Effects of some volatile sedative-hypnotics on punished behavior

Lever-press responses of rats were established under a schedule in which punished and unpunished responding alternated. Every 30th response produced food (unpunished responding) during one schedule component, while every tenth response produced both food and shock (punished responding) during an alternate schedule component. Each schedule component was correlated with a different visual stimulus. Unpunished behavior was characterized by high sustained rates which followed brief pauses after food delivery. Punished behavior occurred at less than 10% the rate of unpunished behavior. Oral administration of diazepam, ethchlorvynol, chloral hydrate, tertiary-butanol, and ethanol all produced marked dose-related increases in punished behavior at doses that decreased or had little effect on unpunished responding. Potency estimates for increasing punished responding varied over a 400-fold range. The potency ranking was diazepam > ethchlorvynol > chloral hydrate > tertiary-butanol > ethanol. Higher doses of all drugs decreased unpunished responding with relative potencies comparable to those found for doses producing maximal increases in punished responding. increases in punished behavior appear to be a characteristic feature of drugs with sedative-hypnotic properties.     

Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam

This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1–18 mg/kg), cyproheptadine (1–18 mg/kg), metergoline (0,25–2.0 mg/kg) and cinanserin (10–100 mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3–100 g/kg) administered 1,10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6–30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25–2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25–1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.     

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.     

Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans

 Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30^food:FR30^food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons. Received: 22 May 1998 / Final version: 4 August 1998     

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.     

beta-Carboline and pentylenetetrazol effects on conflict behavior in the rat.

The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as "anxiogenic" in several animal models for anxiety. The present study examined the effects of the beta-carboline noreleagnine (NOR) and PTZ, administered alone and in combination with the benzodiazepine antagonist, Ro 15-1788, on behavior in the conditioned suppression of drinking (CSD) conflict procedure. In daily 10-min sessions, water-deprived female SD rats were trained to drink from a tube that was electrified (0.25 mA). Electrification was signaled by a tone. Acute (20-min) treatment with NOR or PTZ resulted in a dose-dependent decrease in both punished responding (shocks received) and unpunished responding (water intake). Both NOR and PTZ decreased punished responding only at doses that also depressed unpunished responding. Coadministration of Ro 15-1788 (2 mg/kg) reduced the effects of NOR on punished, but not unpunished, responding; this Ro 15-1788 cotreatment reduced the effects of PTZ on both punished and unpunished responding. These data suggest that both PTZ and NOR produce benzodiazepine receptor-mediated anxiogenic-like effects on conflict behavior.     

A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.     

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.     

Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

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.     

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.     

Anxiolytic effects of benzodiazepines in amygdala-lesioned rats

The role of the amygdala in the anxiolytic action of benzodiazepines was examined. Performance on a water-licking conflict paradigm was tested in rats with localized damage to the central nucleus of the amygdala (ACE) or with general damage to the entire amygdaloid complex. The effects of the benzodiazepine chlordiazepoxide (2.5–20.0 mg/kg) on conflict behavior in these animals was also examined. Electrolytic lesions of either ACE or of the entire amygdaloid complex resulted in a pronounced increase of punished responding, an effect that persisted for at least 12 sessions postoperatively. After shock levels were adjusted in the lesioned groups to match their baseline punished behavior to that of the controls, various doses of chlordiazepoxide were administered. Not only did the lesioned animals show an increase in punished behavior in response to the drug, they were more sensitive than controls to the lower drug doses. A complete model of anxiolytic action may have to include both mechanisms that block anxiogenic regions and those that activate anxiolytic regions.     

A sensitive and selective monkey conflict test

A conflict model is described in which clinically effective antianxiety agents exhibit pronounced anticonflict activity. Male squirrel monkeys were trained to depress a bar for 5 sec to obtain food reinforcement. The 6 hr test session was comprised of an initial 3 hr period in which each 5 sec response was punished and then a 3 hr unpunished period. Trained monkeys would rarely be shocked and would make most of their responses during the non-punished period. Both benzodiazepine (chlordiazepoxide and diazepam) and non-benzodiazepine (meprobamate and phenobarbital) anxiolytics produced pronounced and unequivocal increases in punished responding. Other psychoactive agents (d-amphetamine, chlorpromazine, ethanol, morphine, amitriptyline and imipramine) did not produce an increase in punished responding. Sensitivity (i.e., large magnitude effects), selectivity, stable baseline performance and fully automated features make this test useful in identifying potential anxiolytic agents in primates.     

Effects of alcohol on punished and unpunished responding of squirrel monkeys

Lever pressing of two squirrel monkeys was maintained initially under a multiple 5 min fixed-interval sched fixed-interval of food presentation where, in each of 2 separate stimulus conditions, the first response after 5 min elapsed produced food. Subsequently, during one of the fixed-interval components responding was punished by the presentation of a 5 mA electric shock following each 30th response; rates of responding were markedly suppressed during this component. Unpunished response rates occuring during the alternate fixed-interval component remained unchanged for one monkey and decreased for the other. Alcohol (1.0–3.0 g/kg) increased overall punished rates of responding and decreased unpunished response rates; at higher doses (3.5–4.0 g/kg) all responding was decreased. Where lower local rates of both punished and unpunished responding were comparable, as measured in successive quarters of the fixed-interval, these rates were increased equivalently with alcohol. Comparable higher local rates of punished and unpunished responding were both decreased to about the same extent. The effects of alcohol were determined by the control rate at which behavior occurred, ir respective of whether responding was punished or unpunished.     

The effects of FG 7142 and RO 15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat

Previous results in our laboratory have shown that both chlordiazepoxide and ethanol will release punished responding in a rat operant conflict test using incremental shock. In the present study, a benzodiazepine antagonist and a benzodiazepine inverse agonist were used to explore the neurochemical basis for this behavioral action. N-methyl--carboline-3-carboxamide (FG 7142) at high doses (20 and 40 mg/kg) produced suppression of both punished and unpunished responding, and reversed the release of punished responding produced by both chlordiazepoxide and ethanol, but only at doses that produced an effect on its own. FG 7142 thus acted to oppose the actions of both ethanol and benzodiazepines but in an additive, not interactive, manner. In contrast, RO 15-1788 produced no changes when injected by itself in doses as high as 12 mg/kg and reversed chlordiazepoxide-induced but not ethanol-induced release of punished responding. RO 15-1788 also reversed the decrease in punished responding produced by FG 7142. Results suggest that ethanol does not interact directly with the benzodiazepine binding sites on the GABA/benzodiazepine ionophore complex to produce its anxiolytic action.     

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.     

Anticonflict effect of ipsapirone, buspirone and gepirone is not mediated by their common metabolite 1-(2-pyrimidinyl)piperazine

Pyrimidinylpiperazine anxiolytic drugs-ipsapirone, buspirone and gepirone-dose- dependently increased punished responding in an anticonflict (shock-induced suppression of drinking) paradigm in rats. Similar effect was also produced by their common metabolite 1- (2-pyrimidinyl)piperazine (1-PP). Anticonflict effects of ipsapirone, buspirone and gepirone, administered in maximal doses, were considerably stronger when tested 30 min than 120 min after their administration. Furthermore, anticonflict effects of these drugs, given in subthres hold or medium effective doses, were significantly potentiated by the non-selective drug metabolism inhibitor proadifen. Comparison of these results with literature pharmacokinetic data indicate that the pharmacological effect of ipsapirone, buspirone and gepirone parallels better cerebral concentrations of the parent drugs than 1-PP. Therefore anticonflict activity of the investigated drugs does not seem to be mediated by their common metabolite 1-PP.     

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (−)S 20500

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT_1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT_1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock (conflict procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01–3.0 mg/kg) and (–) S 20500 (0.3–5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03–5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (–)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (–)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (–)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT_1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (–)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [³H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (–)S 20500 in displacing [³H]8-OH-DPAT (IC₅₀=2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT_1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.     

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)     

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.