A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics

In a double-blind, cross-over study, the comparative therapeutic effects of 6-week courses of two prototypic neuroleptics — haloperidol and chlorpromazine — and the reversal of those effects with benztropine were investigated in a group of 18 schizophrenics. Periodic measurements were made for 32 dimensions of psychopathology, social participation, span of attention, sleeplessness, pulse rate and neurological side effects. The results showed that haloperidol was generally a more effective drug over the period studied. This was particularly apparent in terms of social and emotional responsiveness, communicativeness and cognitive processes. The only superiority of chlorpromazine seemed to be that patients felt less dysphoric on it than they did on haloperidol. Haloperidol also proved to be more rapid in its action. The data failed to support the clinical validity of the distinction often made between sedative and activating neuroleptics. Consistent with previous reports, benztropine had the effect of diminishing therapeutic response to both neuroleptics. However, haloperidol again proved less susceptible to this effect. The slowness and lesser therapeutic efficiency of chlorpromazine and its greater susceptibility to benztropine reversal were all considered to be due to its built-in anticholinergic properties acting in opposition to its antipsychotic activity. The low potency of chlorpromazine-like drugs was attributed to their inherent anticholinergic characteristics. It was suggested that one of the factors determining potency differences among neuroleptics may be the degree of built-in anticholinergic activity.     

Prolonged antidopaminergic actions of single doses of butyrophenones in the rat

Rats were treated once with doses of haloperidol or of droperidol below and above the acute ID₅₀ vs the dopamine agonist apomorphine; they were later challenged with an acute dose of apomorphine (0.3mg/kg, SC) and rated for stereotyped behavioral responses. The two neuroleptics were similar in acute anti-apomorphine potency (ID₅₀=0.12 and 0.18mg/kg for haloperidol and droperidol, respectively). The antidopaminergic effects of droperidol persisted for nearly 1 week and those of haloperidol lasted for 20–40 days, depending on the dose given. The computed half-time of disappearance of their antidopaminergic effects was 7.6±1.0 days and 0.59±0.17 days for haloperidol and droperidol, respectively, following a dose of 0.3 mg/kg, and these indices of duration of action did not vary significantly at doses between 0.1 and 1.0mg/kg. Haloperidol reduced the acute entry of ³H-apomorphine into brain by 21.5% 1 week later. Treatment with apomorphine alone just prior to haloperidol (both at 0.3 mg/kg) prevented the prolonged antidopaminergic effects of the neuroleptic evaluated 1 week later. These results indicate that some neuroleptics may have very prolonged activity or retention in tissue at sites of action, even after moderate, single doses. Caution is recommended in the interpretation of studies which assume neuroleptic-free conditions of subjects previously exposed to a neuroleptic agent.     

Progressive changes in the acute dyskinetic syndrome as a function of repeated elicitation in squirrel monkeys

Various neuroleptic-induced motor disorders that appear in primates previously treated with neuroleptics are collectively designated the acute dyskinetic syndrome. The relative incidence of these motor disorders was examined as the syndrome was repeatedly elicited by haloperidol and other dopamine antagonists in individual monkeys. After several weekly or biweekly treatments with haloperidol (1.25 mg/kg orally), catalepsy began to appear, which was then accompanied by athetoid movements (writhing and limb extensions) as intermittent neuroleptic treatment continued. Other dyskinetic movements (duck walk, oral dyskinesias, pushing of the head into a cage corner, and perseverative circling) that were suggestive of hyperkinesia subsequently began to be clicited by haloperidol and other neuroleptics after additional treatments with these drugs had intervened. As intermittent treatments continued, tolerance to the athetoid movements gradually developed and, eventually, only circling and pushing could be consistently elicited by haloperidol. In monkeys that had reached this phase, the athetoid movements were not again induced by higher doses of haloperidol (up to 5 mg/kg), chlorpromazine (3 mg/kg), or metoclopramide (3 mg/kg). In these tolerant monkeys, haloperidol impaired Sidman avoidance performance less and benztropine more than in drugnaive monkeys. Neither pharmacokinetic changes nor behavioral tolerance could readily account for these results. It is hypothesized that they reflect progressive functional alterations in dopaminergic or cholinergic neurotransmission.     

Mesolimbic dopamine and its control of locomotor activity in rats: differences in pharmacology and light/dark periodicity between the olfactory tubercle and the nucleus accumbens

To compare the functions of the lateral olfactory tubercle (OT) and the medial nucleus accumbens (ACC), dopamine (DA), (3,4-dihydroxyphenylimino)-2-imidazoline (DPI), and ergometrine were injected into the brain of rats familiarized with the experimental cage in which locomotor activity was assessed. In all tests a volume of 0.5 l per side was used. Both DA (1–10 g) and apomorphine (1–10 g) increased locomotor activity when injected into the OT; similar injections into the ACC produced inconsistent effects. The OT effects were short-lasting, dose-dependent and antagonized by haloperidol (0.5–2.5 g) in a dose-dependent manner. DPI (1–10 g) too produced an increase when injected into the OT; this response was long-lasting, dose-dependent and potentiated by ergometrine (0.1–1.0 g). Ergometrine (0.1–1.0 g) dose-dependently increased activity over a period of 200 min in ACC and OT rats, although the response in OT rats was much smaller than that in ACC rats. Only the ergometrine response in ACC rats was dose-dependently suppressed by DPI (1–10 g). ACC rats tested during the light period showed a weak stimulatory response to ergometrine in comparison with ACC rats tested during the dark period; OT rats showed reversed light/dark periodicity. Thus, OT rats significantly differed from ACC rats with respect to locomotor responses to dopaminergic agents, their pharmacological profile and their light/dark periodicity. Evidence is provided that the lateral tuberculum, but not the medial accumbens, is responsible for the stimulatory effect of dopamine and related compounds.The results were presented during the 14th C.I.N.P. Congress (Collegium International Neuro-Psychopharmacologicum), held at Florence (Italy), June 19–23, 1984     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

A study of the effects of zimeldine on the pharmacokinetics and pharmacodynamics of temazepam in healthy volunteers

In this double-blind two-period crossover study, ten healthy volunteers received either 200 mg zimeldine each morning for 5 days, or placebo on the same schedule. On day 5 they received 20 mg temazepam 2 h after zimeldine or placebo. A battery of psychometric tests and subjective measurements was carried out on days 4 and 5. Blood samples were collected on day 5 for pharmacokinetic analysis of temazepam.All the measures of psychomotor performance showed the effects of temazepam, as did two of the subjective measures, the alert/drowsy and steady/dizzy visual analogue scales. No effect of zimeldine alone on performance or subjective state was seen. Zimeldine showed no discernible interaction with the effects of temazepam as assessed by subjective reports, by psychomotor tests, or by pharmacokinetic analysis.     

Nicotine-containing chewing gum as an anti-smoking aid

Chewing gum containing nicotine or placebo was given to smokers attending an anti-smoking clinic. During a one week double-blind study subjects receiving nicotine smoked less and chewed less gum than those receiving placebo. The difference in tobacco consumption between the two treatment groups was most apparent among previous heavy smokers. During a 6 month follow-up phase all subjects were offered nicotine-containing chewing gum; the number of nonsmokers then remained fairly constant in the initial-nicotine group while it increased in the initial-placebo group.     

Opposite interactions between α- and β-endorphin fragments with dopamine mediated responses on the rat rectum in vitro

Summary Dopamine causes a dose-dependent contraction of the rat rectum in vitro followed by a relaxation. This contraction can be inhibited by apomorphine and phenylephrine. This inhibition can be attenuated by the -endorphin (E) fragments 2–17 (des-Tyr¹--endorphin, DTE) and 6-17 (des-enkephalin--endorphin, DEE). E 6-17 seems to be the shortest sequence with full activity in this respect since a shorter fragment (E 10-17) was less effective. The atypical neuroleptics oxypertine, sulpiride, and clozapine, the classic neuroleptic haloperidol and metoclopramide have a similar action to DEE. The peptides and atypical neuroleptics do not affect the dopamine response per se while the classic neuroleptics haloperidol and metoclopramide enhance the dopamine response.The effects of the -type endorphins are opposite to those of the -type endorphins, since des-Tyr¹--endorphin (DTE, E 2-16) and des-enkephalin--endorphin (DEE, E 6-16) enhance the phenylephrine-induced decreased responsiveness to dopamine. Structure-activity studies revealed that the active moiety of the -endorphin fragments probably resides in the 6–9 region. In addition the -type endorphins directly inhibit the dopamine response.It is concluded that the rat rectum may be used to analyse neuroleptic-like action. In this model - and -endorphin fragments may directly or indirectly influence the interaction of dopamine with the rectum. Because of the strong similarities between the effects of -type endorphins and that of neuroleptics the results support the purported neurolepticlike action of -type endorphins. The influence of -type endorphins and -type endorphins on the apomorphine or phenylephrine induced decreased responsiveness to dopamine, although opposite, seems to be mediated by an influence on different dopamine sensitive systems.     

Effects of supidimide in schizophrenic inpatients undergoing neuroleptic maintenance therapy with haloperidol

Summary Forty schizophrenic inpatients, on constant low-dosage maintenance therapy with haloperidol, entered a superimposed, double-blind, placebo-controlled clinical trial with supidimide 2×200 mg per day. The double-blind phase lasted 5 days and was preceded and followed by single-blind base line and washout periods, respectively, during which all patients received matching placebos. The therapeutic effects were evaluated by BPRS, NOSIE, a post-sleep questionnaire, and, in a subgroup of patients, by objective monitoring of movements during sleep. Supidimide substantially relieved sleep disturbances, as demonstrated by subjective (p<0.05;n=20) and objective (p<0.1;n=3) measurements. In addition, the following drug-related effects (p<0.05 versus base line and placebo) on daytime behaviour were observed: a decrease in somatic concern (BPRS), items related to agitation (BPRS), irritability and manifest psychosis (NOSIE), and a slight increase in retardation (NOSIE). No adverse effects attributable to supidimide were detected. It is concluded that supidimide exerts beneficial effects on day-time behaviour and sleep in agitated schizophrenic patients undergoing low-dosage maintenance neuroleptic therapy.     

Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

Effects of cannabidiol in animal models predictive of antipsychotic activity

The effects of cannabidiol (CBD) were compared to those produced by haloperidol in rats submitted to experimental models predictive of antipsychotic activity. Several doses of CBD (15–480 mg/kg) and haloperidol (0.062–1.0 mg/kg) were tested in each model. First, CBD increased the effective doses 50% (or) ED₅₀ of apomorphine for induction of the sniffing and biting stereotyped behaviors. In addition, both CBD and haloperidol reduced the occurrence of stereotyped biting induced by apomorphine (6.4 mg/kg), increased plasma prolactin levels and produced palpebral ptosis, as compared to control solutions. However, CBD did not induce catalepsy even at the highest doses, in contrast to haloperidol. Such a pharmacological profile is compatible with that of an atypical antipsychotic agent, though the mechanism of action is uncertain and may not be identical to that of the dopamine antagonists.     

Effect of haloperidol on reflex activation of rat α-motoneurones

Summary Effects of haloperidol on rat flexor and extensor -motoneurones were studied in ventral roots of laminectomized rats under halothane anesthesia. The -motoneurones were activated by tetanic stimulation of low-threshold afferents (group I and II), either of the ipsilateral peroneal nerve (flexor -motoneurones) or gastrocnemius-soleus nerve (extensor -motoneurones).Haloperidol, given in the doses of 0.075, 0.15 and 0.30 mg/kg i.p. inhibited the reflex activation of flexor -motoneurones; higher doses seemed to be more effective than lower ones. Apomorphine (2 mg/kg s.c.) partially antagonized the inhibitory action of haloperidol with some latency. Higher doses of haloperidol (0.15–0.60 mg/kg i.p.) also inhibited the reflex activation of extensor -motoneurones; this inhibitory effect was, at least for a short time, antagonized by apomorphine (2 mg/kg s.c.).The threshold for reflex activation both of flexor and extensor -motoneurones was raised by haloperidol and lowered by a subsequent administration of apomorphine.Our results suggest that akinesia and catalepsy, induced in rats by haloperidol might be, at least in part, due to a decrease in sensitivity of -motoneurones to proprioceptive stimuli.     

Effects in vitro of cadmium ions on some membrane and nuclear parameters of normal and irradiated thymic lymphoid cells

Effects of cadmium chloride upon ³H-Con A binding, number of autologous rosette-forming cells (ARFC), cell viability and the degree of DNA supercoiling were studied in normal and irradiated thymic lymphoid cells, isolated from rats and incubated up to 6 h in vitro. Cd (10–100 M) did not significantly alter the patterns of surface markers and viability of normal thymocytes, as measured by supravital staining or nuclear pyknotic criteria. The following effects of Cd were noted for irradiated thymic cells: 1) Cd ions (25 M) caused elimination of radiation-induced increase of Con A binding; 2) the characteristic loss of ARFC receptors, like development of nuclear pyknosis, was prevented in the presence of CdCl₂ (10–100 M); 3) the postradiation relaxation of nuclear supercoiled DNA was distinctly less pronounced with Cd. Possible reasons for these effects of Cd are discussed. Irradiated lymphoid cells are proposed as a suitable experimental model for the studies of different toxic actions of Cd and other heavy metals.     

Differential effects of dopamine receptor antagonists on the sexual behavior of male rats

In the present experiments, the dose-response effects of the dopamine (DA) receptor antagonists haloperidol, pimozide, clozapine, sulpiride, and metoclopramide, were assessed on patterns of copulatory behavior in intact, sexually active male rats with a high level of sexual experience and performance. The typical neuroleptics haloperidol (0.01–0.5 mg/kg) and pimozide (0.1–5.0 mg/kg) dose-dependently delayed the initiation of copulation and reduced the number of intromissions that preceded ejaculation. The atypical neuroletpics clozapine (0.1–5.0 mg/kg), and sulpiride (0.1–5.0 mg/kg) dose-dependently delayed the initiation of copulation but had no effect on copulatory behavior once it was initiated. In contrast, metoclopramide dose-dependently reduced the number of intromissions that preceded ejaculation but had no effect on the ability of rats to initiate copulation. These experiments suggest that aspects of copulatory behavior in male rats are affected differently by DA antagonists depending upon their site of action in the brain. Blockade of mesolimbic DA receptors by typical and atypical neuroleptics may delay the initiation of copulation, whereas blockade of mesostriatal DA receptors by typical neuroleptics and metoclopramide may decrease the ejaculation threshold.A preliminary report of these data was presented at the 17th Annual Meeting of the Society for Neuroscience in New Orleans, L.A., (Pfaus and Phillips, 1987b)     

Effect of foot-shock intensity on amount of memory retrieval in rats by emotionally important stimuli in a drug-dependent learning escape design

Rats were kept on a 12-h light-dark cycle. One hour after the light was switched on, physiological saline, (+)-amphetamine 1 mg/kg, and H 77/77 5 mg/kg were injected s.c.; the number of groomings was counted 1–2h after the treatments. (+)-Amphetamine and H 77/77 produced increased grooming which was antagonized by the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg), the dopamine--hydroxylase inhibitor FLA 63 (40), the neuroleptics haloperidol (0.1 and 0.5), and clozapine (1 and 5). The (+)-amphetamine-induced grooming was also antagonized by the NA-receptor blocker aceperone (10) but not by the sedative phenothiazines mepazine (10) and diphenhydramine (20) nor diazepam (1).These results indicate that NA-release is involved in the mediation of (+)-amphetamine- and H 77/77-induced grooming. The inhibition of haloperidol and clozapine is presumably due to NA-receptor blockade.     

Effects of haloperidol and trifluperidol on operant behavior in the rat

Summary The effects of trifluperidol (20 to 80 g/kg), haloperidol (40 to 160g/ kg) and caffeine (10 mg/kg) on a fixed-ratio operant behavior were studied in young Long-Evans male rats. A significant decrease in the number of emitted lever presses was observed with the largest dose of each of the two butyrophenone derivatives. Trifluperidol was 1.2 times as potent as haloperidol, on a g/kg basis, in disrupting this food-reinforced behavior. Haloperidol, at the 40 g/kg dose, and caffeine significantly increased the number of responses in comparison with placebo injections of solvent; this supports the suggestion of biphasic central actions of the butyrophenones. During a chronic drug state produced by daily injections of trifluperidol or haloperidol, there was no evidence of transfer of training, although the daily doses were each less than the acute ED50.Investigation supported by USPHS grants MH03241 and TW-794.     

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat

Summary Additional experimental evidence was obtained for an inhibitory function of prejunctional ₂-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed ₂-adrenoceptor receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used.In pithed normotensive rats, DPDA (30 and 100 g/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent.DP-6,7-ADTN (10 and 30 g/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia.B-HT 920 (1, 3 and 10 g/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation. Inhibitory dopamine as well as ₂-adrenoceptors participated in the vascular effects of B-HT 920, whereas ₂-adrenoceptors were only involved in the cardioinhibitory response to this agonist.B-HT 933 (0.6 and 1 mg/kg/min) dose-dependently reduced the stimulation-evoked increase in arterial pressure through selective stimulation of inhibitory ₂-adrenoceptors, dopamine receptors not taking a part.The results confirm and extend the observations that in addition to ₂-adrenoceptors inhibitory dopamine receptors are located on the sympathetic neurons connected with the arterial vasculature of the pithed normotensive rat. The sympathetic nerves innervating the rat heart do not contain inhibitory dopamine receptors; their activity only can be modulated by ₂-adrenoceptor stimulation. In the pithed normotensive rat, activation of prejunctionally located ₂-adrenoceptors more effectively inhibits the sympathetic activity directed to the heart than that to the resistance vessels.     

Acute dyskinesias in monkeys elicited by halopemide,mezilamine and the “antidyskinetic” drugs,oxiperomide and tiapride

Oxiperomide and tiapride are dopamine receptor antagonists claimed to have antidyskinetic properties in animal models and in the clinic. Halopemide and mezilamine are other dopamine antagonists predicted to lack extrapyramidal side effects in man on the basis of animal studies. Acute dyskinesias, a neuroleptic-induced acute extrapyramidal syndrome, were elicited in squirrel monkeys by oxiperomide (1 mg/kg), tiapride (30 mg/kg), and halopemide (10 mg/kg). The dyskinesias were virtually indistinguishable from those caused by a standard behaviorally equivalent dose of haloperidol (1.25 mg/kg PO) in the same individual monkeys. Mezilamine (0.3 mg/kg) also induced dyskinesias, which appeared to be less pronounced than those following haloperidol. The antidyskinetic properties of oxiperomide and tiapride evidently do not confer protection against dyskinetic movements induced by dopamine antagonism.     

Diazepam attenuates the antagonism of haloperidol against apomorphine-induced stereotypic behavior after subchronic but not acute treatment in rats

Summary Apomorphine-induced stereotypic behavior was investigated in rats treated with diazepam or haloperidol and with the combination of both drugs in a one day trial or subchronically. The drugs were administered via the drinking water.Diazepam dose-dependently reduced apomorphine stereotypies after the subchronic (6 days) but not after the acute treatment. Haloperidol suppressed apomorphine-induced stereotypic behavior dose-dependently after acute as well as after subchronic administration apparently without the development of tolerance. This discrepancy to other studies may be explained by the concomitant increase in maximum number of D₂-receptors in the striatum.The apomorphine antagonistic effect of haloperidol was attenuated when the neuroleptic was administered subchronically in combination with the benzodiazepine. This finding was unexpected since both drugs reduced apomorphine-induced stereotypic behavior when administered alone. The further increase in maximum number of D₂-receptors due to combined treatment with low doses of diazepam, suggesting a sort of over adaptation, possibly explains the haloperidol-antagonistic action of diazepam in the behavioral experiments.Binding studies on dopamine (D₁), 5-hydroxytryptamine (5-HT₂) and benzodiazepine receptors revealed that modification of the apomorphine-induced stereotypies by the combined treatment with haloperidol and diazepam cannot be explained by interactions of the drugs at the level of the D₁, 5-HT₂ or benzodiazepine-receptors.     

Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.