The relationship between binding of antipsychotic drugs and o psychotomimetic opiates to binding sites

On fixed-interval schedules of reinforcement, subjects are reinforced for the first response which occurs after a fixed time interval has elapsed. Responses occurring before the interval has elapsed are recorded, but have no specified consequences. Fixed-interval schedules produce characteristic response patterns. A period without responses (initial pause) occurs at the start of each interval, and is followed by accelerated responding which reaches a constant high rate that is maintained until reinforcement. The present paper reports the development of a mathematical index for describing characteristics of fixed-interval curves. Examples from behavioral and pharmacological studies will illustrate applications of this index. DERIVATION OF THE INDEX OF CURVATURE'A cumulative-response record drawn to approximate the performance of a pigeon trained on a 10-minute, fixed-interval schedule (FI 10) is presented in Fig. 1.If the response rate were constant throughout the interval, the cumulative-response record could be completely described by the straight line O Y. However, the actual cumulative record departs from a straight line. Insofar as we can indicate the extent and the direction of this departure from a straight line, we indicate the curve characteristic of the cumulative record.The extent to which the cumulative record departs from a straight line can be determined by comparing the area under the cumulative record with the area under the straight line. That is, the difference between the area of the triangle OXY and the area of the figure 0 a'b'c'YX can be used to indicate the curvature of the cumulative record.

No abstract

sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.

In his analysis of temporal discriminations, Skinner (1938) described an experiment in which the response rates of rats were decreased by reinforcing only interresponse times (IRT's) which exceeded 15 seconds (p. 306). Wilson and Keller (1953) confirmed and extended this finding by demonstrating that the rate of responding is inversely related to the duration of the minimum required IRT. This type of schedule of reinforcement is referred to as the "differential reinforcement of low response rates" (DRL). Recent investigations indicate that DRL schedules engender temporal discriminations which can be analyzed by means of the relativefrequency distribution of IRT's or the distribution of response probabilities (Anger, 1956; Sidman, 1956).On DRL schedules of reinforcement, each response starts the required delay interval. Responses which occur before the delay interval has elapsed not only are unreinforced but they also postpone reinforcement by starting a new delay interval. To the extent that the animal can discriminate the delay interval, these two contingencies should eliminate responding during the delay interval. Wilson and Keller (1953) reported that their rats adapted to the DRL schedule by developing varioua chains of overt behavior which persisted between lever presses and which occupied enough time so that the lever presses following the chains were reinforced.More recent investigations, which include detailed analyses of the temporal response patterns which develop on DRL, have consistently indicated that a large proportion of IRT's occur at about 0-3 seconds (Conrad, Sidman, & Herrnstein, 1958; Sidman, 1955;Sidman, 1956a;Sidman, 1956b). These short IRT's result from frequent "bursts" of responding, and they generate IRT relative-frequency distributions and probability distributions which are bi-modal. One mode occurs in the vicinity of the minimum IRT which is required for reinforcement; the second mode, which is a result of these bursts, occurs at about 0-3 seconds. Sidman presented evidence indicating that the probability of a burst was high near the minimum IRT required for reinforcement. le suggested that "late in the delay period, a single lever press often fails to reset the animal's 'clock,' with the result that several quick responses are emitted" (Sidman, 1956a, p. 472).A very precise control of the rate of responding can be developed by reinforcing only those IRT's which fall within a specified range (Ferster & Skinner, 1957, pp. 498-502); that is, a reinforced IRT must not only be longer than some minimum value (as in DRL) but also shorter than some maximum value. Thus, reinforcements are available for only a limited period of time. This type of schedule is referred to as DRL with a "limited hold" (DRL LH). For example, on DRL 20 LH 3, only responses which are emitted between 20 and 23 seconds after a preceding response will be reinforced; responses emitted at less than 20 seconds or more than 23 seconds after a preceding response start the timing interval again. On DRL LH 91