Seroquel was compared to clozapine and several other antipsychotic agents in tests predictive of antipsychotic activity or extrapyramidal symptoms. In the conditioned avoidance test in squirrel monkeys as well as several paradigms using apomorphine or amphetamine-induced behavioral alterations, seroquel displayed the profile of a drug with potential antipsychotic activity. In these paradigms the potency of seroquel was somewhat less than clozapine in rodent tests, while the reverse was true in higher species, i.e. monkeys, cats. In tests designed to evaluate the propensity to induce EPS or tardive dyskinesia, for example, the production of dyskinetic reactions in haloperidol-sensitized cebus monkeys, seroquel displayed a profile similar to clozapine and disparate from typical antipsychotic drugs. In drug-naive cebus monkeys seroquel sensitized significantly fewer monkeys than haloperidol and the dyskinetic reactions were of significantly less intensity. It is anticipated that this novel antipsychotic agent will have a significantly reduced propensity to produce extrapyramidal symptoms and tardive dyskinesia than typical antipsychotics.

Rats were trained to press two keys consecutively for reinforcement. During stimulus one (slow clicker) a 6-sec time delay was required between the two responses. During stimulus eight (fast clicker) no time delay was required between the two responses. When tested with intermediate stimuli (intermediate click rates) the median time delays emitted by the animals were intermediate between their performances on the original training stimuli, resulting in typical generalization gradients. Closer examination of the data revealed that the median values were not representative of the behavior of the animals.

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

In the presence of one click frequency, the presses of two hungry rats on one of two levers were reinforced with food on variable-interval schedules; in the presence of a different click frequency, presses on the other lever were reinforced. In stimulus generalization tests, a variety of click frequencies were presented and reinforcement withheld. The test stimuli were found to exert control over which of the two levers the rats pressed, but not over the rate of pressing the selected lever. The results were interpreted as further evidence that intermediate rates in generalization gradients may be the result of the alternation of several distinct behavior patterns.

Rats were trained on a two-response timing procedure which required that response B follow response A by at least a minimum specified interval in order to be reinforced with food. Repeated presentation (5 min on, 5 min off) of an auditory warning stimulus terminated by a brief electric shock to the feet (conditioned fear) produced a marked suppression in the frequency of A-to-B response sequences during the waming stimulus. The distribution of A-to-B interresponse times (timing behavior), however, did not change during the warning stimulus.The suppressing effect of conditioned fear (conditioned emotional response or CER) upon the rate of an ongoing lever-pressing response for food has been well documented in previous reports (Estes and Skinner, 1941;Brady and Hunt, 1955; Stein, Sidman and Brady, 1958). The present experiment examined the effects of the CER procedure upon properties of the operant behavior in addition to the response rate. Specifically, the effects of conditioned fear upon timing behavior using a two-response chain with a time delay required between responses was investigated. METHOD SubjectsThree experimentally naive male albino rats served. The principles of laboratory animal care as promulgated by the National Society for Medical Research were observed. ApparatusThe Ss were housed and tested in the elevator device shown in Fig. 1 the walls and grid floor of an individual test cage. Ad libitum water was provided from a bottle on the wall of each cage. When the test panel was in position in front of a cage, the S was presented with a response key on the left and right sides of the front panel, about nose high, a trough between the keys near the grid floor for pellet delivery, and a small speaker mounted in the center of the front panel near the ceiling. Under program control, the panel moved up from the home position at the bottom of the elevator, not facing any cage, to a cage in which an S lived for a test session. At the termination of the test for one S, the front panel moved up to a second S, and so on through the entire series before returning to the bottom of the elevator.Conventional relay circuitry was used to program the experimental contingencies. The data were recorded on punched paper tape for later sorting and computation by a digital computer. Parallel recording of some of the data by electro-mechanical impulse counters was used to verify the accuracy of the punched tape system. ProcedureOver the course of several days Ss were food deprived, magazine trained, and shaped to nose-press the illuminated key at the right (key B) for continuous reinforcement. Next, key A, on the left, was illuminated and key B was darkened. Pressing key B when darkened had no effect. Pressing key A when illuminated extinguished the light on key A and illuminated key B. A press on Key B at this time was reinforced, the key B light ex-247 VOLUME 7, NUMBER 3 MAY, 1964