Dopamine--acetylcholine "balance" in nucleus accumbens and corpus striatum and its effect on hypothalamic self-stimulation.

Three experiments investigated the suppression of hypothalamic self-stimulation in rats by neuroleptics and its restoration by centrally acting anticholinergic agents. Scopolamine (0.1--1.0 mg/kg i.p.) and benztropine (1.0--10.0 mg/kg i.p.) each enhanced self-stimulation when administered alone, and partially restored performance suppressed by spiroperidol (0.05--0.15 mg/kg i.p.). Benztropine strongly inhibits transmitter reuptake at DA synapses but scopolamine does not, thus inhibition of DA reuptake cannot fully account for the stimulant or antineuroleptic action of anticholinergic drugs. Neuroleptic and anticholinergic effects on self-stimulation rate were mutually subtractive, and statistical evidence of interaction was not obtained. Scopolamine was shown also to restore performance extinguished by discontinuation of the stimulating current. Smaller doses of scopolamine (50 nmol; 19 microgram) injected directly into the nucleus accumbens septi partially restored responding suppressed by spiroperidol, though similar doses of scopolamine injected bilaterally into the caudate-putamen were ineffective. These findings suggest that hypothalamic self-stimulation may be influenced by ACh-and DA-containing systems which exert independent effects on a third system controlling performance. These effects appear to reflect the level of arousal or motivation rather than the reinforcement process itself.     

Chlordiazepoxide-induced hyperphagia in non-food-deprived rats: effects of Ro15-1788, CGS 8216 and ZK 93 426

Chlordiazepoxide (1.25-20.0 mg/kg i.p.) was administered to non-food-deprived male rats given 30 min access to a highly palatable, familiar diet, and produced a potent stimulation of food consumption. At the maximum dose effect, the rats consumed about 24 g food in the 30 min test. The benzodiazepine receptor antagonist, Ro15-1788 (2.5-40.0 mg/kg i.p.) had no effect on food intake when given alone, but did dose-dependently attenuate chlordiazepoxide's hyperphagic effect. The antagonist CGS 8216 (5.0-20.0 mg/kg i.p.) completely abolished the hyperphagic effect, and in doses of 10.0 and 20.0 mg/kg produced significant suppression of feeding when administered by itself. ZK 93 426, in doses (0.625-10.0 mg/kg i.p.) which have previously been shown to antagonize the discriminative cue of chlordiazepoxide produced no significant change in chlordiazepoxide's hyperphagic effect. These data point to an interesting and important distinction between ZK 93426 and the other two benzodiazepine receptor antagonists when given in combination with chlordiazepoxide in the palatable food consumption test.     

Modulation of cholinergic activity and the aversive threshold in the rat

The analgesic potency of atropine sulfate (5.0, 10.0, 20.0, 40.0 mg/kg), eserine sulfate (0.5, 1.0, 1.5 mg/kg), pilocarpine nitrate (5.0, 10.0, 20.0 mg/kg), scopolamine methylbromide (0.5, 1.0 mg/kg) and scopolamine hydrobromide (1.0 mg/kg) was measured in the rat using the spatial preference technique. Enhanced cholinergic tone via the administration of eserine or pilocarpine in conjunction with scopolamine methylbromide produced significant increments in the aversive threshold. These increments could not be accounted for solely by changes in motor activity or the debilitating effects of enhanced peripheral cholinergic stimulation. None of the anticholinergics tested affected the aversive threshold. Scopolamine hydrobromide (1.0 mg/kg), however, was able to fully block the increments in the aversive threshold noted after the administration of pilocarpine (10.0 mg/kg). These results were interpreted to suggest that agents which enhance cholinergic tone can produce significant analgesia in the rat. While no firm conclusions can be made without further evidence, especially with regard to the antianalgesic effects of the anticholinergics, it is possible that central cholinergic mechanisms may mediate the aversive qualities of electric shock in the rat.     

Effects of scopolamine,amphetamine and chlordiazepoxide on punishment

The hypothesis that behavioral suppression due to punishment requires the intact activity of an inhibitory cholinergic CNS mechanism is examined in three experiments in rats and squirrel monkeys. Scopolamine hydrobromide and scopolamine methyl nitrate decreased further operant lever pressing which was suppressed by intermittent or continuous punishment, but scopolamine hydrobromide had a dose-dependent slight facilitatory effect on punished dextrose solution intake in monkeys and non-reinforced operant lever pressing in rats. d-Amphetamine enhanced non-reinforced responding drastically, and had a dose-dependent biphasic effect on intermittently punished operant lever pressing in rats and punished consummatory behavior in monkeys. Chlordiazepoxide consistently enhanced behavior which was suppressed by various punishment procedures; however, response suppression due to non-reinforcement remained unaltered by chlordiazepoxide. It was concluded that only few drug effects on behavior which is suppressed by punishment or non-reinforcement can be accounted for by the drugs' disinhibitory action on a cholinergic CNS mechanism or by the response rate dependency principle.This research report is based on Chapter II of a dissertation submitted to the University of Chicago in partial fulfillment of the requirements for the Ph. D. degree.     

A comparative study of the behavioral effects of scopolamine and 4-(1-naphthylvinyl) pyridine hydrochloride (NVP), an inhibitor of choline acetyltransferase

A selective inhibitor of choline acetyltransferase, 4-(1-naphthylvinyl) pyridine hydrochloride (NVP), was compared with a central cholinergic antagonist, scopolamine, in a number of behavioral procedures in rats. Scopolamine (1 mg/kg, i.p.) caused alterations in performance of animals trained on nondiscriminated avoidance, punishment discrimination and conditioned suppression behavior, and had no effect on discrete avoidance behavior after doses as high as 8 mg/kg. After nonataxic doses (10–50 mg/kg, i.p.), NVP had no inhibitory effects in these behavioral schedules, and only after higher doses (100–200 mg/kg, i.p.) was an inhibitory effect on discrete avoidance obtained. It is suggested that less than complete inhibition of choline acetyltransferase does not provide sufficient attenuation of central cholinergic function to mimic the behavioral effects of a cholinergic antagonist. NVP was found to potentiate the pharmacological effects of chlorpromazine and physostigmine, suggesting an inhibitory action on drug metabolizing enzymes; it also had a protective effect upon maximal electroshock seizures in mice.Presented in part at the 7th International Congress of the Collegium Internationale Neuro-Psycho-Pharmacologicium, Prague, Czechoslovakia, August 1970     

Alterations by centrally acting drugs of the suppression of self-stimulation behavior in the rat by tetrabenazine,physostigmine, chlorpromazine and pentobarbital

The effects of pre-treatment (32 min) with d-amphetamine (2 mg/kg), scopolamine (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) were studied on the suppression of self-stimulation behavior in the male albino rat by central depressants. The antagonism of each compound was determined against the suppressant action of tetrabenazine (2 mg/kg), physostigmine (0.1 mg/kg), chlorpromazine (2.5 mg/kg) and pentobarbital sodium (10 mg/kg).Against the suppression produced by tetrabenazine, only d-amphetamine gave partial protection throughout the test. Scopolamine and chlordiazepoxide had a transient delaying action. Against the suppressant effect of chlorpromazine, protection was given by d-amphetamine, scopolamine and chlordiazepoxide.Against physostigmine, scopolamine gave full protection, d-amphetamine partial protection, and chlordiazepoxide was without effect.Against the effect of pentobarbital on self-stimulation behavior, there was no protection by d-amphetamine and scopolamine when the animal showed motor deficits, and a stimulant action when these had worn off, but the rates of responding were still depressed. Chlordiazepoxide potentiated the action of pentobarbital.These results are interpreted in terms of a short-run stimulant action on depressed rates of responding, and a longer-run protective action against changes produced by the compounds suppressing self-stimulation behavior in levels of transmitter-like substances.Supported by grant MH-16978, U. S. Public Health Service.The author is indebted to Mrs. S. Foster and Mrs. H. Cevallos for technical assistance.     

Effects of azaprophen, scopolamine and trihexyphenidyl on schedule-controlled behavior, before and after chronic physostigmine

The effects of the muscarinic acetylcholine receptor antagonists, azaprophen (0.3-10.0 mg/kg), scopolamine (0.01-3.0 mg/kg) and trihexyphenidyl (0.3-10.0 mg/kg) were examined in rats using a VI 18 s schedule of food reinforcement, before and after chronic physostigmine administration. All three compounds produced dose-dependent decreases [corrected] in the rate of responding. Scopolamine was more potent than trihexyphenidyl which was equipotent to azaprophen. All three compounds antagonized the response rate-decreasing effects of physostigmine in a dose-dependent fashion. Following 43 consecutive daily administrations of physostigmine (0.4 mg/kg), partial tolerance developed to its response rate-decreasing effects. When the three antagonists were again examined (alone and in combination with physostigmine), their effects were generally unchanged. These results further characterize the behavioral effects of azaprophen, scopolamine and trihexyphenidyl. These results also suggest that tolerance to physostigmine's effects can be mediated through behavioral rather than pharmacological mechanisms.     

Assessment of a cholinergic contribution to chlordiazepoxide-induced deficits of place learning in the Morris water maze.

This investigation sought to characterize the interaction between benzodiazepine and cholinergic systems in place learning in the Morris water maze. In the first experiment, rats were treated with scopolamine (1 mg/kg) alone or concomitantly with one of two doses of flumazenil (15 and 30 mg/kg) or with chlordiazepoxide (5 mg/kg) alone or concomitantly with flumazenil (15 mg/kg). Chlordiazepoxide and scopolamine severely impaired place learning but not cue learning. The low dose of flumazenil completely reversed the impairment produced by chlordiazepoxide and both high and low doses of flumazenil attenuated the place learning deficit produced by scopolamine. Neither dose of flumazenil affected place learning when administered alone. In the second experiment, rats were administered chlordiazepoxide (5 mg/kg) or scopolamine (1 mg/kg) alone or concomitantly with one of four doses of physostigmine (0.05, 0.10, 0.25, and 0.5 mg/kg). Once again, both chlordiazepoxide and scopolamine impaired place but not cue learning. Physostigmine reversed the impairment produced by scopolamine in a dose-dependent manner but failed at every dose to attenuate the impairment produced by chlordiazepoxide. The higher doses of physostigmine impaired place learning when administered alone. None of the drug treatments impaired cue learning. Together, these results suggest that the scopolamine-induced impairment of place learning is due to an increase in benzodiazepine/GABA activity, and contradict the notion that benzodiazepines impair memory by cholinergic mechanisms.     

Intraspecies aggression in rats: Effects of d-amphetamine and chlordiazepoxide

d-Amphetamine sulfate and chlordiazepoxide hydrochloride, administered to either the dominant or subordinate rat, altered several components of fighting behavior in a dose-dependent biphasic manner. Stereotypic sequences of attack, threat, defense, and submission were generated between pairs of previously isolated Sprague-Dawley rats by extinction of a food-reinforced response. Low doses of amphetamine (0.05, 0.1 mg/kg) and chlordiazepoxide (2.5, 5.0 mg/kg) given i.m. to the dominant rat 30 min prior to 15 min tests increased attack bites and leaps and the display of aggressive postures and threats, whereas higher doses of both drugs (0.5, 1.0 mg/kg amphetamine; 20 mg/kg chlordiazepoxide) suppressed attacks and threats. Amphetamine and chlordiazepoxide, administered to the subordinate rat, caused a more prolonged display of submissive-supine and defensive-upright postures; chlordiazepoxide (10.0, 20.0 mg/kg) prolonged immobile crouching whereas amphetamine (0.5, 1.0 mg/kg) greatly reduced this response. Drugged subordinate rats also provoked more attacks and threats by the non-drugged opponents. The multi-response analysis of fighting reveals that various elements of aggressive and defensive-submissive behavior patterns are differentially sensitive to drug action. The results indicate that amphetamine and chlordiazepoxide can facilitate or inhibit attack or defense depending on the dose level and which of the opponents was injected, but do not reverse dominance-subordination relationships.     

Effects of d-amphetamine and of diazepam on non-punished and punished schedule-induced drinking in rats

Drinking induced in food-deprived rats by a Fixed-Time 1min schedule of food presentation was measured by the amount of water consumed per session and the number of licks per inter-food interval. Subsequently each lick initiated a 10-sec signalled delay in the delivery of food, which led to a decrease in drinking (punishment). With three rats the effects of d-amphetamine (0.25, 0.5, 1.0, 2.0mg/kg) were assessed on non-punished and then on punished drinking. With another three rats, the effects of diazepam (0.5, 1.0, 2.0, 4.0mg/kg) were assessed. The smaller doses of d-amphetamine had no consistent effect on overall measures of non-punished schedule-induced drinking, but the largest dose decreased them. With the signalled delay d-amphetamine increased punished schedule-induced drinking. Non-punished drinking was increased by small doses of diazepam and decreased by the largest dose, but no dose of diazepam affected punished drinking.     

A two-compartment exploratory model to study anxiolytic/anxiogenic effects of drugs in the rat

The response of a recently described light/dark choice novelty situation to anxiolytic and non-anxiolytic agents as well as to putative anxiogenic drugs was assessed in rats. Diazepam (1.0-10.0 mg/kg, i.p.), chlordiazepoxide (2.5-10.0 mg/kg, i.p.), and pentobarbital (pentobarbitone) (7.5-15.0 mg/kg, i.p.) enhanced rats' activity in the dark and brightly lit compartments as well as crossings between the two, while imipramine (5-20 mg/kg, i.p.) had no effects. None of these drugs changed animal locomotion in activity cages. d-Amphetamine (1.5 mg/kg, i.p.) caused a significant increase in the three parameters used to measure rats' exploratory activity, but the effect was due to an increase in the general activity of the animal. No tolerance to the effects of diazepam developed after daily treatment with 5 mg/kg i.p. for 15 days. Non-sedative and non-convulsant doses of putative anxiogenic drugs such as yohimbine (2.5-5.0 mg/kg, i.p.), picrotoxin (2.0-4.0 mg/ml, i.p.) and ethyl-beta-carboline-3-carboxylate (2.5-5 mg/kg, i.p.) reduced the exploratory activity of rats in the dark compartment. The advantages and problems of using this test to identify anxiolytic and anxiogenic drugs are discussed.     

Pro-cognitive effects of 5-HT<Subscript>6</Subscript> receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex

Rationale 5-HT₆ receptor antagonists improve cognitive processes in rodents. However, their site(s) of action remains unexplored and their influence upon social memory has been little investigated. Objectives We examined the influence of 5-HT₆ receptor ligands upon social memory in rats by use of systemic or local administration into the frontal cortex (FCX), striatum, or nucleus basalis magnocellularis (NBM). Materials and methods The social recognition test is based upon the ability of an adult rat to recognize a younger conspecific during the second of two 5-min sessions. In a procedure without an inter-session interval, the actions of drugs alone and the ability to reverse “amnesia” induced by the muscarinic antagonist, scopolamine (1.25 mg/kg, s.c.), were examined. The potential promnesic effect of drugs was also investigated in another procedure where a spontaneous deficit of recognition was induced by a 120-min inter-session interval. Results The 5-HT₆ receptor agonist, WAY-181187 (10.0 mg/kg, i.p.), significantly impaired social recognition. This effect was abolished by the 5-HT₆ receptor antagonists, SB-271046 (20.0 mg/kg, i.p.) and SB-258585 (10.0 mg/kg, i.p.). These agents also abolished scopolamine-induced amnesia (10.0 and 2.5 mg/kg, i.p., respectively) and reversed the delay-induced deficit (10.0–20.0 and 2.5–10.0 mg/kg, i.p., respectively). WAY-181187 into the FCX significantly impaired social recognition (0.16–0.63 μg/side). Conversely, SB-271046 into the FCX (2.5–5.0 μg/side), but neither into the striatum nor the NBM, significantly reversed spontaneous deficit. Conclusion These results indicate that 5-HT₆ receptors modulate social recognition by actions in the FCX and underpin their pertinence as targets for the treatment of psychiatric disorders in which cognitive function is compromised.     

Effects of drugs on behaviour of aggressive mice

1 The occurrence of 11 aggressive and non-aggressive activities was observed in aggressive male mice treated with drugs in paired interactions with non-aggressive males given water. Effects of chlordiazepoxide, diazepam, barbitone, chlorpromazine, imipramine, (+)-amphetamine, lysergic acid diethylamide (LSD) all given orally and of intraperitoneal scopolamine were investigated.2 Scopolamine (0.25 and 0.75 mg/kg), (+)-amphetamine (0.25 and 1 mg/kg), chlorpromazine (2.5 mg/kg), diazepam (10 mg/kg) and chlordiazepoxide (50 mg/kg) reduced aggressive activities (attacks, aggressive unrest) without inhibiting walking across the cage or rearing in the aggressive mice. Thus, the inhibition of aggression induced by these drugs does not seem to be due to neuromuscular impairment and seems to this extent specific. On the other hand, imipramine lessened aggressive activities only at a dose (80 mg/kg) which also decreased walking across the cage and rearing. Barbitone or LSD did not change aggression at either dose tested (20 and 60 or 0.01 and 1 mg/kg, respectively). Aggressive activities were increased significantly only by chlordiazepoxide at a dose of 5 mg/kg.3 (+)-Amphetamine (0.25 mg/kg) and scopolamine (0.75 mg/kg) increased escapes and alert postures, respectively, in the aggressive mice.4 Diazepam and chlordiazepoxide decreased tail rattling at 1 and 5 mg/kg, respectively, doses 10 times lower than those inhibiting attacks. The other drugs tested inhibited tail rattling only at doses reducing attacks. Tail rattling appears to be a convenient measure for testing effects of drugs on behavioural conflict.5 Diazepam (5 and 10 mg/kg), chlordiazepoxide (20 and 50 mg/kg), barbitone (60 mg/kg) and scopolamine (0.25 and 0.75 mg/kg) increased sociable activities (sniffing, following partners and climbing over them) whereas (+)-amphetamine, chlorpromazine, imipramine and LSD did not. Effects of the drugs on sociable activities in aggressive mice seem to correlate with their action on punished responding and other types of suppressed behaviour.     

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on food and water intake in the rat.

1. Idazoxan (1, 3, 10 mg kg-1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2. The more selective and specific alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg kg-1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3. The peripherally acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.     

Combined use of tertiary amine parasympathomimetics with a quaternary amine parasympatholitic--a new perspective to use parasympathomimetic drugs for systemic analgesia

The interactions on antinociception between a muscarinic agonist arecoline (arec), an anticholinesterase physostigmine (physo) which both cross CNS, and a peripherally acting antimuscarinic hyoscine-N-butyl bromide (hyo), were assessed by tail flick test in mice. All drugs were administered intraperitoneally (i.p.). While hyoscine-N-butyl bromide (0.15 and 4.00 mg/kg, i.p.) did not produce antinociception, physostigmine salicylate (0.3 mg/kg, i.p.) and arecoline hydrobromide (8.00 mg/kg, i.p.) exerted significant antinociceptive effect. In combined applications, physo + hyo (0.075 + 0.15; 0.15 + 0.30; 0.30 + 0.60 mg/kg) and arec + hyo (1.00 + 0.50; 2.00 + 1.00; 4.00 + 2.00; 8.00 + 4.00 mg/kg), respectively, produced significant antinociception and the tail flick latencies produced by physo 0.30 + hyo 0.60 mg/kg and arec 8.00 + hyo 4.00 mg/kg were not significantly different from those of physo 0.30 mg/kg and arec 8.00 mg/kg, respectively, showing that hyo did not antagonise the antinociceptive effects of physo and arec. We believe that combining an centrally acting cholinergic drug applied systemically with a peripherally acting (quaternary amine) antimuscarinic compound might be used as an effective analgesic in clinical practice.     

Cholinergic drug effects on antidepressant-induced behaviour in the forced swimming test

The contribution of anticholinergic effects to the action of desipramine and nomifensine was investigated in the forced swimming test in rats. The immobility time was reduced by high doses of atropine (10-25 mg/kg i.p.) and scopolamine (1.5 mg/kg i.p., 1 and 0.5 h before the test, respectively) and was unaffected by physostigmine (0.25-0.5 mg/kg i.p., 1 h before the test). Unlike atropine (25 mg/kg), scopolamine (1.5 mg/kg) increased motor activity (open-field). The anti-immobility effect of i.p. desipramine (20 or 30 mg/kg) and nomifensine (2.5 or 5 mg/kg), administered 24, 5 and 1 h before the test, was potentiated by scopolamine (0.5-1.0 mg/kg) and antagonized by physostigmine (0.25-0.5 mg/kg). The brain levels of desipramine and nomifensine were unaffected by scopolamine or physostigmine. Motor performance was impaired in rats treated with physostigmine and desipramine whereas hypermotility was observed in rats treated with scopolamine and nomifensine. The anti-immobility effect of atropine (25 mg/kg) and scopolamine (1.5 mg/kg) was not antagonized by physostigmine (0.5 mg/kg). These results indicate that anticholinergic mechanisms alone are not sufficient to influence immobility time and suggest that the cholinergic system may control, the neural circuitry upon which desipramine and nomifensine act to reduce immobility time.     

The morphine sparing effect of physostigmine

The antinociceptive effect of morphine was studied in tail-flick- and acetic acid-induced writhing in mice. Morphine effect was dose-related (1, 2 and 5 mg/kg s.c.). Physostigmine (0.05 and 0.1 mg/kg i.p.) potentiated the antinociceptive effect of morphine, and the anticholinergic, scopolamine (1 mg/kg i.p.), reversed the potentiating effect of physostigmine, indicating the involvement of the cholinergic system in pain. Coadministration of physostigmine would increase the therapeutic index of morphine thereby sparing the dose of morphine and also possibly the side effects including the development of tolerance and addiction.     

Is delay of reward mediated by shock-avoidance behavior a critical targer for anti-punishment effects of diazepam in rats?

The present study investigated in rats whether variables which may affect the animals' tolerance for delay of reward could be critical for the benzodiazepine-induced release of punished behavior. Rats were subjected to conflict situations during which signalled FR4 non-punished periods (lights-off) alternated with punished periods of different durations signalled by lights-on stimuli. Lever presses during punished periods resulted in the delivery of both one food-pellet and one electric foot-shock (0.45 mA). The antipunishment effect of diazepam (2 mg/kg IP) clearly depended on the duration of the punished periods, release of punished behavior being observed only when punished periods exceeded 1 min. The duration of punished periods required for diazepam-induced release of responding was affected by factors which modified the contrast between rewards received in punished and non-punished periods. One of these factors was the FR schedule imposed during non-punished periods, since the anti-punishment effect of diazepam was observed during short-lasting (30-s and 1-min) punished periods separated by FR24 non-punished periods. A second factor was the ratio of the durations of punished and non-punished periods: diazepam released behavior during 2-min punisheds when the duration of the intercurrent non-punished periods was 1 min, but not when it was 4 min. The predictability of the duration of the punished periods also modulated the effect of diazepam since: with 1 min punished periods, diazepam released punished responding during the first exposures of the rats to the experimental session, but lost part or all its efficacy in animals extensively trained to the procedure.It is tentatively proposed that not only punishment, but also delay of reward induced by passive avoidance of the punished response, are affected by benzodiazepines.     

Effect of minor tranquilizers, tryptamine antagonists and amphetamine on behavior punished by brain stimulation

Earlier observations have shown that septal lesions released operant responding punished by foot-shock, but did not change behavior punished by electrical stimulation of the dorsal periaqueductal gray (DPAG) substance of the rat brain. In contrast, chlordiazepoxide facilitated both kinds of punished responding. In order to further study the mechanism of brain stimulation punishment, dose-response curves of two minor tranquilizers, chlordiazepoxide and pentobarbital, of two tryptamine antagonists, methysergide and cyproheptadine as well as of amphetamine on lever-pressing behavior of rats maintained by water reinforcement and punished by DPAG stimulation were determined. A multiple schedule with a variable-interval 2 min (VI 2) non-punished component and a continuous reinforcement (CRF) component in which every response was both rewarded and punished was used. Chlordiazepoxide and pentobarbital caused dose-dependent increases in punished responding. Unpunished VI response rates were also moderately increased by the minor tranquilizers. In contrast, neither methysergide nor cyproheptadine increased punished or unpunished responding at doses that have been previously shown to markedly release behavior punished by foot-shock, in the rat. Conversely, amphetamine, a drug that usually does not release responding punished by peripheral noxious stimulation, caused dose-dependent increases in responding suppressed by DPAG punishment without affecting VI response rate. These and previous results with septal lesions suggest that neither the septo-hippocampal system nor its serotonergic input from the mesencephalon mediate response suppression by DPAG electrical stimulation, in contrast to their active role in peripheral punishment. This difference may also explain the marked facilitatory effect of amphetamine on responding punished by brain stimulation shown by the present results.     

Modelling the anxiety-depression continuum in chicks

The clinical syndromes of anxiety and depression are now thought to exist along a temporal continuum and this construct has been modelled in a preclinical setting in chicks separated from conspecifics. This research sought to further the validity of the chick anxiety-depression continuum model. Dose-response studies using two classes of anxiolytics (chlordiazepoxide: 2.5, 5.0, 10.0, 15.0 mg/kg, and clonidine: 0.1, 0.15, 0.2, 0.25 mg/kg) and three classes of antidepressants (imipramine: 1.0, 3.0, 10.0, 15.0 mg/kg, maprotoline: 2.5, 5.0, 10.0, 20.0 mg/kg and fluoxetine: 1.0, 5.0, 10.0, 20.0 mg/kg) showed an ability to detect anxiolytic activity of chlordiazepoxide, clonidine, imipramine and maprotoline in the anxiety-like phase of the model and to detect antidepressant effects of imipramine, maprotoline and fluoxetine in the depression-like phase of the model. In addition, blood plasma interleukin-6, a biomarker of stress, was found to be elevated in response to social-separation stress. Collectively, these findings further characterize the model as a simulation of the anxiety-depression continuum and begin to establish the paradigm as a high-utility adjuvant to rodent screening assays for putative anxiolytic and antidepressant compounds.