The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons.

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Effects of procedural parameters on response accuracy: lessons from delayed (non-)matching procedures in animals.

The experimental analysis of behaviour in operant paradigms has identified numerous variables which affect performance. We will focus on the delayed (non-)matching tasks in order to illustrate the influence of procedural variables on acquisition and performance in operant tasks of cognitive function. Systematic variation of these parameters can help dissociate different cognitive processes which may be differentially affected by drug treatment or brain lesions. Use of different parameters, however, could equally account for controversial drug or lesion effects reported in the literature. Consideration of these factors will increase our understanding of the relative contribution of these and other features and parameters of the procedural arrangements to the final behavioural outcome.

Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex.

The morphological and behavioral effects of neonatal electrothermal lesions of the mediodorsal thalamus on the development of the prefrontal cortex were studied. Lesions of the mediodorsal nucleus (MDT), inflicted on the day of birth, caused no significant changes in prefrontal architecture on day 35. On the other hand, a significant decrease in cortical width (4.7-7.7%) was observed at some places within the lateral and supragenual parts of the prefrontal cortex. However, these local decreases in cortical width were not reflected by a significant decrease of the total volume of the particular prefrontal subareas. In adulthood, rats with neonatal MDT lesions were exposed to an operant delayed alternation task, which is known to depend upon the integrity of the prefrontal cortex, in order to investigate the behavioral consequences of the lesions for prefrontal functioning. The lesions did not impair the rats abilities to learn the spatial delayed alternation task. Neonatally lesioned and control rats scored equally. Given the relatively mild effects of MDT lesioning, thalamic fibers do not seem to play a crucial role, at least not during the postnatal period of prefrontal cortical development. It is discussed whether or not this is a specific characteristic of agranular association cortex, in which the termination of thalamic and cortical afferents overlap in layer III.

Effects of local application of dopaminergic drugs into the dorsal part of the medial prefrontal cortex of rats in a delayed matching to position task: comparison with local cholinergic blockade.

Lesions of the medial prefrontal cortex (mPFC) disrupt performance in a variety of delay tasks, which suggests that the mPFC supports short-term memory processes. The putative involvement of the dopaminergic innervation of the mPFC in these mnemonic processes was investigated by evaluating the effects of local infusions of dopaminergic drugs into the mPFC of rats in an operant delayed-matching-to-position (DMTP) task. Trained animals were provided with bilateral guide cannulae aimed at the dorsal part of the mPFC. Two separate groups of rats were tested after microinfusion of several doses of either the dopamine agonist apomorphine (APO) or the dopamine antagonist cis-flupenthixol (FLU). In addition, all animals were tested after infusion of several doses of the muscarinic antagonist scopolamine (SCO). Animals were tested 0 and 135 min after each infusion. At the 0 min interval, neither APO nor FLU affected accuracy of DMTP performance, while both drugs dose-dependently increased response latencies and decreased nosepoke frequencies. At the 135 min interval, APO had almost no effect, whereas the effects of FLU were very prominent. A number of animals no longer responded after infusion of the highest doses of FLU and those that did showed a delay-independent decrease in response accuracy. In contrast, SCO infusions into the mPFC induced a dose- and delay-dependent deterioration of DMTP performance. Taken together, these results support a direct involvement of the rat mPFC in short-term memory processes, although they implicate cholinergic rather than dopaminergic mechanisms in this function.

Preclinical evidence on the psychotropic profile of fluvoxamine.

Serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluvoxamine are interesting compounds. Initially launched as antidepressants, they have been found to be active in various psychiatric disorders besides depression, including obsessive-compulsive disorder, panic disorder, and eating disturbances. Preliminary data suggest their efficacy in alcohol and drug abuse, aggression, and posttraumatic stress disorder as well. Along with those clinical findings, new preclinical data have emerged. For example, fluvoxamine has demonstrated activity in various models of anxiety in rodents. Its anxiolytic activity can be clearly discriminated from that of the benzodiazepines. In the DRL 72-sec paradigm, fluvoxamine exhibits a good antidepressant profile, similar to those of imipramine and flesinoxan. Studies have shown that fluvoxamine does not down-regulate beta-adrenoceptors; apparently, that property is not a conditio sine qua non for antidepressant activity. Results of studies of the mechanism of action of fluvoxamine in which drug discrimination tests were performed with rats and pigeons suggest that the fluvoxamine stimulus is not (or is only to a very limited degree) dependent on activation of 5-HT1A receptors or 5-HT1B/1D receptors, or both. Experimentation is ongoing in those animal models.

Assessment of the stimulus properties of anxiolytic drugs by means of the conditioned taste aversion procedure.

The conditioned taste aversion (CTA) procedure has recently been described as a more rapid alternative to two-lever operant procedures in drug discrimination research. We trained different groups of rats to discriminate the benzodiazepine chlordiazepoxide (CDP, 20 mg/kg) or the 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.4 mg/kg) from saline by means of the CTA procedure. The results were in agreement with findings from two-lever operant drug discrimination procedures. However, discrimination training took 40 sessions in the case of CDP and 72 sessions for 8-OH-DPAT, which is comparable to results obtained with two-lever operant procedures. Dose-response curves were determined and generalization tests were performed for different benzodiazepine and nonbenzodiazepine anxiolytics. Baseline behavior deteriorated in the course of generalization and substitution testing, thus preventing further generalization testing. Our experience is that the use of the CTA procedure in drug discrimination research does not have sufficient advantages over traditionally used procedures to replace the latter.

Flesinoxan shows antidepressant activity in a DRL 72-s screen.

Schedules which selectively reinforce low rates of responding (DRL, differential reinforcement of low rate) distinguish between antidepressants and other types of drugs. In a DRL schedule a subject is required to pause for a specified minimum period of time between two consecutive responses in order to obtain a reinforcer. The dependent variables are rate of responding and rate of reinforcement. Response patterns of rats treated with clinically effective antidepressant drugs such as imipramine (2.0-32.0 mg/kg) or fluvoxamine (4.0-32.0 mg/kg) are characterized by a decrease in response rate and an increase in reinforcement rate. Treatment with the 5-HT1A agonist flesinoxan (0.1-3.0 mg/kg) also dose-dependently decreased response rates while at the same time increasing reinforcement rates. Chlordiazepoxide (2.5-20.0 mg/kg) and diazepam (0.25-2.0 mg/kg) had no effects in the present experiment. d-Amphetamine increased response rates at low doses (0.5-2.0 mg/kg), and decreased it at the higher doses (4.0 mg/kg), but reinforcement rates were unaltered. Overall analysis of the effects of haloperidol (0.02-0.32 mg/kg) showed decreased responding and increased reinforcement rates. Post hoc analysis, however, clearly differentiated between haloperidol's profile and that of the antidepressants. As such, the results of the present experiment show that flesinoxan might possess antidepressant activity in humans.

Preclinical evidence for the role of serotonin receptor-subtypes in depression.

Serotonin (5-HT) plays an important role in depression and specific 5-HT reuptake blockers appear to be clinically important antidepressants. It is unclear however, which serotonergic mechanism is involved in the antidepressant effect, certainly when regarding the existence of at least seven 5-HT receptor subtypes. By testing different 5-HT ligands in two animal models of depression (forced swimming and DRL72-S test) and comparison with data from literature, evidence is provided for potential antidepressant qualities of 5-HT1A receptor-agonists and 5-HT1C receptor-antagonists. Compounds binding to 5-HT1B, 5-HT2 and 5-HT3 receptors do not have an antidepressant profile. Results of clinical research support the predicted antidepressive effects of 5-HT1A receptor-agonists.

Sex-dependent effects of inescapable shock administration on shuttlebox-escape performance and elevated plus-maze behavior.

The present experiment investigated the effects of exposure to inescapable shocks (IS) on subsequent behavior in an elevated plus-maze and on shuttlebox-escape performance in male and female rats. In the elevated plus-maze, exposure to IS resulted in suppression of "total number of arm entries" and "rearings" in males but not in females. In addition "time on open arms" was reduced in both sexes after exposure to IS, but this effect seemed stronger in males than in females. Exposure to IS disrupted shuttlebox-escape performance of males, whereas escape performance of females was unaffected. Affected escape performance in males was transient and limited to the initial phase of escape training. A sex difference in emotional reaction to stress might contribute to the observed sex difference in the acquisition of an escape response. The strong passive avoidance tendency observed in males, which may be strengthened by IS, strongly interferes with the acquisition of the escape response by this sex, resulting in sex differences in susceptibility to behavioral disturbances induced by IS.

Scopolamine differentially disrupts the behavior of male and female Wistar rats in a delayed nonmatching to position procedure.

Evidence is available that pharmacological interference with the cholinergic system may disrupt behavior in experimental procedures designed to investigate learning and memory processes. Recently it has been suggested that the cholinergic system may be sexually dimorphic. The present experiment was designed to investigate whether or not manipulation of the cholinergic system differentially affected memory processes in both sexes. Male and female Wistar rats were exposed to a delayed nonmatching to position procedure and were challenged with increasing doses of scopolamine hydrobromide (a central and peripheral muscarinic receptor blocker) and scopolamine methyl bromide (which does not pass the blood-brain barrier). Response accuracy decreased in both sexes as the delay interval duration increased. Behavioral differences between saline-treated males and females were not observed. Response accuracy decreased dose-dependently after subjects were injected with scopolamine hydrobromide. Response accuracy also decreased after treatment with scopolamine methyl bromide, but to a smaller extent. Males showed less accurate responding after treatment with either drug than females. These results provide behavioral evidence for the hypothesis that cholinergic functioning may differ between the sexes.

Fixed-consecutive-number performance in male and female Wistar rats.

The present experiment was designed to investigate whether or not response rate differences between male and female Wistar rats observed in many different experimental procedures could be attributed to sex differences in behavioral perseverance, as has been suggested by the results of previous experiments. Male and female Wistar rats were thus exposed to different fixed-consecutive-number schedules of reinforcement. Fixed-consecutive-number schedules require subjects to emit a specified number of responses on one (work) lever, before a response on another (food) lever results in the presentation of reinforcement. The response requirement on the work lever was manipulated in different experimental conditions. Subjects had to emit between 3 and 7, 8 and 12 or 13 and 17 responses on the work lever before a response on the food lever produced reinforcement. When subjects emitted fewer or more than the required number of responses on the work lever, a 5-s time-out period was presented. Males responded at higher rates than females during all experimental conditions; response rates of males and females increased as the response requirement on the work lever was increased. Sex differences in response efficiency were not observed, but males seemed to reach final response efficiency faster than females. Response efficiency decreased as the response requirement on the work lever was increased. Error analysis showed that both males and females made more errors by not producing enough responses on the work lever than by producing too many. However, males were more likely than females to emit more responses than the requirement on the work lever, while females were more likely than males not to produce enough responses on the work lever.

Visual and auditory delayed discriminations in male and female Wistar rats.

Different groups of male and female Wistar rats were exposed to a discrete-trial delayed discrimination procedure, in which subjects were required to discriminate between a continuously or intermittently presented visual (half of the subjects) or auditory (other half of the subjects) stimulus. The opportunity to respond was delayed for 0, 5, 10 or 20 s after stimulus presentation. Both response levers were inserted into the experimental chamber immediately upon the termination of the delay interval. A press on the left lever was followed by food if the continuous stimulus had been presented, while food was presented following a press on the right lever if the intermittent stimulus had been presented. During sessions 1-60, each incorrect response or failure to respond during the 5-s lever presentation was followed by presentation of the same visual or auditory stimulus, and the same delay interval, once the intertrial interval was terminated. This sequence was repeated until a correct response occurred. During sessions 61-90, repeated presentations of the same trial following incorrect responses or a failure to respond on initial trials were no longer presented. All other experimental contingencies remained unchanged. Response accuracy increased with prolonged training. Subjects exposed to the visual delayed discrimination procedure showed less accurate performance than subjects who were exposed to the auditory delayed discrimination procedure. Response accuracy was higher when the delay interval was short than when it was long. Males made more correct responses than females.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral differences between male and female rats: effects of gonadal hormones on learning and memory.

The organizational, activational and reorganizational effects of gonadal hormones have been extensively investigated with respect to sexual, aggressive and maternal behavior. It has thus been established that manipulations of gonadal hormones during critical periods in development functionally affect reproductive behavior. The effects of gonadal hormones on nonreproductive behavior are not immediately obvious because of the fact that the behavioral effects of gonadal hormones on learning and memory have been investigated in a large number of unrelated experimental procedures. The present paper provides an organized overview of these different experimental procedures, summarizes the most important findings and discusses some of the variables which determine the effects of manipulations in gonadal hormones on learning and memory in male and female rats.

Scopolamine and methylscopolamine differentially affect fixed-consecutive-number performance of male and female Wistar rats.

Male and female Wistar rats were trained on a fixed-consecutive-number schedule in which a response on a food lever was followed by the presentation of reinforcement when at least three, but not more than seven responses had been completed on a work lever. Subjects were treated with different doses of the centrally acting cholinergic antagonist scopolamine hydrobromide or the more peripherally active cholinergic antagonist scopolamine methylbromide (0.08, 0.16 or 0.32 mg/ml/kg) once behavior had stabilized. Scopolamine hydrobromide and scopolamine methylbromide dose-dependently decreased response rates in males and females. Scopolamine methylbromide decreased response rates more than equivalent doses of scopolamine hydrobromide and the rate-suppressant effects of both drugs were more marked in males than in females. Scopolamine hydrobromide dose-dependently decreased response accuracy, but differences between males and females were not observed. Response accuracy also decreased after scopolamine methylbromide, but did not vary as a function of the dose of the drug. The decrease in response accuracy induced by both drugs was attributable to an increase in the percentage of trials with a premature switch from the work lever to the food lever. Both scopolamine hydrobromide and scopolamine methylbromide dose-dependently increased the number of premature switches. Differences between males and females were not observed. Administration of scopolamine hydrobromide and scopolamine methylbromide also decreased the number of obtained reinforcers in a dose-dependent manner. Females obtained significantly fewer reinforcers than males, while scopolamine methylbromide affected the number of obtained reinforcers to a larger extent than scopolamine hydrobromide.

The effects of scopolamine and methylscopolamine on visual and auditory discriminations in male and female Wistar rats.

The present experiment was designed to investigate whether or not the administration of scopolamine hydrobromide would differentially disrupt auditory or visual discrimination performance in male and female Wistar rats. Two groups of male and female Wistar rats were trained to discriminate between a continuous and intermittent visual stimulus, while two other groups were trained to discriminate between a continuous or intermittent auditory stimulus in a discrete-trial discrimination procedure. Once discrimination performance had stabilized, subjects were treated with different doses (0.125, 0.25, 0.50 or 1.0) of scopolamine hydrobromide or scopolamine methylbromide. Treatment effects were assessed with respect to discrimination performance, as well as with respect to the number of trials which were not completed. Scopolamine hydrobromide, but not scopolamine methylbromide, disrupted visual and auditory discrimination performance. The auditory discrimination was more seriously disrupted. However, both the administration of scopolamine hydrobromide and of scopolamine methylbromide increased the number of trials which were not completed suggesting that the accuracy of visual and auditory discriminations after drug treatment may have been influenced by other variables than drug effects on memory processes. Sex differences were not observed, neither with respect to discrimination performance, nor with respect to the number of trials which were not completed.

Operant conditioning of response variability in male and female Wistar rats.

It has previously been suggested that some of the behavioral differences between the sexes in food motivated operant procedures may be a function of the fact that males are more likely than females to exhibit stereotyped behavior. If such is the case, then it might be expected that behavioral variability is more easily conditioned in females than in males. The present experiment was designed to investigate this notion. Male and female Wistar rats were trained to respond in a procedure in which response variability was explicitly reinforced. In this procedure subjects had continuous access to two response levers in the experimental chamber. In the first experimental condition, each sequence of four responses was followed by the presentation of a food pellet, if the sequence differed from the two sequences which preceded it (Lag 2). Time-out was presented when such was not the case. During time-out the levers were retracted from the chamber and all stimulus lights were extinguished for 4 sec. In subsequent experimental conditions, subjects had to produce four-response sequences which differed from the preceding four, eight and sixteen sequences respectively (Lag 4, 8, 16). Response sequences were classified by the number of switches between levers. Behavioral variability increased as the lag requirement was increased, showing that variability is a conditionable dimension of behavior. Differences between males and females were however not observed. These results thus contradict the previously reported finding that males exhibit more behavioral stereotypy than females. It is suggested that procedural variables may account for these seemingly contradictory findings.

Perseverative responding in male and female Wistar rats: effects of gonadal hormones.

Response perseveration was investigated in an experimental procedure which has previously been shown to be sensitive to pharmacologically induced behavioral perseveration and response stereotypy. Different groups of intact, gonadectomized, and gonadectomized plus chronically testosterone-treated male and female Wistar rats were exposed to this procedure in which reinforcers were randomly assigned to one of two levers in an operant chamber. One response on the lever to which the reinforcer was assigned was sufficient to produce a food pellet. Response perseveration, defined as the percentage of trials on which more than one response on the lever not selected for reinforcement was made prior to switching to the selected lever was highest in testosterone-treated subjects. Females made more responses on the lever which had been selected for food on the preceding trial, suggesting that females may be more sensitive than males to the consequences of their behavior. This behavioral difference between the sexes may be mediated by the male hormone testosterone.

The acquisition of visual and auditory discriminations in male and female Wistar rats.

Different groups of male and female Wistar rats were trained to discriminate between visual or auditory stimuli in a discrete-trial experimental procedure. Presentation of one of the two visual stimuli or one of the two auditory stimuli was immediately followed by a 5-s presentation of the two levers. A press on the left lever was followed by food if one stimulus had been presented, while food was presented following a press on the right lever if the other stimulus had been presented. Incorrect responses or failure to respond during level presentation was always followed by presentation of the same visual or auditory stimulus once the intertrial interval had again expired. This sequence was consistently repeated until a correct response occurred. Discrimination performance improved as training progressed. Acquisition of the visual and auditory discrimination did not differ between males and females, although males were more likely than females to respond effectively during repeated trials (those trials which were initially incorrectly completed or not completed at all). The results of the present experiment make it likely that behavioral differences between the sexes in other experimental procedures are not due to differences in sensory discrimination abilities.

Acquisition of conditional associations and operant delayed spatial response alternation: effects of lesions in the medial prefrontal cortex.

In this article 8 male Wistar rats received bilateral lesions of the medial prefrontal cortex, whereas another 8 rats were control operated. Three weeks after surgery, they were exposed to an autoshaping procedure in which the insertion of a lever into the experimental chamber (conditioned stimulus) always preceded the delivery of a response-independent food pellet (unconditioned stimulus). Subjects with lesions acquired this conditional association faster than control-operated subjects as evidenced by the fact that they were more likely than control-operated subjects to contact the conditioned stimulus at higher rates. Locomotor activity, observed in a standard open-field preceding autoshaping sessions, decreased for both groups of subjects with repeated exposure to the open-field, whereas differences between groups were not observed. The same subjects were also exposed to an operant delayed spatial response alternation procedure in which they were required to alternate responding between two levers that were inserted into the experimental chamber after delay intervals of either 5, 10, or 20 s had elapsed. Alternation response accuracy of both subjects with lesions and control subjects decreased as a function of the duration of the delay interval, but control-operated subjects responded more accurately than did lesion subjects at each interval duration. Response accuracy increased with prolonged training for both groups of subjects, but faster for control-operated than for subjects with lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Memory in male and female Wistar rats: effects of gonadectomy, and stimulus presentations during the delay interval.

The present experiment was designed to investigate the effects of gonadectomy on the response accuracy of male and female Wistar rats in an operant delayed spatial response alternation procedure. Subjects were exposed to 3 randomly presented delay intervals during each experimental session (15, 30 and 60 s). Response accuracy decreased as a function of the duration of the delay interval. Prolonged exposure to the experimental procedure differentially affected the behavior of intact and gonadectomized males and females. Intact males showed a more rapid increase in response accuracy as compared to any of the other groups of subjects, but differences in steady-state behavior were not observed. The effect of stimulus presentations during the delay interval on the alternation accuracy of intact and gonadectomized male and female Wistar rats was studied in a second experimental condition. The presentation of stimuli during the delay interval equally affected response accuracy of intact and gonadectomized subjects at all delay interval durations. Differences between the sexes, or between intact and gonadectomized subjects were not observed in the second experimental condition. The results of the present experiments thus suggest that intact and gonadectomized male and female Wistar rats do not differ with respect to memory as measured in operant delayed spatial alternation tasks, since both males and females were equally susceptible to the presentation of stimuli meant to disrupt ongoing memory processes.