/kg had no effect on punished bar pressing, although it markedly inhibited unpunished responding due to sedation. The effect of clonidine on shock-suppressed lever pressing was prevented by yohimbine 5 mg/kg and partially antagonized by phenoxybenzamine 2.5 mg/kg but was not significantly altered by phenoxybenzamine 1 mg/kg, atropine 5 mg/kg, methysergide 5 mg/kg, or naloxone 10 mg/kg. This activity of clonidine does not seem to be due to its analgesic or food intake-increasing properties. It may be a true anxiolytic effect, brought about by presynaptic stimulation of noradrenergic neurons which could result in an inhibitory influence on the locus coeruleus.     

Effects of opiate antagonists and putative κ agonists on unpunished and punished operant behavior in the rat

The effects of naloxone and diprenorphine, opiate antagonists with different receptor-binding properties, and the putative -receptor agonists, ketocyclazocine and ethyl-ketocyclazocine (EKC), were studied on food-reinforced responding in rats. Behavior was maintained under a multiple-component 1-min variable-interval schedule in which 12-min periods of unpunished responding alternated with 4-min periods in which each response was punished by a brief electric footshock. Daily sessions were 1 h. Naloxone (0.01–10 mg/kg) decreased unpunished responding only slightly; punished responding was decreased significantly to 66% of control by 10 mg/kg. Diprenorphine (0.01–10 mg/kg) did not affect unpublished responding and increased punished responding dose-dependently to as much as 190% of control. EKC (0.01–1.0 mg/kg) decreased unpunished and punished responding dose-dependently and comparably, whereas ketocyclazocine (0.01–1.0 mg/kg)decreased unpublished responding but did not significantly affect punished responding. Diprenorphine was more potent than naloxone in blocking the decreases in responding produced by the agonists. Differences in the behavioral effects of naloxone and diprenorphine appear to reflect the different receptor-binding properties of the two opiate antagonists.     

Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with I mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.     

Role of 5-hydroxytryptamine in amphetamine effects on punished and unpunished behaviour

In order to assess the contribution of serotonergic (5-HT) mechanisms in the suppressant effect of amphetamine on punished responding, dose-effect curves of amphetamine on key-pecking behaviour of pigeons maintained by food presentation and punished by electric-shock were determined before and after pretreatment with methergoline, a potent and specific 5-HT receptor blocker in the central nervous system. A multiple fixed-interval 5 min, fixed-interval 5 min schedule of reinforcement in which every response, except the reinforced one, was punished in one of the two components (mult FI5 FI5-shock) was used. Effective doses of amphetamine decreased unpunished as well as punished FI response rates. However, the decreases in punished behaviour were more evident and dose-dependent. Methergoline markedly increased FI responding in the punished FI component but only slightly increased or decreased unpunished FI response rates. The most effective dose of methergoline for increasing punished responding was 0.56 mg/kg. Pretreatment with this dose of methergoline unmasked the facilitatory effects of amphetamine on unpunished responding, but did not antagonize its suppressant effect on punished responding. Therefore, although 5-HT seems to mediate punishment-induced response suppression and to inhibit the facilitatory effects of amphetamine on unpunished responding, it is not apparently involved in the suppressant effect of amphetamine on punished behaviour.     

Anxiolytic-like effects of alpha-2-adrenoceptor agonists on conflict behavior in the rat: pre- versus postsynaptic receptor mechanisms.

The effects of acute pretest administration and chronic posttest administration of clonidine or the selective alpha 2-adrenoceptor agonist UK-14,304 on conflict behavior were investigated. In daily 10-min sessions, water-deprived rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. Prior to treatment, subjects accepted 25-30 shocks/session (punished responding) and consumed approximately 12-15 ml/session (unpunished responding). Acute pretest administration of clonidine or UK-14,304 did not increase punished responding. In contrast, chronic posttest clonidine administration (40 micrograms/kg, IP, twice daily for 8 weeks) resulted in a robust and time-dependent increase in punished responding (60-70 shocks/session) relative to saline-treated controls. Moreover, the selective alpha 2-adrenoceptor agonist UK-14,304 also increased punished responding when administered chronically (1.0 mg/kg, BID). Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine HCl (DSP4, 65 mg/kg, IP) significantly decreased punished responding in control conditioned suppression of drinking sessions. The anticonflict effect associated with chronic posttest clonidine treatment was not altered by DSP4 pretreatment. These findings suggest that chronic posttest alpha 2-adrenoceptor agonist treatment produces an anticonflict effect independent of its actions at presynaptic alpha 2-adrenoceptors.     

Interaction of buspirone and dopaminergic agents on punished behavior of pigeons

The non-benzodiazepine anxiolytic buspirone was studied alone and in combination with either haloperidol or apomorphine. Drug effects were evaluated under a baseline of punished and unpunished keypeck responses of pigeons; every 30th response produced food (no punishment) in the presence of a white keylight and, when the keylight was red in alternate 3 min periods, every 30th response produced both food and a brief electric shock (punishment). Buspirone (0.03-3 mg/kg, IM) increased the low rates of punished responding to a maximum of 1000% of control at doses of 0.1-1 mg/kg. Unpunished responding was only marginally affected at lower doses and dose-dependent decreases were obtained from 1 to 10 mg/kg. Although less potent, chlordiazepoxide (1-100 mg/kg IM) produced effects which were similar to those of buspirone, a finding which contrasts with the greater efficacy of benzodiazepines for increasing punished behavior in mammals. Dose-effect functions for buspirone were unchanged by haloperidol administration (0.01 and 0.03 mg/kg, IM, 5 min prior) or by concurrent treatment with a behaviorally-ineffective dose of apomorphine (0.003 mg/kg, IM). Rate-decreasing doses of apomorphine (0.01-0.1 mg/kg) reversed the increases in punished responding produced by lower doses of buspirone (0.03 and 0.1 mg/kg) and the apomorphine-induced decreases in unpunished responding were antagonized by buspirone at doses which had little affect when given alone. The ability of buspirone to reverse the rate-decreasing effects of apomorphine on unpunished responding suggests that buspirone does exhibit dopaminergic antagonist properties in vivo. However, effects of buspirone on punished responding of pigeons do not appear to be due to dopaminergic mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of compounds varying in selectivity as 5-HT(1A) receptor antagonists in three rat models of anxiety

Compounds varying in selectivity as 5-HT(1A) receptor antagonists have recently been reported to produce benzodiazepine-like antianxiety effects in mice. To assess the cross-species generality of these findings, the present experiments compared the effects of diazepam (0.625-5 mg/kg) with those of several non-selective (MM-77, 0.03-1 mg/kg and pindobind-5-HT(1A), 0.1-5 mg/kg) and selective (WAY100635, 0.01-10 mg/kg, p-MPPI, 0.01-3 mg/kg and SL88.0338, 0.3-10 mg/kg) 5-HT(1A) receptor antagonists in three well-validated anxiolytic screening tests in rats: punished lever-pressing, punished drinking, and the elevated plus-maze. In the punished lever-pressing conflict test, none of the 5-HT(1A) receptor antagonists modified rates of punished responding, whereas in the punished drinking test, WAY100635 (0.3-1 mg/kg), SL88.0338 (3-10 mg/kg), p-MPPI (1 mg/kg), MM-77 (0.03-0.3 mg/kg), but not pindobind-5-HT(1A), produced clear anticonflict activity. However, the increase in punished responding with the 5-HT(1A) compounds was smaller than that produced by diazepam, indicating weaker anxiolytic-like activity. In the elevated plus-maze test, WAY100635 (0.1-0.3 mg/kg), SL88.0338 (0.3-10 mg/kg), MM-77 (0.01-3 mg/kg), pindobind-5-HT(1A) (0.1-3 mg/kg), but not p-MPPI, showed anxiolytic-like activity on traditional behavioral indices, increasing the percentage of time spent in open arms and the percentage of open arm entries. As was the case in the punished drinking test, the magnitude of the positive effects of the 5-HT(1A) compounds was generally smaller than that of diazepam. Of the ethological measures recorded in the plus-maze, all compounds markedly decreased risk assessment (i.e. attempts) over the entire dose-range, but only diazepam clearly increased directed exploration (i.e. head-dipping). Although the present results demonstrate that 5-HT(1A) receptor antagonists elicit anxiolytic-like effects in rats, this action appears to be test-specific and, unlike previous findings in mice, smaller than that observed with benzodiazepines. The data are discussed in relation to the possible relevance of species differences in 5-HT(1A) receptor function and the nature of the anxiety response studied.     

Anticonflict effects of the 5-HT1A compound flesinoxan

The new phenylpiperazine derivative flesinoxan, a potent and selective serotonin(1A) (5-HT(1A)) agonist, was examined under a procedure that has proved to be a reliable and sensitive method for detecting novel anxiolytic drugs believed to produce their effects at the 5-HT( 1A) receptor subtype. Key pecking by pigeons was maintained by the presentation of food following every 30th response in the presence of a white keylight; during an alternate component, correlated with a red keylight, every 30th response produced food and electric shock which suppressed responding (punishment). Flesinoxan doses from 0.001 to 0.3 mg/ kg, intramuscularly, produced significant increases in punished responding at doses that did not affect unpunished responding. Doses of flesinoxan between 1.0 and 3.0 mg/kg also increased punished responding but produced decreases in responding that was not punished. In a second study flesinoxan substituted for the 5-HT(1A) anxiolytic buspirone under a drug discrimination procedure, providing further evidence that the behavioural effects offlesinoxan are mediated by 5-HT(1A) mechanisms. Based on these findings, it would appear that flesinoxan should be a useful compound in the clinical management of anxiety.     

Alnespirone and buspirone have anxiolytic-like effects in a conflict procedure in rats by stimulating 5-HT(1A) receptors

We studied the anxiolytic-like activity of alnespirone and buspirone, two 5-HT(1A) receptor agonists, in a modified Geller-Seifter conflict model, and examined the role of 5-HT(1A) receptors by studying whether WAY-100635, a selective antagonist at these receptors, blocked their effects. Administered s.c. 30 minutes before testing, 0.5 and 1mg/kg alnespirone significantly increased punished responding, whereas lower doses (0.125 and 0.25 mg/kg) had no effect. At 1mg/kg, alnespirone significantly reduced the rates of unpunished responding. One dose of buspirone (1mg/kg) significantly increased punished responding and reduced unpunished responding. Lower doses were ineffective. Administered s.c. 40 minutes before testing, WAY-100635 had no effect on any parameter but completely antagonized the effects of alnespirone (1mg/kg) and buspirone (1mg/kg) on punished responding. The ability of buspirone to reduce unpunished responding was not antagonized by WAY-100635, probably reflecting a sedative effect of buspirone due to dopamine D2 receptor blockade. The results suggest that alnespirone and buspirone have anxiolytic-like activity in a conflict procedure by stimulating 5-HT(1A) receptors, presumably at a presynaptic level. Like buspirone, alnespirone may have useful effects in the treatment of anxiety disorders.     

Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis

Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB(1) receptors. Whether central and/or peripheral cannabinoid CB(1) receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the head-twitch response (a centrally mediated serotonin 5-HT(2A) receptor-induced behavior) and emesis (a serotonin 5-HT(3) receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both head-twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the head-twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced head-twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews. Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced head-twitch response in a dose-dependent manner with similar ID(50) values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID(50s), at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose-response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT(3) receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1-1 mg/kg) nearly completely prevented 2-methylserotonin-induced, centrally mediated, head-twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT(3) receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced head-twitch and emesis via cannabinoid CB(1) receptors since the CB(1) receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours.     

Antagonism of diazepam's anticonflict effects in rats by nicotine,but not by arecoline

The purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague-Dawley rats were tested with a modified Geller-Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed-interval 60-sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed-ratio 1 schedule. In Experiment 1 (?)-nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (?)-nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley-Liss, Inc.     

The effect of benzodiazepines on the 5-HT agonist-induced head-twitch response in mice

The effects of four benzodiazepines (diazepam, clonazepam, oxazepam and clobazam) were studied on the head-twitch response induced in mice by several 5-HT receptor agonists. All the benzodiazepines tested potentiated the effects of the directly acting agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine and mescaline, without themselves inducing head-twitches. In contrast, none of them potentiated head-twitches induced by the indirectly acting agonist 5-hydroxytryptophan (5-HTP; with carbidopa 25 mg/kg), and in some experiments a clear inhibition was seen. The clonazepam (10 mg/kg) potentiation of 5-MeODMT-induced head-twitches was not antagonised by flumazenil, (+)-bicuculline, or by pretreatment with p-chlorophenylalanine. Neither was it mimicked by muscimol, which inhibited head-twitches. These results indicate that the observed potentiation is not mediated by benzodiazepine receptors and that it occurs postsynaptically to the initiating 5-HT receptors. The inability of the benzodiapines to potentiate 5-HTP-induced head-twitches probably reflects a reduction in 5-HT neuronal activity mediated by benzodiazepine receptors, as co-administration of flumazenil and clonazepam potentiated the effects of 5-HTP whereas each compound alone had no effect.