A comparison of clozapine,chlorpromazine, and thioridazine upon DRL performance in the squirrel monkey

Clozapine (0.16–10 mg/kg, p. o.), chlorpromazine (0.25–2 mg/kg, p.o.), and thioridazine (0.25–2 mg/kg, p. o.) were administered to squirrel monkeys subjected to a DRL 10 s schedule. The reinforcer consisted of 50% unsweetened orange juice. Chlorpromazine and thioridazine had no effect at the lower doses, but decreased response rate at the highest dose. Clozapine increased response rates at the low doses (0.31–2.5 mg/kg) and decreased rates at the high dose (10 mg/kg). Clozapine appears to show a major difference from other neuroleptic drugs in this test by increasing response rate. Since clozapine produces few extrapyramidal side effects in man, this procedure may be useful in selecting and developing new anti-psychotic drugs with less liability for side effects.Parts of this paper were presented at the Eastern Psychological Association meeting in Washington, D. C., 1978.     

Effects of amphetamine and chlorpromazine on second-order escape behavior in squirrel monkeys

Three squirrel monkeys received extensive training under a concurrent free-operant avoidance, fixed-ratio escape schedule. The independent effects of D-amphetamine and chlorpromazine were assessed over a range of dose levels. The effects of D-amphetamine (0.03, 0.1, 0.3, and 1.0 mg/kg) on each monkey were dependent upon the subjects' control rates of responding. However, there was a clear rate-increasing effect on a relatively low rate of responding, and a rate-depressant effect on high response rates. Administration of chlorpromazine characteristically was followed by an overall depression of response rates. Dose combinations of 0.3 mg/kg chlorpromazine with D-amphetamine (0.1, 0.3, 1.0 mg/kg) illustrated the antagonistic effects of the two drugs. At the lowest amphetamine dosage, the chlorpromazine effect was unimpaired; at the 0.3 mg/kg dosage of each drug it was abolished. The rate-suppressive effect on high response rates of 1.0 mg/kg D-amphetamine was abolished when given together with 0.3 mg/ kg chlorpromazine. The present experiment demonstrates the phenomenon of amphetamine-chlorpromazine antagonism under conditions in which responding was maintained by the scheduled presentation of aversive stimulation.     

Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine

Both clonidine and chlorpromazine reduced the amplitude of electrodermal responses (EDR) evoked by stimulation of the hypothalamus at a constant submaximal frequency (10–16 Hz). The ED₅₀ for clonidine was approximately 5 μg/kg and that for chlorpromazine was about 1 mg/kg. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but did not alter the effectiveness of clorpromazine in inhibiting these responses. Yohimbine alone was without effect on these sympathetic-cholinergic responses. These results suggest that clonidine and chlorpromazine depress central sympathetic reactivity by different mechanisms.     

Differential behavioral effects of sulpiride in the rat and squirrel monkey

Despite its clinical efficacy as an antipsychotic agent, sulpiride differs from other neuroleptics in that it has been reported to exert erratic effects in several animal models. The effects of sulpiride were investigated on Sidman avoidance responding by the rat and squirrel monkey. At 100 mg/kg i.p. or orally, sulpiride failed to impair rat Sidman avoidance responding appreciably while exerting marginally toxic effects, but at 30 mg/kg orally, this drug strongly impaired Sidman avoidance responding by the squirrel monkey. This effect, which manifested delayed onset, was reversed by benztropine, indicating that dopamine receptor blockade was most likely responsible for the impairment of responding. The gross behavioral effects of sulpiride in the squirrel monkey resembled those of haloperidol, and dyskinetic postures induced by haloperidol could be mimicked by sulpiride in some instances. It is concluded that the behavioral effects of sulpiride in the rat may not be representative of its action in primates or in the clinic.     

Amphetamine,scopolamine and chlorpromazine interactions on delayed matching performance in monkeys

Summary Two drug combinations, amphetamine-chlorpromazine and amphetamine-scopolamine, were examined in monkeys performing on a delayed matching test. Antagonism between the effects of amphetamine and chlorpromazine on both response rate and accuracy measures of performance was found. Amphetamine and scopolamine had antagonistic effects on response rate but synergistic effects on accuracy.Supported by Public Health Service Grant MH 01225. The authors wish to thank Mr. Bruce Levin for performing the computer analysis using the facilities of the Albert Einstein College of Medicine Computer Center. We also wish to thank Mrs. Toni Goldfarb, Mr. Jay Carley and Mr. Richard Pybus for indispensable technical assistance.     

Behavioral and neurochemical effects of amphetamine analogs that release monoamines in the squirrel monkey

To date, there are no effective pharmacotherapies for treating psychostimulant abuse. Previous preclinical and clinical studies have shown that continuous treatment with the monoamine releaser amphetamine reduces cocaine self-administration, but amphetamine selectively targets the dopamine system and is reinforcing. In the present study, we examined the consequences of administration of amphetamine and three structurally related analogs that vary in their potencies for releasing dopamine and serotonin on behavioral-stimulant effects and nucleus accumbens dopamine levels in squirrel monkeys. Amphetamine and PAL-353, which have relatively high selectivity for releasing dopamine vs. serotonin, increased accumbens dopamine levels and induced stimulant effects on behavior maintained by a fixed-interval schedule of reinforcement. PAL-313, which has a relatively low selectivity for releasing dopamine vs. serotonin, increased dopamine levels, but did not induce behavioral-stimulant effects. PAL-287, which is relatively nonselective in releasing dopamine and serotonin, did not increase dopamine levels or induce behavioral-stimulant effects. These results demonstrate that increasing serotonergic activity attenuates dopamine release and dopamine-mediated behavioral effects of monoamine releasers. In addition, these results support further investigation of PAL-313 and similar compounds as a potential medication for treating psychostimulant abuse.     

Effects of clonidine and chlorpromazine on a sympathetic-cholinergic reflex

Intravenous administration of clonidine and chlorpromazine resulted in a dose-dependent inhibition of the amplitude of reflexly evoked electrodermal responses in intact and spinal cats. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but not chlorpromazine in both preparations. These findings confirm and expand previous observations that both clonidine and chlorpromazine inhibit the amplitude of centrally evoked responses in this sympathetic-cholinergic system. In addition, both drugs appeared to have a spinal site of action. The antagonism of the effects of clonidine by yohimbine suggests that the mechanism of the action of clonidine may be a result of activation of central inhibitory alpha-adrenergic receptors. The failure of yohimbine to antagonize the effects of chlorpromazine suggests that clonidine and chlorpromazine may depress these sympathetic reflexes by different mechanisms.     

Effects of naloxone on the self-stimulation behavior of the postero-lateral area of the hypothalamus in rats — Influence of procedural conditions

Rats exhibiting self-stimulation behavior through chronic electrodes implanted in the posterolateral part of the hypothalamus were subcutaneously injected with low doses (0.003–0.3 mg/kg) of naloxone. The animals were allowed to self-regulate the duration of rewarding brain stimulation. It was found that naloxone increases the duration of self-stimulation in rats in which the brain stimulation had previously been associated with footshock. Vehicle injections or injections of naloxone in rats that had not received footshock prior to testing, did not modify self-stimulation behavior. It is suggested that naloxone may facilitate an aversive central component of the brain stimulation; the conditioned rats therefore increased the duration of brain stimulation to compensate for this negative process.     

Comparison of inhibitory effects of substituted benzamides and classical neuroleptics on operant behavior in rats and squirrel monkeys

The operant behavioral effects of the substituted benzamides metoclopramide, sultopride and sulpiride were compared with those of chlorpromazine and haloperidol using lateral hypothalamic self-stimulation of the brain in rats and Sidman avoidance responding in rats and squirrel monkeys. All the drugs inhibited both phenomena dose-dependently in rats. The order of potency was: haloperidol > chlorpromazine > metoclopramide > sultopride > sulpiride. Sulpiride only produced moderate inhibition even at 128 mg/kg s.c. All drugs also suppressed Sidman avoidance in squirrel monkeys, which were far more sensitive than rats to the inhibitory effects of all three benzamides. In monkeys, sulpiride 8 mg/kg i.m. apparently suppressed Sidman avoidance with a delayed onset and a prolonged duration, which contrasted with the rapid onset and short duration of metoclopramide action. Thus, long-term observation of the behavioral effects of benzamides in squirrel monkeys may provide more precise information on the clinical antipsychotic efficacy of substituted benzamides.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Effects of dopamine supersensitivity on lateral hypothalamic self-stimulation in rats

Dopamine (DA) receptor supersensitivity was demonstrated by potentiated d-amphetamine stereotypy after a three-day treatment regimen in which the DA receptor blocker pimozide (4.0 mg/kg) was administered twice daily. Similarly-induced DA supersensitivity produced a significant increase in the rate of lever-pressing for lateral hypothalamic (LH) intracranial self-stimulation (ICSS) and a significant decrease in ICSS thresholds. No change from pretreatment baselines was observed in vehicle-treated control animals. Following three-day treatment with the noradrenaline-(NA) and DA-receptor blocker, haloperidol (4.0 mg/kg twice daily), a single injection of the alpha-adrenergic agonist clonidine (0.15 mg/kg) caused increased running behavior. In contrast clonidine decreased running in rats pretreated with chronic pimozide or vehicle. These results indicate an increase in the sensitivity of central NA receptors following chronic haloperidol but not chronic pimozide. Taken together, these findings were interpreted as a potentiation in the reinforcing properties of LH-ICSS after chronic pimozide treatments due to increases in the sensitivity of DA and not NA receptors.     

Conditioned approach: An analogue of conditioned avoidance; Effects of chlorpromazine and diazepam

An analogue of the conditioned avoidance test, the conditioned approach test, was designed in which the reinforcing event was eating food rather than avoiding or escaping shock. A response to the approach stimulus resulted in immediate delivery of food. Failure to respond to the approach stimulus for 15 sec resulted in the delivery of a food pellet. Administration of chlorpormazine at 2–4 mg/kg, PO to squirrel monkeys resulted in the failure of the monkeys to respond to many approach stimuli although they promptly responded to the freely delivered food pellet. Diazepam was without effect at doses up to 100 mg/kg, PO.     

Comparative involvement of dopamine and noradrenaline in rate-free self-stimulation in substantia nigra,lateral hypothalamus,and mesencephalic central gray

Summary Previous research has shown that self-stimulation (SS) is found in substantia nigra (SN) and that SS in other loci is altered by drugs preferentially influencing dopaminergic neurotransmission. In the first part of this investigation the effects of pimozide (0.35 and 0.5 mg/kg), apomorphine (0.25, 0.5, 0.75 and 1.5 mg/kg), d-amphetamine (0.1, 0.25, and 1.0 mg/kg) and L-amphetamine (0.25, 1.0, and 2.5 mg/kg) on SS in lateral hypothalamus (HL) and SN were separately determined. To reduce possible confounding of drug effects on SS with non-specific changes in motor activation, a rate-free test of SS was employed. Pimozide (0.5 mg/kg) reduced SS more strongly in SN than in HL, confirming the existence of a dopaminergic substrate of SS in SN, but HL SS was also reduced by this drug. Low doses of apomorphine (0.25 and 0.5 mg/kg) elevated SS in HL while not influencing or slightly reducing SS in SN. Higher doses of apomorphine reduced SS in both regions. The enhancing effect of 0.1 mg/kg d-amphetamine on SS was greater in HL than in SN. However, d-amphetamine tended to increase SS more strongly than did L-amphetamine in SN as well as HL. It was concluded that HL SS may be mediated by both noradrenergic and dopaminergic substrates.An investigation was also undertaken into the possibility of noradrenergic or dopaminergic mediation of SS in other brain regions. Self-stimulation in the dorsal raphé area of mesencephalic central gray matter was not increased by 0.1 or 0.25 mg/kg d-amphetamine and was elevated only at 1.0 mg/kg, a dose level well above that needed to elevate HL or SN SS. In this region, therefore, SS did not appear to have either a noradrenergic or a dopaminergic substrate.This report is based on portions of a dissertation submitted by J. M. L. in partial fulfillment of the requirements for the Ph. D. degree at the University of California, Los Angeles.     

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0–30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1–3.0 mg/kg), meperidine (1.0–30 mg/kg), oxymorphone (0.03–1.0 mg/kg), and d-amphetamine (0.1–3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0–30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for self-stimulation responding were: oxymorphone > levorphanol > methadone > morphine > meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for self-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.     

alpha-Adrenergic modulation of hypothalamic self-stimulation: effects of phenoxybenzamine, yohimbine, dexamphetamine and their interactions with clonidine.

The alpha-adrenoceptor agonist clonidine (12.5--50.0 microgram/kg) produced a dose-dependent increase in the latency to initiate lateral hypothalamic stimulation. The insurmountable postsynaptic alpha-adrenoceptor antagonist phenoxybenzamine (0.2-0.8 mg/kg) had no effect on self-stimulation by itself, but potentiated the inhibitory effects of clonidine. The fact that the concurrent escape behavior to the intracranial stimulation was unchanged by either clonidine or the phenoxybenzamine-clonidine combination suggests that the inhibition is specific to the rewarding component of hypothalamic stimulation. Yohimbine (0.5--2.0 mg/kg) produced a dose-dependent increase in both response latencies. This lack of behavioral specificity may reflect yohimbine's wide range of pharmacological activity, Dexamphetamine (0.25--0.50 mg/kg) reversed clonidine's inhibition of self-stimulation reward in a specific and dose-dependent fashion. This reversal could be blocked by previous inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. These data support the concept that the alpha-adrenoceptors play a critical role in the modulation of hypothalamic self-stimulation reward. They further suggest that the inhibitory effects of clonidine on self-stimulation reward represent an agonist effect on presynaptic alpha-adrenoceptors.     

The tetracyclic antidepressant mianserin: evaluation of its blockade of presynaptic alpha-adrenoceptors in a self-stimulation model using clonidine

It has been suggested that the tetracyclic antidepressant mianserin may be an antagonist at inhibitory presynaptic alpha-adrenoceptors. If mianserin exerted a selective antagonist effect it should produce effects that are essentially opposite to those of a selective agonist such as clonidine. This hypothesis was investigated in a shuttle-box self-stimulation model previously shown to be sensitive to alpha-adrenergic drugs. In this model a presynaptic alpha-adrenoceptor antagonist would be expected to enhance self-stimulation and to reverse the inhibitory effects of clonidine. Mianserin (2.5-4.0 mg/kg) did not enhance self-stimulation, but instead produced a selective inhibition of reward. Further, mianserin did not reverse the inhibitory effects of clonidine on self-stimulation. These data suggest that if mianserin is an antagonist of the presynaptic alpha-adrenoceptors it is not a selective antagonist. It is possible that the presynaptic alpha-adrenoceptor antagonism may be effects on postsynaptic alpha-adrenoceptors and/or on a presynaptic noradrenaline reuptake mechanism.     

Effects of d-amphetamine and methylphenidate upon auditory threshold in the squirrel monkey

The effects of d-amphetamine sulfate and methylphenidate hydrochloride on auditory thresholds in ten squirrel monkeys were examined using a 4.2 kHz stimulus in a free field. The results indicated that d-amphetamine raised auditory thresholds but methylphenidate did not alter the thresholds. The elevation of sensory thresholds by d-amphetamine was in agreement with previous studies suggesting that the drug acts as a behavioral depressant in diurnal animals.     

Differential effects of drug treatments on nose-poke and bar-press self-stimulation

To assess the possibility of dissociating drug-induced gross performance deficits from effects on brain stimulation reward, the nose-poke and bar-press operants were systematically compared. Pentobarbital and methocarbamol (a muscle relaxant) reduced bar-pressing more strongly than nose-poking. In contrast, clonidine and haloperidol, which disrupt noradrenergic and dopaminergic neurotransmission respectively, had no differential effect on these operants. The nose-poke operant appears less vulnerable to drug-induced gross motor impairment and may be more suitable for pharmacological studies of self-stimulation.     

Maternal responsiveness in the squirrel monkey following chronic administration of delta 9-THC.

Mother squirrel monkeys were orally administered gradually increasing doses of delta 9-THC (from 0.5 to 5.0 mg/kg) 5 days/wk from 2 wk to approximately 6 mo after birth. After having received a dose of 5.0 mg/kg for an average of 3.5 mo, drug-treated mothers were then compared with control mothers in terms of theri responsiveness both to their own and to unrelated infants. In contrast to the control mothers whose response pattern clearly showed differentiation of their own and other infants, the mothers that received delta 9-THC responded in much the same manner to the alien infant as they did to their own infant. The results show that the behavior of the THC-exposed mothers was not attributed simply to a general reduction in their responsiveness toward their offspring or to an overall reduction in their own state of arousal. Rather, the results suggest that chronic ingestion of delta 9-THC caused the mothers to be less disturbed by separation from their infants and/or produced degree of perceptual distortion that prevented them from responding selectively to the different infants.     

Effects of apomorphine on self-stimulation behaviour in dorsal and ventral area of lateral hypothalamus in mice

Intraperitoneal injections of low doses of apomorphine, a dopaminergic receptor agonist, depressed briefly, and then enhanced self-stimulation behaviour in the dorsal area of lateral hypothalamus. In contrast, only depressant effects were observed in the ventral area. These differential effects suggests the presence of a dopaminergic componant in the dorsal hypothalamic self-stimulation system.