Avoidance Responding Research Articles

Avoidance responding and closed-head injury: Replication and reevaluation of the “anticipatory behaviour deficit”

Abstract Previous research suggests that survivors of closed-head injury (CHI), tested while inpatients, took more trials to learn to avoid a noxious noise in a conditioning task than did controls. In contrast, patients with CHI learned to escape at latencies equal to those of controls. The authors attributed these results to defective anticipation of the consequences of either the warning stimulus and/or the subject's own behaviour. They called this pattern of intact escape with putatively impaired avoidance an Anticipatory Behaviour Deficit (ABD). We tried to detect an ABD in nonhospitalized CHI survivors who had sustained an injury significant enough to produce a detectable deficit on a standard neuropsychological battery. The CHI group (n=24) and controls (n=13) had comparable avoidance latencies, escape latencies, and trials to criterion. Both groups escaped more quickly than they avoided. We conclude that ABD may not be ubiquitous in CHI survivors or that it may be a temporary condition, limited to ...

A new computer-assisted two-way avoidance conditioning equipment for rats: Behavioral and pharmacological validation

A new PC-controlled two-way avoidance conditioning equipment for rats is described. The position of the rat within the two-compartment shuttle-box is monitored by means of 4 + 4 horizontal photocell beams. Experimental conditions and procedures, such as CS-UCS interval, photocell operations, shock strength, and so on, can conveniently be preset by the experimenter. The successful operation of the shuttle-box is evidenced by rapid and efficient acquisition of the avoidance behavior, and approximately 100% median avoidance performance was obtained within 5 successive days of training (20–25 trials per day). In a separate experiment, different groups of rats received avoidance training (0–5 sessions) at 8 weeks of age, and a retention avoidance performance was weak ( r = 0.33, NS), and performance during the acquisition process appears to be a poor predictor of final performance. As expected, a number of dopamine (DA) receptor blocking agents (DA D 1 and/or D 2 selective) produced a selective suppression of the avoidance behavior, that is, the suppression of avoidance responding was matched by a corresponding increase in escape responding (with no escape failures).

Effects of dopamine depletions in the medial prefrontal cortex on active avoidance and escape in the rat

Dopamine systems have been implicated in the performance of avoidance behavior, and the dopaminergic innervation of medial prefrontal cortex is known to be responsive to stressful stimuli. In the present investigation, injections of 6-hydroxydopamine were used to produce moderate depletions of dopamine in the medial prefrontal cortex of rats trained to perform an active avoidance/escape task. In this task, 0.5 mA shock was presented for 5 s every 30 s, and the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. Depletion of dopamine in the medial prefrontal cortex did not affect total number of responses, and did not impair avoidance responding (i.e. responding when the shock was off), and in fact dopamine-depleted animals tended to make slightly more avoidance responses than control animals. Prefrontal dopamine depletions did result in a significant decrease in the number of escape responses (i.e. responding to terminate shock when the shock was on). Moreover, dopamine depletions significantly decreased response efficiency, which is an index of the reduction of shock time produced per level pressing response. Previous work has indicated that dopamine antagonists and accumbens dopamine depletions have dramatic effects on avoidance behavior; thus present results indicate that prefrontal cortex dopamine depletions do not mimic the effects of interference with subcortical dopamine systems. The selective effects of dopamine depletions on escape behavior in the present study suggest that rats with medial prefrontal dopamine depletions have an impairment in the ability to respond appropriately to the direct presentation of footshock. These findings may have implications for the functional significance of stress-induced increases in prefrontal cortex dopamine activity.

Uridine potentiates haloperidol's disruption of conditioned avoidance responding

The pyrimidine nucleoside, uridine, has been proposed as a potential supplement in the treatment of psychosis based on its ability to reduce haloperidol-induced dopamine release. These experiments investigated the effect of uridine (32 mg/kg, i.p.) coadministered with the neuroleptic haloperidol, on rats engaged in one way conditioned avoidance responding. Uridine itself had no effect on animals' performance, while haloperidol (dose range 0.05–0.4 mg/kg, i.p., 90 min before test session) decreased number of avoidances and increased avoidance and escape latencies in a dose-dependent manner. When coadministered with haloperidol, uridine significantly potentiated the disruption of avoidance and avoidance latency induced by haloperidol. This potentiation was still evident after chronic (27 days) uridine treatment. Importantly, coadministration of uridine did not potentiate haloperidol-induced increase of escape latency. The potentiation of haloperidol-induced disruption of conditioned avoidance responding suggests that uridine coadministration might enhance the antipsychotic action of traditional neuroleptics. This would allow for a reduction in the therapeutic dose of the antipsychotic, thereby reducing side effect frequency.

Some functional characteristics of avoidance of timeout from response-dependent food presentation in rats

Three male and three female rats were first trained to respond on a Random-Interval 15-s schedule on one (food) lever in a rodent operant conditioning chamber. They were then exposed to a condition in which food could only be obtained during a timein period which lasted 10 s or longer dependent upon whether or not subjects pressed another (avoidance) fever. If subjects did not press the other level during the 10-s timein, a 50-s timeout was presented during which food could not be obtained. Subjects first had the opportunity to avoid timeout presentation by pressing the avoidance level during timein or to escape the timeout by pressing the lever during timeout. A changeover delay of 2-s prevented food presentation immediately following avoidance lever-food lever sequences. All subjects pressed the avoidance lever to avoid or escape timeout, but only one of the subjects consistently pressed the avoidance lever when escape was no longer available. One more subject acquired consistent avoidance responding after reexposure to the avoidance/escape and avoidance only conditions. The four remaining subjects were then exposed to a signalled avoidance procedure in which a 5-s stimulus change preceded timeout presentation. Three of the subjects came to respond reliably on the avoidance lever when switched back to the unsignalled avoidance procedure. One of the subjects never acquired consistent avoidance responding. Functional control by the avoidance contingency was demonstrated during the final two experimental conditions in which the contingencies associated with the avoidance lever were systematically removed and reintroduced.

Methylatropine blocks the central effects of cholinergic antagonists.

These studies were conducted in order to establish the dose dependency and relative peripheral versus central activity of four prototypical cholinergic antagonists on the rodent passive avoidance response, a widely used animal model of retention. Subcutaneous administration of 0.1 to 100mg/kg revealed a potency profile of scopolamine > atropine methylscopolamine >/= methylatropine for the impairment of passive avoidance responding. A series of neurological assessments of the doses used indicated that side effects alone were not sufficient to impair passive avoidance responding. Although inactive when delivered peripherally, methylatropine was able to produce retention deficits at 10nmol (3.66µg) when administered intracerebrally. To further evaluate whether systemic methylatropine could enter the central nervous system, either scopolamine or atropine was administered subcutaneously in mice and rats pretreated with 10-100mg/kg methylatropine. The deficit-producing effects of scopolamine and atropine were abolished with methylatropine. Thus methylatropine is an exclusive peripheral antagonist; its ability to block the deficit-producing effects of scopolamine and atropine may occur through a change in blood-brain barrier permeability or through uncharacterized pharmacokinetic properties.

Leu]enkephalin enhances active avoidance conditioning in rats and mice.

The effects of intraperitoneal (IP) administration of the endogenous opioid peptide, [Leu]enkephalin (LE), on avoidance conditioning in rodents were investigated. At a dose of 30 micrograms/kg (IP), LE enhanced acquisition of a one-way step-through active avoidance response when administered 2 minutes before training to Swiss Webster mice. [Leu]enkephalin produced a U-shaped dose-response function because both lower and higher doses of LE did not affect avoidance responding. [Leu]enkephalin-induced enhancement of avoidance acquisition was also observed in Sprague-Dawley rats; the intraperitoneal injection of 10 micrograms/kg LE, administered 5 minutes before training, enhanced acquisition of a jump-up one-way active avoidance response. When administered to Sprague-Dawley rats immediately after training, LE (30 micrograms/kg IP) enhanced jump-up avoidance responding at test 24 hours after peptide injection. Previously, we found LE to impair acquisition in the same tasks in both rats and mice, also at microgram doses, and also in a U-shaped manner. Thus, LE can either enhance or impair learning within the same species and the same task; these findings are in agreement with recent theoretical proposals regarding the nature of compounds, such as LE, that modulate learning and memory.

Dissociation of behavioral changes in rats resulting from lesions of the habenula versus fasciculus retroflexus and their possible anatomical substrates.

Lesions in either the habenula or its primary efferent pathway, the fasciculus retroflexus (FR), impaired avoidance responding. However, lesions of only the FR provided a persistent elevation of locomotor activity. Immunocytochemical study of the interpeduncular nucleus (IPN) through injection of retrograde tracers into the IPN and the overlying ventral tegmental area indicated that habenular lesions spared both rostral habenula and forebrain projections to the caudal midbrain, but these projections were axotomized by FR lesions. Rostral sparing of the habenula resulted in normal peptidergic staining in the IPN, and normal cholinergic innervation was absent. Performance of individual rats in behavioral tests was consistent with variations in anatomical sparing. Such considerations may account for previous discrepancies in functional effects of habenular lesions.

The quipazine- and YFMPP-increased conditioned avoidance response in rats: Role of 5-HT 1C/5-HT 2 receptors

The role of serotonin (5-HT) in the acquisition of the conditioned avoidance response was investigated. The effects of different serotonin agonists and antagonists, administered prior to learning sessions, were studied in groups of naive rats using the two-way shuttle box. Quipazine, an agonist at 5-HT 1B/1C/2 receptors, significantly increased avoidance responding in a dose-dependent manner (1.25–10 mg/kg, s.c.). The putative 5-HT 1B/1C receptor agonist TFMPP (1-[ m-trifluoromethylphenyl] piperazine) at doses of 1.25 and 2.5 mg/kg (s.c.), increased acquisition of conditioned avoidance but showed no significant difference from control at doses of 5 and 10 mg/kg. The 5-HT 1A agonist, buspirone, significantly decreased acquisition of conditioned avoidance. Increased acquisition of conditioned avoidance induced by either quipazine or TFMPP was effectively antagonized by the mixed 5-HT 1C/2 receptor antagonists, ketanserin (0.2 and 2 mg/kg, s.c.) and mianserin (1 mg/kg, s.c.). In contrast, spiperone (5-HT 1A/2 receptors antagonist: 0.2 mg/kg, s.c.) only inhibited the increased acquisition induced by TFMPP. On the other hand, the 5-HT 1A/1B receptors antagonist, pindolol, failed to antagonize the increase in acquisition of conditioned avoidance caused by quipazine or TFMPP. These results suggest that quipazine increases the conditioned avoidance behaviour by an action that might be mediated through stimulation of 5-HT 1C receptors. The acquisition of conditioned avoidance induced by TFMPP, which was blocked by ketanserin, mianserin and spiperone but not by pindolol, suggests the involvement of 5-HT 1C/2 receptors in the action of TFMPP.

Vasoactive intestinal peptide (VIP) causes memory impairment in passive avoidance responding of the rat

Our previous studies demonstrated that CCK-8 and its analog, cerulein (CER), have a potent preventive action on experimental amnesia, and that VIP has reciprocal action against CCK-8 and CER. Since VIP has been reported to cause amnesia, we carried out the present experiments to confirm this action and to examine the preventive effect of CER on VIP-induced amnesia. In the passive avoidance response, central administration, but not peripheral injection, of VIP caused amnesia; the effective portion of the molecule was found to be located in the N- terminus amino acid sequence. Secretin and PACAP, which have similar molecular structures to that of VIP, had no amnestic action. Preadministration of CER prevented VIP-induced memory deficit. The VIP antagonists did not affect amnesia induced by electroconvulsive shock and scopolamine. It was concluded that CER prevents VIP-induced memory deficit in the passive avoidance response of the rat.

Adenosine agonists reduce conditioned avoidance responding in the rat

Because adenosine agonists may possess therapeutic potential as antipsychotic agents, we examined the activity of several prototypic agents in vivo in blocking conditioned avoidance responding (CAR) in the rat, a behavioral test predictive of antipsychotic efficacy in humans. Potency in blocking CAR is directly proportional to potency in alleviating schizophrenia. Hence, the adenosine A 1-selective agonists [cyclopentyl adenosine (CPA) and ( R)-phenylisopropyl adenosine ( R-PIA)], A 2-selective agonists [CV-1808 and (2-( p-(carboxyethyl)-phenethylamino)-5′- N-ethyl-carboxamido adenosine (CGS 21680)], and a nonselective agonist [5′- N-carboxamido adenosine (NECA)] were examined in this test. Block of CAR was first determined for standard antipsychotic agents [ED 50 mg/kg, IP, and 95% confidence level (CL) in parentheses], such as haloperidol [0.23 (0.18, 0.39)], trifluoperazine [(0.9 (0.7, 1.0)], thioridazine [12.5 (10.5, 15.3)], metoclopramide [7.8 (6.4, 9.2)], and chlorpromazine [4.9 (4.2, 5.9)]. The paradigm consisted of a light- and tone-signaled footshock that could be avoided via a discrete lever press. Affinity for A 1 and A 2 binding sites in brain tissue from Fischer 344 rats was ascertained to be similar to that seen in other rodent strains. Each adenosine agonist blocked CAR. NECA [ED 50 value (95% CL)=0.07 (0.004, 0.12) mg/kg, IP] was the most potent agent, followed by: R-PIA [0.34 (0.23, 0.44)]; CGS 21680 [1.1 (0.8, 2.0)]; CV-1808 [1.3 (1.0, 1.8)]; and CPA [1.5 (1.3, 1.7)]. Pretreatment with caffeine (25 mg/kg, IP, −10 min) blocked the inhibition of CAR produced by the adenosine agonists, suggesting the event is mediated via purinergic receptors. As a test for extrapyramidal side effect potential, each agonist was administered at dose levels corresponding to the ED 25, ED 50, and ED 75 values for block of CAR and catalepsy was measured. Catalepsy was prominently produced by NECA and CPA, whereas CGS 21680 and R-PIA produced little. Neither potency in blocking CAR nor inducing catalepsy could be highly correlated with either relative affinity or selectivity for either A 1 or A 2 binding sites. The data suggest purinergic agonists might be effective antipsychotic agents but may possess side effects that might preclude their use.

Shock avoidance but not DRL history reverses the effects of cocaine on punished behavior of squirrel monkeys

A history of responding maintained by a shock-avoidance procedure can alter the effect of psychomotor stimulant drugs on punished responding. This study was designed to evaluate whether another type of historical intervention could also alter the effects of cocaine on punished responding and, as a result, clarify certain variables contributing to this effect. Lever pressing of four squirrel monkeys was suppressed by a punishment procedure consisting of a fixed-interval 5-min schedule of food presentation in which every 30th response also produced a 200-ms 5-mA electric shock. Cocaine (0.03-1.0mg/kg) had no effect on or reduced punished responding. Conditions were then changed and responding was maintained for several sessions by a differential reinforcement of low rate (DRL) schedule in which food was delivered only when one response followed another by at least 25s. The punishment schedule was then reinstated and the effects of cocaine redetermined; the dose-response curve was similar to that initially obtained. The monkeys then responded on a shock-avoidance schedule in which each response postponed the next scheduled shock for 25s; shocks occurred every 5s in the absence of responding. Subsequently, the shock-avoidance schedule was replaced by the punishment schedule and the effects of cocaine were redetermined. In contrast to the initial determination of the effects of cocaine on punished responding, and the effects obtained following training on the DRL schedule, cocaine then produced response rate increases or no change in rate at several doses that formerly reduced responding. These results demonstrate that the rate-decreasing effects of cocaine on punished responding may be reversed by a history of responding on a shock-avoidance schedule and also indicate that a history of responding on a DRL schedule is not sufficient to reverse the effects of cocaine. These data suggest that a history of responding under schedules, such as the DRL, that engender responding that is typically increased by psychomotor stimulant drugs, is not sufficient to reverse the effects of these drugs on punished responding. The reversal of the effects of cocaine on punished responding resulting from a history of avoidance responding appears to be attributable to factors other than the rate-increasing effect of cocaine on responding maintained by avoidance.

A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance

Two experiments were conducted to investigate the role of nucleus accumbens dopamine in the performance of a lever press avoidance task in the rat. In this task, 0.5 mA shock was presented for 5s every 30 s, but the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. In the first experiment, dialysis probes were implanted into the nucleus accumbens of rats previously trained on the avoidance procedure, and also two groups of untrained rats. On the day after dialysis probe implantation, rats trained to press a lever to avoid shock ( n = 10) were exposed to a 45 min avoidance test session. Untrained rats were either exposed to periodic shock ( n = 9) or the control procedure in which lights were dimmed but no shock was presented ( n = 8). Performance of the avoidance task led to significant increases in extracellular dopamine and dopamine metabolites. There was a significant positive correlation between increases in extracellular dopamine and the number of avoidance responses emitted. In the second experiment, groups of rats were trained on the lever press avoidance procedure. After training, rats received intra-accumbens injections of the neurotoxic agent 6-hydroxydopamine or ascorbic acid vehicle. Dopamine depletion produced by 6-hydroxydopamine injection led to a substantial decrease in lever pressing to avoid or escape shock. These results indicate that dopamine in nucleus accumbens is important for operant avoidance responding, and that the involvement of accumbens dopamine in instrumental behavior is not unique to positively reinforced responses.

Autonomic nervous system and mental imagery

Central to a fear interpretation of how avoidance responses are maintained in the absence of further CS-UCS pairings is the underlying assumption of an existing gradient of fear across the CS-UCS interval. Extrapolations based on this gradient lead to a number of differential predictions concerning the topography of avoidance responding during extinction. The present research was concerned with the differential effects of extinguishing separate components of the CS complex upon responding to the complete CS complex during extinction. In Phase 1 of the study, rats were classically conditioned to a three-component serial CS (S1/S2/S3) followed by shock. Each subject was then given avoidance training in a one-way apparatus to a criterion of one successful avoidance. In Phase 2, subjects were divided into four groups, with three of the groups receiving nonreinforced exposure for 25 trials to one of the components of the serial CS (S1, S2, or S3). The fourth group (S0) was exposed for the same period of time to the apparatus cues. In Phase 3, the total stimulus complex was reintroduced in its original order, and animals were tested until extinction of the instrumental response was reached. The results are consistent with the hypothesis that a fear gradient exists in extinction and decreases in magnitude as the distance from the point of UCS onset increases.

Nonlethal rodent repellents: Differences in chemical structure and efficacy from nonlethal bird repellent

At least some anthranilates (e.g., methyl anthranilate), and acetophenones (e.g., orthoaminoacetophenone) are aversive to mice as well as to birds. Here we systematically examined nine acetophenone isomers (ortho, meta, para) and moieties (amino, hydroxy, methoxy) previously tested as drinking and feeding repellents for European starlings (Sturnus vulgaris). All nine substances reduced intake by mice in single-bottle tests. When molecular characteristics were examined, amino group reactivity and, to a lesser extent, isomeric position (i.e., resonance), were related to the strength of the avoidance response. Unlike effective avian repellents, the presence of intramolecular hydrogen bonds did not appear to affect avoidance responding.

Synthesis and biological characterization of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents.

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

Behavioural, biochemical and histological effects of AF64A following injection into the third ventricle of the mouse

Behavioural, biochemical and histological effects were assessed following AF64A injected into the third ventricle of female NMRI mice. Doses from 3 to 7 nmol produced significant changes in behaviour, causing hyperactivity, reduced hole-board exploration, rotational behaviour in a symmetrical Y-maze corresponding to a loss of alternation, abnormal behaviour in a plus-maze task of fear/anxiety with markedly increased exploration of the open arms and finally deficits in passive avoidance responding and spatial orientation in a Morris-type water maze. In this latter test, a cue learning deficit was noted for the two highest doses only. No histological changes of consequence were observed up to 5 nmol. Beyond this dose, at 6 and particularly 7 nmol, necrosis of parts of the hippocampus and septum was apparent. ChAT and AChE activity were decreased in the hippocampus but not in the cortex although the decreases were smaller than generally reported for AF64A-treated rats. ChAT and AChE reductions correlated highly with hyperactivity in the open-field and to a lesser extent, with spatial learning deficits. Monoaminergic activity was also affected in the hippocampus, but not in the cortex, at 4 nmol and above. NE and particularly 5-HT and 5-HIAA levels were reduced although the rate of 5-HT turnover was unaltered. A highly significant correlation was obtained between 5-HT effects and the increased open arm exploration in the plus-maze task of fear/anxiety. The behavioural effects and biochemical changes lasted at least 8-9 weeks postop.

Evaluation of a stable CCK agonist (A68552) in conditioned avoidance responding in mice, rats, and primates: Comparison with typical and atypical antipsychotics

In a variety of in vivo and in vitro tests, cholecystokinin (CCK) has been shown to produce effects that would suggest a functional antagonism of dopamine. On that basis, it has been hypothesized that CCK could have antipsychotic effects. We compared the CCK agonist, A68552, to the antipsychotics haloperidol (HAL), clozapine (CLOZ) and sulpiride (SULP) in various forms of conditioned avoidance using rats, mice, and cynomolgus monkeys. In rats, HAL disrupted both acquisition of a conditioned shelf-jump avoidance response and performance of the response by previously trained animals. CLOZ and SULP were ineffective in suppressing performance by previously trained rats but blocked acquisition of the response. CLOZ disrupted avoidance responding on the first 3 of 4 consecutive days of acquisition. SULP significantly suppressed avoidance responding on the last 3 days and significantly increased escape failures on day 2. A68552 administered during acquisition failed to significantly suppress avoidance responding. In mice, both HAL and CLOZ blocked performance of two-way shuttle conditioned avoidance at doses (0.1 and 3.0 mg/kg, IP, respectively) that had no effect on escape responding. A68552 at doses up to 1.07 mg/kg IP had no effect on performance. Mice treated with A68552 during acquisition showed a mild but statistically significant suppression of avoidance and an equivalent suppression of escape responding. Cynomolgus monkeys trained in a conditioned avoidance procedure were sensitive to the disruptive effects of HAL at a dose of 0.03 mg/kg IM while A68552 was without significant effect at doses up to those producing emesis (0.214 mg/kg, IM). A68552 does not resemble either HAL or the “atypical” antipsychotics, CLOZ or SULP, in conditioned avoidance tests.

Cocaine enhances one-way avoidance responding in mice

We reported previously that posttraining cocaine injections enhance subsequent performance of an automated jump-up avoidance response and trough avoidance response in rats. In the present study we examined the species generality of the cocaine enhancement by investigating the effects of posttraining cocaine injection on subsequent performance of a one-way active avoidance response in mice. Cocaine (30 mg/kg, IP) administered to mice immediately following completion of two escape-only trials on day 1 significantly enhanced avoidance response performance on day 2. Neither lidocaine nor cocaine methiodide, when administered in doses equimolar to the effective cocaine dose, altered performance on day 2. These data indicate that cocaine's enhancement of avoidance responding in mice probably is neither peripherally mediated nor attributable to its local anesthetic properties.

Pyrrole mannich bases as potential antipsychotic agents.

Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.