Brain and heart catecholamine levels after l-Dopa administration in reserpine treated mice: Correlations with a conditioned avoidance response

Summary Mice were tested with reserpine before receiving an injection of l-DOPA. At various times after the l-DOPA injection they were sacrificed and the brains and hearts were analyzed for their catecholamine content. Effects on the conditioned avoidance response were further analyzed using reserpine and l-DOPA, and the correlations between the two were discussed.United States Public Health Service Postdoctoral Fellow (MPD-10, 562-C 3), National Institute of Mental Health.This research was supported by the United States Air Force under Grant No. AF-EOAR 63-14 and monitored by the European Office, Office of Aerospace Research (to A. Carlsson).     

Drugs,shock intensity,and the CER

Summary The effects of chronic small doses of reserpine (0.2 mg./kg.) and of chlorpromazine (1.5 mg./kg.) upon the CER were studied using albino rats as subjects. It was found that reserpine reliably reduced the CER at a relatively low shock intensity (0.8 ma.) but, with a more severe shock (1.0 ma.), the results were equivocal. Chlorpromazine inhibited the CER at 1.0 ma. At the dosage and time parameters studied, chlorpromazine induced less depression of VI rate than did reserpine; recovery from reserpine effects was generally more gradual than was recovery from chronic chlorpromazine treatment.This research was supported by Research Grant MY 3363 from the National Institute of Mental Health. The author would like to thank D. X. Freedman, M.D., for providing laboratory facilities and to acknowledge the technical assistance of Miss C. V. Perotti.     

Alteration of basal ganglia evoked responses by reserpine and L-Dopa

The effects of reserpine and L-Dopa on basal ganglia evoked potentials were investigated in cats. The caudate response resulting from substantia nigra stimulation and the substantia nigra response elicited by globus pallidus stimulation were increased at several hours after the systemic administration of reserpine. L-Dopa in the presence of dopa decarboxylase inhibition (MK-486) depressed these responses and reversed the effect of reserpine at 0.5 h after administration. Reserpine did not reverse the L-Dopa effect. Reserpine and L-Dopa caused no significant change in responses between other basal ganglia structures. These data give evidence that the basal ganglia are major sites for reserpine and L-Dopa action.     

Locomotor stimulation by l-Dopa: Relative importance of noradrenaline receptor activation

The importance of brain noradrenaline synthesis and receptor activation for the hyperkinesia induced by carbidopa plus l-Dopa in reserpine-treated or normal mice was analyzed in four different models. After pretratment with reserpine and the monoamine oxidase inhibitor nialamide, the hyperkinesia induced by l-Dopa (25 mg/kg i.p.) was partly mediated via stimulation of noradrenaline receptors since it was significantly antagonized by the noradrenaline receptor-blocking agent phenoxybenzamine. Treatment with reserpine plus l-Dopa (125 mg/kg i.p.) produced an increase in motor activity probably due to stimulation of dopamine receptors since it was not accompanied by an accumulation of noradrenaline and it was not inhibited by phenoxybenzamine. The hyperkinesia following treatment with reserpine and a higher dose of l-Dopa (250 mg/kg i.p.) was probably due to stimulation of both dopamine and noradrenaline receptors since the dopamine--hydroxylase inhibitor FLA-63 partly reduced the effect of l-Dopa. Phenoxybenzamine potentiated the motor stimulation by l-Dopa (125 mg/kg i.p.) in mice not pretreated with reserpine, perhaps depending on a slight enhancement of the net accumulation of brain dopamine. Thus, noradrenaline receptor activation is of importance for the l-Dopa-induced hyperkinesia, at least after high doses or after monoamine oxidase inhibition.     

Evidence for different sites of action of reserpine and guanethidine

Summary Isolated atria were obtained from guinea pigs pretreated with reserpine or guanethidine; the response of the atrial pacemaker to tyramine and the total norepinephrine content of the atria were determined. Twenty-four hours after pretreatment with doses of reserpine and guanethidine which were equieffective in depleting the norepinephrine stores, the response to tyramine of guanethidine-pretreated atria was smaller than that of reserpine-pretreated atria. The same relation between response to tyramine and norepinephrine content was observed during recovery from the depletory effect of a single injection of reserpine or guanethidine (i.e., 4–8 days after pretreatment).The pacemaker of the normal heart-lung preparation of the dog was stimulated by acute injections of tyramine, reserpine or guanethidine. This response of the pacemaker was absent in preparations obtained from dogs pretreated with reserpine. Infusions of norepinephrine into heart-lung preparations obtained from pretreated dogs partly restored the response of the pacemaker to tyramine and to guanathidine, but failed to affect the response to injections of reserpine.The results are discussed on the basis of a two-compartment theory of the norepinephrine stores. They indicate that guanethidine differs from reserpine in its site of action, since the former appears to act more strongly on the small compartment of tyramine-sensitive norepinephrine than the latter. This is true for both the depletory and the releasing action of guanethidine.With 5 Figures in the TextDedicated to Prof. Otto Krayer with the best wishes of the author.This work was supported by U. S. Public Health Service Grants NB-01713 and HE-02205.     

On the mechanism of action of chlorpromazine in releasing 5-Hydroxytryptamine from blood platelets in vitro

Summary The action of chlorpromazine in releasing 5HT from the blood platelets of the rabbit was compared with that of tetrabenazine and reserpine. Platelet-rich plasma was incubated for 3 hours with the 5HT releasing agents under various conditions, and the 5HT content of the separated platelets was subsequently determined.An increase in the concentration of chlorpromazine clearly increases the amount of 5HT liberated and, with high enough concentration, practically all of the 5HT is released. With tetrabenazine or reserpine only about half of the 5HT can be released in vitro.The 5HT releasing effect of chlorpromazine is increased when tetrabenazine is first added to the platelet-rich plasma. The action of reserpine in similar experiments is not increased by tetrabenazine but rather it is slightly inhibited.The inhibition of the monoamine oxidase activity of the platelets by pheniprazine or by nitrogen atmosphere has no such clear inhibitory influence on the 5HT releasing action of chlorpromazine as on the action of tetrabenazine or of reserpine.At lower temperatures, the effects of tetrabenazine and reserpine are inhibited more than the action of chlorpromazine.The packed platelet volume is decreased by chlorpromazine but not by tetrabenazine or by reserpine. This and the other results obtained indicate that the mechanism of action of chlorpromazine is different from that of tetrabenazine and reserpine and the mechanism involves the increased permeability of the membranes of the platelets.With 2 Figures in the TextDedicated to Professor Otto Krayer on his 65th birthday.Pressented in part at the Second Internat. Pharmacol. Meeting (Paasonen 1963).     

The role of catecholamines in behavioral arousal during ontogenesis

Effect of catecholamine depletion on normal hyperactivity in the neonatal rat was examined. Both -methyl-para-tyrosine and reserpine significantly depressed behavioral arousal at 15 days postpartum, the age of greatest excitability. Heightened activity could be restored in drug-treated animals by administration of l-Dopa. These results indicate that the ontogenetic hyperactivity effect is a result of accelerated catecholamine function.This work was supported in part by National Institute of Mental Health Grants MH01562 and MH08501 to Byron A. Campbell.     

Effects of l-dihydroxyphenylalanine (l-Dopa) and d,l,5-hydroxytryptophan (d,l,5-HTP) on reserpine-induced amnesia

In a series of experiments the effects of reserpine, l-Dopa, and d,l,5-hydroxytryptophan (d,l,5-HTP) on retention of a passive avoidance training in mice were investigated. Reserpine (2.5 mg/kg) produced amnesia when given at 120 min before but not at 30 min before or at 0, 10, 30, or 90 min following training. This time-dependent reserpine effect did not appear to be due to either an alteration in footshock sensitivity during training or to the drug producing state-dependent learning. The amnesic effect of reserpine could be blocked when both l-Dopa and d,l,5-HTP were also administered up to 10 min but not at 30 or 90 min following training. The drugs, l-Dopa or d,l,5-HTP, given alone or in higher doses, could not at any time counteract the reserpine effect. The retrograde effects of the combined administration of these biogenic amine precursors on the reserpine-induced amnesia are discussed in terms of the possible role of biogenic amines in memory formation.     

Antagonism between physostigmine and atropine on the behavior of the pigeon

Summary The effects of physostigmine upon food-maintained operant behavior of the pigeon were investigated. Physostigmine completely suppressed responding for a period up to 180 minutes and small doses of atropine could antagonize this suppression. Neostigmine produced a similar suppression of behavior of shorter duration. Methylatropine, much less potent than atropine in antagonizing behavioral suppression by physostigmine, was more potent in antagonizing neostigmine. Nicotine produced a suppression of behavior similar to that produced by the two anticholinesterases, but neither methylatropine nor atropine antagonized this effect. These findings support the general supposition that suppression of behavior by physostigmine is in part mediated by muscarinic receptors in the central nervous system.With 5 Figures in the TextDedicated to Professor Otto Krayer on his 65th birthday.Thus study was supported by grants MH-02645, MH-02094 and 2M-7084 from the United States Public Health Service.     

Potentiation of opioid — Induced cataracts by catecholamines injected into the mouse brain

Summary The cataractogenic effect of parenteral levorphanol was increased by the injection of catecholamines into the mouse brain. Although l-epinephrine potentiated this effect most strongly, the potency of dl-isoproterenol unexpectedly equaled that of l-norepinephrine. Phenoxybenzamine, however, blocked the effect of l-norepinephrine, whereas pronethalol failed to inhibit dl-isoproterenol. That dl-isoproterenol may act indirectly is supported by the finding that treatment of the mouse with reserpine blocked the potentiation induced by dl-isoproterenol but did not inhibit the action of the pressor catecholamines.     

The effects of dl-amphetamine and reserpine on runway performance

Summary Rats, 23 1/2 hrs. hungry, were trained to run a 5-ft. straight alley for food reward. After extensive training, they were tested for speed of response at varying doses of dl-amphetamine and reserpine. Both drugs produced decrements in performance of the response.In two additional experiments, similarly trained animals were tested for the effects of amphetamine and reserpine on inhibition which was induced by the addition of trials and by non-reinforcement. Amphetamine generally attenuated the effects of non-reinforcement. Reserpinized animals displayed behavior which was inhibited regardless of reinforcement conditions.These results suggest that amphetamine (an adrenergic stimulant) interferes with inhibitory mechanisms (i.e. disinhibits), allowing interference of irrelevant responses during performance, but attenuating extinction effects. Further, they suggest that reserpine (which depletes adrenergic substances) renders the organism non-resistant to inhibitory influences.This research was supported by USPHS Grant No. MY-3364.     

Alterations in urinary 17α-Hydroxycorticosteroid excretion associated with administration of reserpine in the rhesus monkey

Summary Following single injections of reserpine in the Rhesus monkey, marked elevations of urinary 17-OH-CS excretion occurred, beginning 4 hours after administration of the drug, persisting about 8 to 10 hours, then levels subsided to return to normal by the next morning. The intensity and duration of the urinary 17-OH-CS response to reserpine are compared with the normal diurnal rhythm and with the response to the injection of standard doses of ACTH in the monkey. Repeated daily injection of reserpine for eight consecutive days produced a threefold urinary 17-OH-CS elevation the first three days followed by twofold elevations for the remaining five days. A marked increase in the percentage of free or unconjugated 17-hydroxycorticosteroids was also observed in these animals, suggesting possibly a concomitant renal or hepatic effect of reserpine administration.From thesis submitted by N. R. Rosenthal to the Department of Chemistry, Graduate School, Georgetown University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy.     

The effects of psychotropic drugs on the double alley frustration effect

Summary Central nervous system stimulants (amphetamine, methylphenidate), depressants (sodium amobarbital, reserpine, tetrabenezine, chlorpromazine) and anti-depressants (iproniazid, pargyline) were administered intraperitoneally to rats prior to their daily trials in an Amsel double runway in an attempt to modify the frustration effect using within-subject comparisons. Absolute running speeds following reinforcement and nonreinforcement were markedly affected by the drugs. However, in contradistinction to conditioned frustration which has proven amenable to pharmacological intervention, the primary frustration in the present paradigm, involving a response that immediately follows nonreward, proved highly resistant to modification.This research was supported, in part, by a grant from the Graduate Research Board of the University of Illinois. The authors acknowledge the assistance of A. Strojney, E. Gentry, V. Williams, L. Rosenberg, K. Yamamoto, and R. Wyer, Jr., in the collection and analysis of the data.     

The influence of reserpine pretreatment upon the hemodynamics of dogs during hemorrhagic hypotension

Summary Pretreatment of dogs with two doses of 0.1 mg/kg reserpine, given 72 and 48 hours before the experiment, did not alter the bleeding volume, i.e., the volume of blood that can be withdrawn before the arterial blood pressure falls to 40 mm Hg, or the maximal volume of blood expelled by the animal during maintained hypotension.The uptake of blood during the hypotension was considerably slowed by pretreatment with reserpine. Control animals had taken up 40% of the maximally shed volume after 175 minutes at 40 mm Hg, but no animal pretreated with reserpine had taken up 40% of the maximally shed blood after 360 minutes. The large vessel hematocrit in both groups of animals fell during hemorrhage, but while the hematocrit of the control animals increased again during the hypotension, that of the animals pretreated with reserpine remained low for the duration of the hypotension.It is concluded that impairment or blockade of impulse transmission in the sympathetic nervous system by reserpine did not impair the ability of the animals to compensate for loss of blood volume. It did, however, exert a marked stabilizing effect on the circulation during hypotension. It is likely that the observed stability of the circulation is due to the effect of reserpine upon changes in intracapillary pressure occurring normally during oligemic hypotension and to the movement of fluid across the capillary membrane resulting therefrom.With 4 Figures in the TextDedicated to Professor Otto Krayer in honor of his 65th birthday.This work was supported by funds from the Massachusetts Heart Association, from the Milton Fund of Harvard University, and from USPHS grant H-2204.Part of the results reported here were presented to the American Society for Pharmacology and Experimental Therapeutics during the 1963 Fall Meeting in San Francisco, California, U.S.A.We wish to thank Mrs. Evelyne Shechter and Mr. David Jones for their assistance in these experiments.NATO Research Fellow on leave of absence from the University of the Saarland in Homburg/Saar, Germany.     

Amines cérébrales et comportement d'agressivité intraspécifique induit par l'apomorphine chez le rat

In rats sensitive to apomorphine-induced aggression, similar, but less pronounced aggressive reactions were induced by ET-495, a specific stimulant of dopaminergic receptors and, to a very slight extent by l-Dopa, whereas clonidine was ineffective. In these rats the apomorphine-induced aggressiveness was nearly completely inhibited by phenoxybenzamine, only partially by DDC, 5-HTP, and FLA 63. Conversely it was altered slightly or not at all by PCPA, alpha-mmT, reserpine, alpha-mDopa, iproniazide, and JB-516.In rats not sensitive to the action of apomorphine, simultaneous administration of clonidine and apomorphine induced aggressive reactions, as did a combination of clonidine-ET 495, but to a lesser degree. Pretreatment with reserpine or MAO inhibitors, or to a lesser extent, alpha-mDopa, sensitized these rats to the action of apomorphine. 5 HTP, l-Dopa, PCPA, DDC, and alpha-mmT did not have this inductive effect. The inductive effect of reserpine was completely inhibited by DDC, partially by l-Dopa, but not at all by 5-HTP. That of iproniazid was inhibited by DDC, but not modified by PCPA.On the basis of these data, it was concluded that the aggressive behavior induced by apomorphine might result from a stimulation of dopaminergic receptors, stimulation that would itself induce the setting of noradrenergic structures.

L'auteur remercie vivement le Docteur J. Jacob pour les précieux conseils, qu'il lui a apporté au cours de ce travail et de la rédaction de ce manuscrit et Madame S. Bizeul pour son aide technique; il remercie également le Docteur Baille-Barrelle (Laboratoire Boehringer), le Docteur Régnier (Laboratoire Servier) qui lui ont aimablement fourni, respectivement, de la clonidine et du ET 495.     

Biochemical and behavioural effects of tyrosine hydroxylase inhibition

Summary Selective depletion of the brain catecholamines (CA) was induced in cat and rat by administration of 3, -dimethyl tyrosine methylester-HCl (H 59/64), a specific inhibitor of tyrosine hydroxylase. A concomitant decrease of conditioned avoidance responses (CAR) was observed. The observations give additional support to the view that the brain CA play a role in the maintenance of CAR. The functional significance of the CA synthesis inhibition was further demonstrated in reserpine pretreated cats. In these animals the CAR was restored by (+)-amphetamine but the behavioural restoration failed to appear after the combined reserpine and H 59/64 pretreatment. A small subthreshold dose of l-DOPA given after (+)-amphetamine, restored the activity of amphetamine.     

Zentrale Wirkung des Reserpins auf die Kreislaufreflexe des Carotissinus

Zusammenfassung 1. An Katzen in Chloralose-Narkose wurde die Wirkung von zentral verabreichtem Reserpin auf Blutdruck, Carotissinus-Reflexe [Carotissinus-Entlastungsreflex (CSER), seine Baro- und Chemoreceptorkomponente sowie Chemoreceptorreflex] und auf den Katecholamingehalt in Gehirn, Herz und Aorta untersucht. Die Zufuhr von Reserpin erfolgte in die A. vertebralis über einen A. brachialis- bzw. A. subclavia-Katheter.2. Die Gabe von 80 g/kg Reserpin in die A. vertebralis erniedrigte nach 5 Std, nicht jedoch nach 2 Std signifikant den Noradrenalin- und oft auch den Dopamingehalt des Gehirnes, ließ jedoch den Katecholamingehalt des Herzens und der Aorta unbeeinflußt. Dieses unterschiedliche Verhalten der Katecholamine im Gehirn einerseits und im Herzen und in der Aorta andererseits läßt darauf schließen, daß Reserpin bei unserer Versuchsanordnung praktisch nur zentral gewirkt hat.3. Die Gabe von 80 g/kg Reserpin in die A. vertebralis führte nach einer Latenzzeit von 2–3 Std zu einer Blutdrucksenkung und ebenfalls nach einer Latenzzeit von 2–3 Std zu einer Abschwächung des CSER um mehr als 50% der Norm, die etwa nach 5 Std das Maximum aufwies; es kam jedoch nie zu einer völligen Aufhebung des CSER. Die Abschwächung des CSER war nicht vom Auftreten einer Blutdrucksenkung abhängig und wurde durch Adrenalektomie nicht beeinflußt.4. Es konnte gezeigt werden, daß die reserpinbedingte Abschwächung des CSER ihre Ursache in einer Abschwächung und schließlich völligen Aufhebung der Chemoreceptorkomponente hatte, während die Baroreceptorkomponente durch Reserpin nicht abgeschwächt wurde. Der durch lokale Applikation von KCN ausgelöste Chemoreceptorreflex wurde ebenfalls durch Reserpin abgeschwächt und aufgehoben.5. Zwischen den Reserpineffekten auf die Carotissinus-Reflexe und auf den Katecholamingehalt des Gehirnes lassen sich gewisse Parallelen feststellen.6. Die zentrale Verabreichung von 0,5 mg/kg l-DOPA führte an unbehandelten Tieren nach einer Latenzzeit von meist etwa 1/2 Std zu einer Verstärkung des CSER; die reserpinbedingte Abschwächung des CSER wurde durch l-DOPA nicht beeinflußt. Die zentrale Gabe von dl-5-HTP hatte keinen eindeutigen Effekt auf den CSER.7. Die Ergebnisse lassen das Vorhandensein von rein zentralen Wirkungen des Reserpins auf Blutdruck und Carotissinus-Reflexe erkennen und machen eine Beteiligung von zentral-adrenergen Mechanismen an diesem Geschehen wahrscheinlich.

---

Summary 1. The effects of centrally administered reserpine on the blood pressure, on the carotid reflexes [carotid occlusion reflex (COR); its baroreceptor and chemoreceptor component; chemoreceptor reflex] and on the catecholamine content of brain, heart, and aorta were investigated in cats under chloralose anesthesia. Reserpine was injected into the vertebral artery by means of a polyethylene catheter inserted into the brachial or subclavian artery.2. Reserpine, injected in a dose of 80 g/kg into the vertebral artery, significantly lowered the noradrenaline (and often the dopamine) content of the brain 5 hrs, but not 2 hrs after administration. By contrast, reserpine did not reduce the catecholamine content of the heart or the aorta at any time. These results were taken as evidence that under our experimental conditions reserpine acted predominantly centrally.3. The injection of 80 g/kg reserpine into the vertebral artery lowered the blood pressure and decreased the COR by more than 50% after a latent period of 2–3 hrs. The maximum decrease in the COR occurred 5 hrs after reserpine. In no experiment was a complete abolition of the reflex obtained. The decrease in the COR did not seem to depend on a lowering of the blood pressure and was not influenced by adrenalectomy.4. It was shown that reserpine decreased the COR by selectively decreasing and finally abolishing the chemoreceptor component, the baroreceptor component being unaffected throughout the experiment. Reserpine also abolished the chemoreceptor reflex, which was elicited by local injection of potassium cyanide.5. The effects of reserpine on the carotid sinus reflexes were paralleled to some extent by its effects on the catecholamine level in the brain.6. l-DOPA, 0.5 mg/kg, administered centrally, increased the COR in untreated animals after a latent period of about 1/2 hr. l-DOPA did not antagonize the reserpine-induced decrease in the COR. dl-5-HTP, injected centrally, had no consistent action on the COR.7. The results seem to indicate that, under suitable experimental conditions, reserpine acts centrally to produce a lowering of the blood pressure and an inhibition of some of the carotid reflexes. Central adrenergic mechanisms might be involved in the reserpine effects examined.

---

---

Ein Teil der Ergebnisse wurde auf der 28. Tagung der Deutschen Pharmakologischen Gesellschaft in Bad Nauheim vorgetragen [Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 250, 291 (1965)].     

The effect of amantadine on motor activity and catalepsy in rats

The effect of amantadine on motor activity was investigated in rats. The compound was used at doses which antagonized the catalepsy induced by spiroperidol, triperidol, chlorpromazine and reserpine. These doses moderately stimulated motor activity in normal rats; their activity was effectively antagonized by spiroperidol, chlorpromazine, phenoxybenzamine but only slightly, if at all, by -methyltyrosine, dimethyldithiocarbamate and reserpine. The behavioral effects of amantadine in normal and reserpinized rats were potentiated by l-DOPA, nialamide, desipramine and, in particular, by cocaine. The cocaine-induced potentiation of the amantadine effect was prevented by spiroperidol. -Methyltyrosine did not influence the antagonism of amantadine towards spiroperidol-induced catalepsy. Noradrenaline and dopamine levels in the whole brain and dopamine levels in the corpus striatum were unaltered by amantadine. The main mechanism of action of amantadine appears to be the activation of central dopamine receptors.     

Bromocriptine potentiates the behavioural effects of directly and indirectly acting dopamine receptor agonists in mice

Summary After an initial period of depression which lasted up to 90 min following injection, bromocriptine (BRC, 5–20 mg/kg, IP) produced dose-dependent and long lasting (7 h) locomotor stimulation in mice. The locomotor stimulation was antagonised by reserpine, alpha-methyl-p-tyrosine (AMPT) or haloperidol. The blockade by AMPT of BRC's locomotor stimulant effect was reversed by prior treatment of the mice with a low, behaviourally inactive dose of L-Dopa plus benserazide. In mice pretreated with reserpine, BRC enhanced the stimulant action of d-amphetamine. Moreover, in mice pretreated with reserpine plus AMPT, BRC significantly enhanced the locomotor stimulant effect of apomorphine. This ability of BRC to enhance the effect of apomorphine commenced as soon as 20 min after BRC administration and lasted for at least 8 h. The dopamine (DA) uptake inhibitor and DA receptor agonist nomifensine potentiated and prolonged the stimulant effect of BRC while inhibitor of the neuronal uptake of noradrenaline (desipramine) and 5-hydroxytryptamine (fluoxetine) were without marked effect. The results clearly show that BRC, in behavioural terms, has no efficacy per se at the postsynaptic DA receptor and that it requires either DA or the administration of an exogenous agonist such as apomorphine for the expression of its effects.     

Decreased sensory responsiveness of noradrenergic neurons in the rat locus coeruleus following phencyclidine or dizocilpine (MK-801): role of NMDA antagonism

The effects of the schizophrenomimetic compound phencyclidine (PCP) on baseline activity and sensory-evoked responses of noradrenergic locus coeruleus neurons were studied with extracellular single-cell recording techniques in the chloral hydrate-anaesthetized male albino rat. PCP dose-dependently decreased firing rate, induced a more regular firing pattern of the neurons, and decreased neuronal responses to a peripheral sensory stimulus (electrical stimulation of the hindpaw). These effects of PCP were significantly decreased by pretreatment with reserpine or yohimbine, indicating that the effects of PCP were largely indirect and mediated through noradrenaline, i.e. by inhibition of its re-uptake, resulting in stimulation of ₂ autoreceptors. The effects of PCP were, however, mimicked by dizocilpine (MK-801), a selective non-competitive antagonist at excitatory amino acid receptors of the N-methyl-d-aspartate (NMDA) subtype, suggesting a role also for NMDA receptors in the suppression of sensory responsiveness of locus coeruleus neurons by PCP. In view of the purported physiological role of the locus coeruleus, this effect of PCP may well contribute to the psychotomimetic properties of the drug.