Sigma Agonist Research Articles

Antagonism of metergoline on the diuretic effect of cyclazocine and U-50488 drugs with a kappa agonist activity

In rats receiving a normal saline load of 2.5 ml/100 g, sc, (moderately hydrated rats), injections of the serotonin (5-HT) antagonist, metergoline (0.25 - 1 - 4 mg/kg), resulted in a dose-dependent decrease in the urine output induced by a dose of 8 mg/kg of cyclazocine (a benzomorphan derivative, mixed kappa and sigma agonist) at the 2-h time period. The antagonist effect of metergoline (1 mg/kg) on cyclazocine doses ranging from 0.25 to 8 mg/kg, was observed only at 2 mg/kg higher doses. Other 5-HT receptor blockers, methysergide, pizotifen, cyproheptadine, caused a significant degree of antagonism. In rats receiving a saline load and a water load of 5.5 ml/100 g, ip (hyperhydrated rats), metergoline (1 mg/kg) completely antagonized the diuretic effect of cyclazocine (8 mg/kg) at the 4-h and 5-h time periods. Similarly, metergoline (1 and 4 mg/kg) administered in moderately hydrated rats, markedly decreased at the 2-h time period, the urine output produced by 5 mg/kg of U-50488 (a non benzomorphan derivative, highly selective kappa agonist), and in hyperhydrated rats, completely suppressed, at the 4-h and 5-h time periods the drug-induced diuresis. Metergoline administered alone had no effect on urine output in moderately hydrated rats or in hyperhydrated rats. These results suggest the hypothesis that 5-HT may be involved in the complex mechanisms of kappa agonist-induced diuresis in rats.

The kappa-opioid receptor: Evidence for the different subtypes

Classification of drugs acting on the kappa-opioid receptors seems to be difficult, since some of these ligands are also sigma agonists and/or display non-opioid actions as well. Furthermore, certain benzomorphans having kappa-agonistic character, are shown to be mu-antagonists too. Therefore the classification of the kappa-opioid receptor has to be presently restricted to two subclasses that also have physiological meaning. Dynorphin and Met-enkephalin-Arg 6-Phe 7 are proposed as endogenous peptide ligands for kappa-receptors. Nonpeptide agonists are benzeneacetamides interacting with the kappa 1 receptor. Benzomorphans bind to both subtypes of kappa-receptors. No selective nonpeptide ligand for the kappa 2 receptor exists as yet. Nor-binaltorphimine, a specific kappa-antagonist also inhibits both kappa-subtypes. Further research for kappa 2 selective drugs is necessary for clear distinction between the two kappa-opioid binding sites. Molecular cloning of opioid receptors including their subtypes are expected to provide direct proof of their existence.

Effects of some opiates and opioid peptide eyedrops on ocular melatonin regulation in rabbits.

Levels of melatonin in rabbit eye tissues were detected by radioimmunoassay. Solutions of met-enkephalin, leu-enkephalin, alpha-endorphin and beta-endorphin were given topically. Met-Enkephalin and alpha-endorphin lowered levels of melatonin in the iris, iris root-ciliary body, retina and choroid; leu-enkephalin raised levels in the retina and lowered them in other tissues. beta-Endorphin only lowered levels in the iris root-ciliary body. DAGO (a mu agonist) given i.v. lowered levels of melatonin in the iris, iris root-ciliary body and retina. The delta and sigma agonists given i.v. only lowered levels in the iris root-ciliary body, and a kappa agonist given i.v. raised levels in the ciliary body. No opiate binding sites could be detected in the rabbit iris or iris root-ciliary body for any class of receptor. Our data suggest opioids may be useful for treating glaucoma.

Synthesis of [N‐C3H3]‐racemic‐trans‐1‐phenyl‐3‐dimethylamino‐6‐chloro‐7‐hydroxy‐1,2,3,4‐tetrahydronaphthalene (PAT‐6)

AbstractThe biological function of the sigma receptor in the central nervous system is not well understood at the present time. Once thought to be an opiate receptor, the sigma receptor has now been shown to have a neuromodulatory effect upon the synthesis of dopamine in the striatal nerve terminal. A novel sigma agonist, racemic‐trans‐1‐phenyl‐3‐dimethylamino‐6‐chloro‐7‐hydroxy‐1,2,3,4‐tetrahydronaphthalene, PAT‐6, has demonstrated the greatest potency of any compound tested to date as a sigma agonist in stimulating the synthesis of dopamine in vitro and may be functioning at a novel sigma receptor subtype. The synthesis of tritiated PAT‐6 at high specific activity is described herein. This labeled ligand was prepared for use in radioreceptor binding studies in order to identify the putative sigma receptor subtype responsible for mediation of the stimulatory effect on in vitro dopamine synthesis.

Phencyclidine and auditory sensory gating in the hippocampus of the rat

The psychotomimetic drug 1-(1-phenylcyclohexyl) piperidine (PCP, phencyclidine) was found to cause a deficit in the gating of the response of the hippocampal neuron to repeated auditory stimuli, which is similar to a particular physiological feature observed in human psychosis. Other drugs, with sigma agonist and/or N- methyl- D - aspartate (NMDA) antagonist effects, were administered and their ability to cause a loss of auditory gating was compared to that of PCP. The rank order of effectiveness was levoxodrol > PCP and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) > N-allylnormetazocine (SKF 10047) > dexoxodrol > 3-(±)2-carboxypiperazine-4-yl) propyl-1-phosphonate (CPP). Further studies of two of the drugs, PCP and MK-801, showed that selective lesioning of the noradrenergic input with the neurotoxin DSP4, as well as less selective depletion of monoamines with reserpine, blocked the loss of gating. Phencyclidine, and other drugs with the same spectrum of action, most likely disrupt gating by increasing noradrenergic activity through a sigma mechanism.

ChemInform Abstract: Novel, Enantioselective Synthesis of Vicinal Cyclohexanediamines as Key Intermediates for Highly Selective Opioid Kappa and Sigma Agonists.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Electrophysiological effects of phencyclidine and the sigma agonist ditolylguanidine in the cerebellum of the rat

The electrophysiological actions of phencyclidine (PCP) and the sigma agonist 1,3-di(2tolyl)guanidine (DTG) were examined in the cerebellum of urethane-anesthetized rats. The object of the study was to determine if PCP and sigma agonists shared a common mechanism of action. The cerebellar Purkinje neuron was chosen because it has sigma receptors but not N-methyl- d-aspartate receptors, where PCP has additional effects. Both DTG and PCP decreased the spontaneous discharge rate of cerebellar Purkinje neurons after parenteral administration. When the drugs were applied locally to single Purkinje neurons, using pressure ejection through multibarrel micropipettes, both compounds decreased the spontaneous activity of the neurons with equal potency. Previous studies have shown that the actions of PCP in the cerebellum are dependent upon an interaction with noradrenergic terminals from the nucleus locus coeruleus. A similar finding was made in this study for DTG. Elimination of the noradrenergic input by lesion with the neurotoxin, 6-hydroxydopamine, diminished equally the effects of PCP and DTG. Treatment of the animals with haloperidol had similar effects. It is concluded that PCP and the sigma agonist DTG both act as indirect noradrenergic agonists in the cerebellum.

Novel, enantioselective synthesis of vicinal cyclohexane-diamines as key-intermediates for highly selective opioid kappa and sigma agonists.

Enantiomers of Cyclohexane-1,2-diamines have been synthesized via two different synthetic approaches by asymmetric catalytic hydrogenation.

Patent Evaluation: Novel N-cycloalkylamines as Sigma Agonists

SummaryNovelty: N-Cycloalkylamines are disclosed with activity as a receptor agonists. These compounds are potentially useful as antipsychotic, anticonvulsant and anti-ulcer agents.Biology: Competitive binding data are presented showing that the compounds have selective affinity for the sigma receptor in comparison to the, μ, δ and PCP receptors. Psychotropic activity is demonstrated by inhibition of picrotoxin-induced convulsion (ED50 values about 50 mg/kg, ip, and 100 mg/kg, po). Anti-ulcer activity is shown by inhibition of cysteamine induced gastrointestinal ulceration.Chemistry: Syntheses of the compounds are outlined in two schemes, forming a subsidiary part of the claim with ten examples. 1-[2-(N-Cycloproyimethyl-N-methyl)amino-2-phenyl-butyl]-2-(2-thienyl)cyclopropane is one of two specifically claimed compounds.

Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs

The present study examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl-D-aspartate (NMDA) antagonists in guinea-pigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg/kg SC) and (-)NANM (1 and 10 mg/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity, whereas the sigma ligand pentazocine induced sedation but no flattened posture. Ketamine (20 mg/kg SC) and (+)dizocilpine (0.025, 0.1 and 1 mg/kg SC) produced similar effects to those of (+) and (-)NANM. However, the putative sigma receptor ligand DTG (1 and 10 mg/kg SC) had no observable effect on behaviours in guinea-pigs, similar to results for other species. The behavioural effects produced by (+) and (-)NANM were not reversed by injection 1 h later of naloxone hydrochloride (15 mg/kg SC), haloperidol (10 mg/kg SC) or DTG (10 and 30 mg/kg SC), but the effects of all drugs were reversed by the selective dopamine D-2 agonist quinpirole (3 mg/kg IP). Moreover, injection of naloxone (15 mg/kg SC), DTG (10 and 30 mg/kg SC) or haloperidol (1 and 10 mg/kg SC) 10 min before, did not reverse the behaviour induced by (+)NANM (10 mg/kg SC). These data indicate that sigma and PCP-like drugs have a similar gross behavioural effect in guinea-pigs, possibly mediated by non-competitive antagonism of the NMDA subtype of glutamate receptors. The results demonstrating behavioural depression were in contrast to the stimulatory effects of these drugs at similar doses in other rodent species.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sigma receptor ligands on schedule-controlled behavior of rats: relation to sigma and PCP receptor binding affinity.

Eleven drugs were examined for their ability to inhibit sigma and phencyclidine (PCP) receptor binding, as labelled by (+)[3H]-R-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), [3H]ditolylguanidine (DTG), (+)[3H]N-allylnormetazocine (NANM) and [3H]1-(1-(2-thienyl)cyclohexyl)piperidine (TCP), in membrane preparations from whole rat brain. The same drugs were studied for their effects under a fixed-ratio (FR) schedule of food reinforcement in rats. The relative potency order of the drugs for decreasing FR responding was: haloperidol greater than (+)-3-PPP greater than (-)NANM greater than BMY 14802 greater than PCP greater than (+)NANM greater than DTG greater than rimcazole greater than JO 1783 greater than JO1784 greater than (-)butaclamol. The binding affinities of all 11 drugs for either the [3H]DTG, (+)[3H]-3-PPP, (+)[3H]NANM or [3H]TCP site did not correlate significantly with the potencies of the same drugs for decreasing FR behavior. Rimcazole, (+)-3-PPP and haloperidol, at behaviorally inactive doses, were studied for their effects as antagonists of the rate-decreasing effects of JO 1784, DTG and (+)NANM: rimcazole attenuated the effects of DTG and (+)NANM but not JO 1784; (+)-3-PPP attenuated the effects of (+)NANM but not JO 1784 and DTG; and haloperidol was devoid of antagonistic actions. Moreover, BMY 14802 did not attenuate the rate-decreasing effects of (+)-3-PPP. These results further indicate that it is difficult to distinguish between purported sigma agonist and antagonist drugs.

Pharmacological characterization of sigma binding sites in guinea pig brain membranes.

The discovery of sigma binding sites has prompted investigation into the functional role of these sites. Binding studies have revealed that sigma sites exhibit a unique pharmacological profile, and have provided evidence favoring the existence of a multiplicity of sigma binding sites in central nervous system. However, the findings that chemicals having diverse structures and therapeutic applications are all potent sigma agents, and that sigma binding sites are present in peripheral tissues, have raised concerns about the physiological and pharmacological relevances of this site. Furthermore, an endogenous ligand for the sigma binding site has not yet been identified. Finally, there is a lack of data regarding the functional coupling of sigma binding sites, although recent studies have provided some clues as to a possible signalling mechanism (Karbon et al., 1990). Besides raising questions about the relevance of sigma sites, the paucity of information on their functional properties has made it difficult to distinguish sigma agonists from and antagonists. While haloperidol is assumed to be a sigma antagonist, the finding that prolonged administration of this neuroleptic decreases the number of sigma sites would seem to argue in favor of it being an agonist for this site. Regardless of the precise nature of the sigma binding site, studies have suggested that it may represent the site of action for a number of important drugs. For example, haloperidol, a butyrophenone antipsychotic, exhibits high affinity for sigma binding sites, and several psychotomimetics, including PCP and (+)-benzomorphans, also bind this site.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential Roles of Opioid Receptors in Respiration, Respiratory Disease, and Opiate-induced Respiratory Depression

In summary, these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction, and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation, and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance, mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters, including RR, VT, VE, and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration, especially in the NTS. In the CNS, the ventral surfaces of the medulla and pons, especially the NTS and NA, seem to be important sites for opioid-induced inhibition of respiration, whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity, whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists, such as fentanyl and oxymorphine, probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition, the effects of mu, delta, kappa, and sigma selective agonists on hypoxic drive should also be determined, as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future, clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising, as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development, combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of sigma agonist and antagonist drugs on food and/or water intake in rats

AbstractDrugs known to interact with sigma receptors were studied for their effects on food and/or water intake, since the putative sigma receptor agonist N‐allylnormetazocine (NANM) has been reported to both increase and decrease food intake under various conditions. Previous investigators have shown that each enantiomer of racemic NANM [(±)‐NANM] is pharmacologically active. (+)‐NANM appears to interact preferentially with sigma receptors, and (−)‐NANM with both mu and kappa opiate receptor sites. In the present study, the effects of subcutaneously administered (±)‐NANM, (+)‐NANM, and (−)‐NANM on food intake in 20 hr food‐deprived male rats were examined. (±)‐NANM and (−)‐NANM decreased food intake stimulated by food deprivation, while (+)‐NANM exhibited no significant effect. Similarly, both (±)‐NANM and (−)‐NANM decreased water intake in 24 hr water‐deprived rats. (+)‐NANM decreased water intake in doses which may have caused disorientation. Locomotor activity was stimulated by intraperitoneal injection of 10 mg/kg of (+)‐NANM but not by the same dose of (−)‐NANM. The effects of (+)‐NANM and (−)‐NANM on food and water intake paralleled those of narcotic antagonists and did not seem related to an interaction with sigma receptors. (±)‐BMY14802 is a sigma receptor antagonist with potential antipsychotic properties. When administered to female rats by daily injection for 28 days, it did not affect weight gain except at the highest dose, 30 mg/kg. Weight gain of animals given a 30 mg/kg dose was significantly greater compared to controls. However, rats treated orally with a similar dose of (±)‐BMY14802 incorporated into the diet daily for 8 weeks did not exhibit significant weight gain compared to controls. The data argue against a significant role for sigma receptors in mediating ingestive behavior. Should sigma antagonist drugs reach the market, they may be less likely to cause weight gain than most classical antipsychotics.

Cardiovascular and respiratory effects of an opioid kappa agonist ethylketazocine and sigma agonist N-allylnormetazocine in acutely decerebrated dogs

Effects of opioid kappa agonist ethylketazocine (EKC), sigma agonist (±)-N-allylnormetazocine (NANM), and naloxone alone and in combination on mean blood pressure (MBP), heart rate (HR), respiratory rate (RR) and minute volume (MV) were studied in acutely decerebrated dogs. EKC (0.5 mg/kg) decreased HR, MBP, RR and MV. Post-EKC NLX increased RR and MV and reversed the bradycardia and hypotension produced by EKC. NANM (1 mg/kg) produced respiratory depression and tachycardia without changing MBP. Post-NANM NLX antagonized tachycardia, increased MBP, however did not significantly change RR and MV. When decerebrate dogs were spinalized at the C-1 level, EKC decreased MBP and HR. These effects were antagonized by NLX. NANM did not change HR but raised MBP in spinalized decerebrate dogs. Since EKC- and NANM-induced cardiovascular and respiratory depression were not observed in conscious intact or chronic spinal dog, it is suggested that: 1) kappaergic system rostral to mesencephalon may play a role in counteracting these depressant effects of EKC; 2) sigma receptor-mediated tachypnea and tachycardia are dissociable; the tachypneic effect may be mediated through higher center while the medulla oblongata is involved in producing tachycardia. These results also suggest that (±)-NANM probably has several mechanisms of action at several brain sites in producing its effects on respiration and cardiovascular function.

Electrophysiological effects of selective ?-receptor agonists, antagonists, and the selective phencyclidine receptor agonist MK-801 on midbrain dopamine neurons

Extracellular single unit recording techniques were used to study the effects of selective sigma-receptor agonist [(+)-3-PPP, (+)-pentazocine, and DTG] and selective sigma-receptor antagonists (BMY 14802 and Rimcazole) on dopamine neurons of the substantia nigra. Intravenous (IV) administration of sigma agonists decreased, whereas IV administration of the sigma antagonist BMY-14802 increased the firing rate of dopamine neurons. The other sigma antagonist Rimcazole produced inconsistent changes in dopamine unit activity. These data, in conjunction with anatomic data suggesting sigma receptor localization on dopamine neurons in the substantia nigra (Gundlach et al: J Neurosci 6:1757-1770, 1986; Graybiel et al: Soc Neurosci Abstr 13:28, 1987) demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist-antagonist interactions of sigma ligands. The selective phencyclidine (PCP) agonist MK-801 was equipotent to PCP in regard to stimulatory properties on dopamine neurons. However, the relative potencies do not correspond to their relative binding affinities, suggesting that non-PCP-receptor properties may mediate this effect.

Facilitation of gamma-aminobutyric acid-induced depression by (+)PCMP and dexoxadrol in the cerebellar Purkinje neurons of the rat.

The purpose of this experiment was to investigate the interaction of GABA (gamma aminobutyric acid) with PCP (phencyclidine) and sigma receptor agonists in the cerebellum. Drugs were applied directly to a single cerebellar Purkinje neuron of urethane-anesthetized rats, through a multibarrel pipette. The PCP receptor agonist, (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], significantly enhanced GABA-induced inhibition. On the other hand, its stereoisomer, (-)PCMP, had no such modulatory effect. Dexoxadrol, a sigma receptor agonist, similar to (+)PCMP, potentiated GABA-induced depression. Its stereoisomer, levoxadrol, although inhibiting the spontaneous firings of Purkinje neurons, did not alter the effect of GABA. In conclusion, the findings indicate that the electrophysiological mechanisms of PCP-induced facilitation of GABA-induced reactions are similar to those triggered by sigma agonists in the cerebellum.

A role played by sigma receptors in the conditioned suppression of motility in mice.

Mice exhibited marked suppression of motility (conditioned suppression) when placed in the same environment in which they had previously received an electric footshock. The conditioned suppression was attenuated by cyclazocine and N-allylnormetazocine (SKF-10047), sigma agonists. The effect of these drugs was reduced by chronic pretreatment with cyclazocine. This behavioral change was related to the change in binding activity of [3H]-phencyclidine to sigma receptors (defined using non-radioactive SKF-10047). In the chronic vehicle-pretreated conditioned suppression group, the Kd and Bmax values of [3H]-phencyclidine binding at the high affinity site were increased when compared to those in the chronic vehicle-pretreated control group. The increased values were restored to the control levels by acute treatment with cyclazocine and SKF-10047. On the other hand, in the chronic cyclazocine-pretreated conditioned suppression group, acute cyclazocine and SKF-10047 treatment failed to change the increased values of Kd and Bmax at the high affinity site. The present behavioral and receptor-binding experiments suggest that the activation of nervous system mediated by sigma receptors may be responsible for the attenuation of conditioned suppression of motility.

Differential effects of opioid and nonopioid analgesics on conditional discriminations in pigeons

Under the fixed-consecutive-number schedule (FCN), pigeons were reinforced for responding eight or more times on one response key (work key), and then responding once on a second response key. In one component of this schedule, an external stimulus signalled the completion of the response requirement on the work key (FCN 8-SD), whereas no stimulus change was programmed under the other (FCN 8). Across a range of doses, the mu opioid agonist morphine, the kappa opioid agonist U50,488 and the opioid antagonist naloxone had no consistent effect on accuracy under either FCN schedule. Naloxone and accuracy under either FCN schedule. Naloxone and U50,488 produced a general flattening of the conditional probability functions by decreasing the conditional probability of response runs exceeding the minimum response requirement of eight consecutive responses on the work key. The sigma agonists phencyclidine and (+)N-allylnormetazocine and the nonopioid analgesics clonidine and l-nantradol produced large decreases in accuracy under the FCN 8 and small decreases under the FCN 8-SD. With the exception of (+)N-allylnormetazocine, these drugs consistently increased the conditional probability of responses runs shorter than the minimum response requirement on the work key. These findings indicate that the accuracy-altering effects of some opioid and nonopioid analgesics depend in part on the type of discrimination task.

Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists.

Evidence has accumulated that the discriminative stimulus effects of phencyclidine (PCP) may be transduced by a specific receptor in mammalian brain. Two major lines of evidence support this hypothesis. One is the structure-activity correlation that arylcyclohexylamine analogs of PCP have for PCP-like discriminative effects and displacement of [3H]PCP binding. The other, even stronger, evidence is that representatives of some nonarylcyclohexylamine classes of drugs are both generalized from PCP and have activity at PCP-binding sites. These include the psychotomimetic sigma-agonist opioids such as (+)-N-allylnormetazocine (NANM), the 1,3-substituted dioxolanes dexoxadrol and etoxadrol and some benz(f)isoquinolines. Early evidence suggested that there may be a complete overlap in the discriminative effects and receptor systems for PCP and sigma-agonists, and there continues to be evidence to support the commonality of these drug groups. On the other hand, binding studies with radiolabeled sigma agonists have revealed a non-PCP site. The role of this site in the behavioral actions of sigma-agonists is at present unknown. PCP analogs and other PCP-like drugs also can function as reinforcers for self-administration behavior, suggesting that the same cellular mechanisms may be responsible for both discriminative and reinforcing stimulus effects of these drugs. PCP has been shown to block many of the in vitro and in vivo effects of N-methyl-D-aspartate (NMDA), a putative specific agonist for a subtype of excitatory amino acid receptor. Recent evidence that NMDA antagonists are generalized from PCP in rats and pigeons provides evidence that modification of excitatory amino neurotransmission may be a physiological function of the PCP receptor and that this receptor complex may be involved in PCP's discriminative stimulus effects.