Effects of pyrethroids on the acoustic startle reflex in the rat

The effects of NAK 1901 (Pentafluorbenzyl (1R, cis)-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylate) and cypermethrin ((S,R)-alpha-cyano-3-phenoxybenzyl-2,2-dimethyl (1R, 1S, cis, trans)-3-(2,2-dichlorovinyl) cyclopropane-carboxylate) (RU 24 501) on amplitude and prepulse inhibition of the acoustic startle reflex were studied in male Wistar rats. NAK 1901 (0, 1, 2.5, 4 mg/kg p.o.) enhanced the amplitude of the startle reflex in a dose-dependent way. Startle latency was not affected. Cypermethrin (0, 0.5, 1, 2 mg/kg p.o.) had no effect on the amplitude or the latency of the startle reflex. Both NAK 1901 and cypermethrin administration produced a dose-dependent increase in toxic signs and a dose-dependent increase in weight loss during the experimental session. None of the pyrethroids affected prepulse inhibition of the startle reflex. Because the neural substrate of the inhibitory processes involved in prepulse inhibition are probably of supraspinal origin, it is suggested that these substrates are not affected by pyrethroids.     

Differential effects of CGP 37849 and MK-801, competitive and noncompetitive NMDA antagonists,with respect to the modulation of sensorimotor gating and dopamine outflow in the prefrontal cortex of rats

In the present study we compared effects of the competitive and non-competitive NMDA antagonists CGP 37849 and MK-801, respectively, on sensorimotor gating in rats, measured as prepulse-induced inhibition of the acoustic startle response, and the outflow of dopamine in the rat prefrontal cortex. CGP 37849 (10, 20 mg/kg), decreased the amplitude of the acoustic startle response, but was without effect on the prepulse-induced inhibition of the acoustic startle response. MK-801 (0.4 but not 0.2 mg/kg) enhanced the amplitude of the acoustic startle response and its doses of 0.2 and 0.4 mg/kg markedly attenuated the prepulse-induced inhibition of the acoustic startle response. The effects of MK-801 (0.4 mg/kg) on the prepulse-induced inhibition of the acoustic startle response were not antagonized by the selective antagonists of D-2 and D-1 dopaminergic receptors, S(–)sulpiride (25 mg/kg) and SCH 23390 (0.1 mg/kg), respectively. When given alone, S(–)sulpiride attenuated the amplitude of the acoustic startle response and failed to altered the prepulse-induced inhibition of the acoustic startle response. SCH 23390 (0.1 mg/kg) failed to alter the amplitude and prepulse-induced inhibition of the acoustic startle response. The effects of CGP 37849 and MK-801 also differed with respect to dopamine outflow. MK-801 (0.2 and 0.4 mg/kg) enhanced the outflow of dopamine in the rat prefronatl cortex, while CGP 37849 (10 and 20 mg/kg) was without any effect on the extracellular concentration of dopamine. Our data indicate that the blockade of phencyclidine binding sites, exerted by the noncompetitive antagonist MK-801, evoked effects qualitatively different from those induced — via blockade of the NMDA recognition — by the competitive NMDA receptor antagonist CGP 37849. It is postulated that — in contrast to the non-competitive antagonist of NMDA receptors — the competitive NMDA antagonist CGP 37849 is/ should be devoid of psychotomimetic and abusing properties. It is also evident that disruption of sensorimotor gating in rats induced by MK-801 does not involve any dopaminergic mechanisms, since it is not modulated by drugs blocking D-1 and D-2 dopamine receptors. Correspondence to: K. Wdzony at the above address     

Apomorphine and haloperidol-induced effects on male rat sexual behavior: no evidence for actions due to stimulation of central dopamine autoreceptors

The administration of apomorphine (0.2-0.8 mg/kg IP) or (+)3-PPP(4-8 mg/kg IP) produced a facilitation of the male rat sexual behavior. Apomorphine in lower doses, as well as the selective DA autoreceptor agonist (-)3-PPP were ineffective. Except for a decrease in number of intromissions and an increase in the postejaculatory interval at the highest dose (0.32 mg/kg IP) there were no effects after administration of haloperidol. These data indicate that activation or inhibition of the presynaptic dopamine receptor does not affect male rat sexual behavior.     

Effects of 8-OH-DPAT,Lisuride and some ergot-related compounds on the acoustic startle response in the rat

Five ergot-related compounds were examined for their effects on the acoustic startle response in the rat. The startle amplitude and the startle latency were registered. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.5–8 mg/kg) and lisuride (0.05–0.8 mg/kg) were found to enhance the startle amplitude, while the mainly DA receptor active ergot derivatives pergolide (0.2–0.8 mg/kg), bromocriptine (5–20 mg/kg) and LY 141865 (5–20 mg/kg) had no, or even the reverse, effect. All five compounds caused a prolongation of the startle latency. The increased startle amplitude caused by 8-OH-DPAT (2 mg/kg) and lisuride (0.2 mg/kg) was successfully antagonized by the 5-HT receptor antagonist methiothepin (0.1 mg/kg) but not by metergoline (1 mg/kg). 5-Hydroxy-L-tryptophan (L-5-HTP; 12.5–50 mg/kg), administered to pargyline- and benserazide-pretreated animals, was included for comparison. The serotonin precursor caused a marked increase in the startle amplitude and a shortening of the startle latency.     

3-(3-Hydroxyphenyl)-N-(1-Propyl)piperidine elicits convulsant effects in mice

• 1.1. The behaviour and EEG effects of the dopamine and sigma (σ) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice.
• 2.2. (+) 3-PPP dose-dependently (60–100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures.
• 3.3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.).
• 4.4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

     

Differential electrophysiological effects of 3-PPP and its enantiomers on dopamine autoreceptors and postsynaptic receptors

The activities of substantia nigra pars compacta dopamine and globus pallidus neurons have been examined following the systemic administration of ( +/- )-3-PPP and the enantiomers of 3-PPP to investigate the relative effects of these putative dopamine agonists on dopamine autoreceptors and postsynaptic dopamine receptors. ( +/- )-3-PPP inhibited the firing rates of 7 out of 10 dopamine cells completely (ED50 = 0.18 +/- 0.06 mg/kg) but caused no consistent or significant alterations in the firing rates of globus pallidus neurons, exhibiting an apparent selectivity for the dopamine D-2 autoreceptors. However, (+)-3-PPP effectively inhibited the activity of all dopamine neurons studied (ED50 = 0.09 +/- 0.03 mg/kg) and, like d-amphetamine, apomorphine and other dopamine agonists, significantly stimulated pallidal activity. (-)-3-PPP was less effective at inhibiting dopamine cell activity; it had no effect on firing rates of pallidal cells when given alone, but it reversed the pallidal rate increases induced by (+)-3-PPP and also blocked the rate increases induced by systemically administered apomorphine. The results show that (-)-3-PPP, given systemically, acts as a partial agonist in the substantia nigra pars compacta and as an antagonist on postsynaptic dopamine receptors. These effects of (-)-3-PPP appear to account for the apparent dopamine autoreceptor selectivity demonstrated by racemic 3-PPP and further indicate that the autoreceptors and postsynaptic dopamine receptors may be differentially affected by a drug with mixed agonist/antagonist properties. These conclusions are consistent with those obtained from other techniques and support the idea that the effects of dopamine agonists on the activity of dopamine neurons and globus pallidus cells can provide an indication of the relative selectivity of these drugs for pre- or postsynaptic dopamine receptors.     

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1-/-) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (0.05, 0.1, and 0.2 mg/kg). The NR1-/- mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1+/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1-/- mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1-/- mice, but did reduce startle amplitude in the NR1+/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1+/+ and NR1-/- mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1+/+ and NR1-/- mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.     

Antagonist effects of the enantiomers of 3-PPP towards alpha 1-adrenoceptors coupled to inositol phospholipid breakdown in the rat cerebral cortex

The effects of the two enantiomers of 3-PPP upon alpha 1-adrenergic and muscarinic receptors coupled to the inositol phospholipid (PI) breakdown response have been investigated. 3-PPP(-) and 3-PPP(+) were found to antagonize the noradrenaline (10 microM)-stimulated PI breakdown in rat cerebral cortical miniprisms with IC50 values of 18 and 61 microM, respectively. The dopamine receptor antagonists haloperidol and raclopride were also antagonists, with IC50 values of 0.4 and 25 microM, respectively. 3-PPP(-) and raclopride were found further to act as competitive antagonists, with pA2 values of 6.03 and 5.44, respectively. 3-PPP(-), 3-PPP(+) and haloperidol also antagonized the muscarinic receptor-mediated carbachol (50 microM)-stimulated PI breakdown in cortical miniprisms, albeit at high concentrations (IC50 values of 91, 170 and 28 microM, respectively) whereas raclopride produced only 24% inhibition at the highest concentration tested (100 microM).     

Alterations in motor behaviour produced by the isomers of 3-PPP in the MPTP-treated marmoset

Alterations in motor activity induced by the isomers of 3-(3-hydroxyphenyl)-N,n-propylpiperidine (3-PPP) were studied in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In both normal and MPTP-treated animals motor activity was suppressed in a dose-dependent manner by the administration of (-)-3-PPP. In control animals (+)-3-PPP caused biphasic changes in motor activity, namely suppression of activity in low doses but stimulation at higher doses. In contrast (-)-3-PPP only caused locomotor stimulation in MPTP-treated marmosets. (+)-3-PPP may potentially be of use as a post-synaptic dopamine agonist drug in Parkinson's disease.     

The effect of the enantiomers of 3-PPP on conditioned avoidance responding in the rat

The effects of the enantiomers of 3-PPP on the maintenance of conditioned avoidance responding (CAR) were studied. The weak classical dopamine (DA) agonist (+)-3-PPP failed to interfere with CAR at any dose tested (0.8-13.6 mg/kg). Low doses of the drug produced sedation, while high doses produced behavioural stimulation. (-)-3-PPP, which acts as an antagonist on postsynaptic and as an agonist on autoreceptor DA sites, reduced avoidance with no effect on escape behaviour (6.8-13.6 mg/kg). However, this reduction of CAR occurred at doses much higher than those previously demonstrated to inhibit locomotor activity. This profile is discussed in relation to the behavioural effects of classical postsynaptic DA receptor antagonists.     

Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission

The effects of two proposed dopaminergic autoreceptor agonists, (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and the azepine derivative B-HT 920, on spontaneous locomotor activity, treadmill locomotion, and catalepsy in the rat have been compared with the effects produced by the postsynaptic dopamine (DA) receptor blocking agent haloperidol. It was found that the threshold dose for suppression of exploratory locomotor activity was 0.5, 0.005 and 0.2 mg/kg for (-)3-PPP, B-HT 920 and haloperidol, respectively. The corresponding doses for suppression of treadmill locomotion were 8.0, 5.12 and 0.2 mg/kg, respectively. Furthermore, (-)3-PPP and B-HT 920, in contrast to haloperidol, did not produce any catalepsy. Thus, using exploratory locomotor activity as an index of limbic forebrain DA functions and treadmill locomotion and catalepsy as indices of extrapyramidal DA functions, the DA autoreceptor agonists, in contrast to the postsynaptic antagonist, show a difference in the doses required to produce these effects. The designation of the behavioral functions as "limbic" or extrapyramidal is supported by the finding that scopolamine, 0.8 mg/kg, antagonized the haloperidol-induced suppression (0.2 mg/kg) of treadmill locomotion, but not the suppression of exploratory locomotor activity.     

Persistent supersensitivity of sigma receptors develops during repeated methamphetamine treatment.

Functional changes in sigma receptors were examined after behavioral sensitization induced by repeated methamphetamine treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than 6 mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing and more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than in saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least one month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (+/-)-sulpiride, a D2 dopamine receptor antagonist, and 30 mg/kg BMY 14802, a sigma receptor antagonist. These results suggest that repeated methamphetamine treatment induces persistent supersensitivity in sigma receptors and that it may subsequently activate the dopamine system.     

Effects of two pyrethroid insecticides on motor activity and the acoustic startle response in the rat

To better characterize the behavioral toxicity of pyrethroid insecticides, comparisons were made of the effects of cismethrin and deltamethrin exposure on motor activity and the acoustic startle response in male Long-Evans rats. Acute dose-effect, acute time course, and 30-day repeated-exposure determinations of 1-hr motor activity were made using figure-eight mazes. The acoustic startle response was measured to a 13-kHz, 120-dB(A), 40-msec tone at each of three background white noise levels (50, 65, and 80 dB). Deltamethrin (0, 2, 4, 6, or 8 mg/kg) or cismethrin (0, 6, 12, 18, or 24 mg/kg) were administered po in 0.2 ml/kg corn oil. Cismethrin and deltamethrin produced similar dosage-dependent decreases in motor activity. The time course of onset and recovery for this decreased activity was rapid (1 to 4 hr). No cumulative effects on motor activity of a 30-day exposure to 2 mg/kg/day deltamethrin or 6 mg/kg/day cismethrin were found. The effects of cismethrin and deltamethrin on the acoustic startle response were dissimilar: deltamethrin produced a dosage-dependent decrease in amplitude and an increase in latency, and cismethrin produced an increase in amplitude and no change in latency. The differential effects of cismethrin and deltamethrin on the acoustic startle response may be related to the contrasting effects previously shown with neurophysiological and/or neurochemical techniques.     

Effects of apomorphine and haloperidol on the acoustic startle response in rats

A series of 3 experiments tested the effects of 0.01, 0.04, 0.19, 0.75, 3.00, and 6.00 mg/kg apomorphine and 0.13, 0.25, and 0.50 haloperidol on the acoustic startle response in rats. Apomorphine markedly facilitated startle amplitude for about 40 min after injection and then depressed startle over the next 40 min. Both the early facilitory and later inhibitory effects were directly related to the dose. Haloperidol (0.5 mg/kg — given 30 min before) completely blocked both the early facilitory and the later depressant effect of apomorphine (3 mg/kg). Haloperidol alone had only a slight depressant effect on startle. The data support the conclusion that DA receptor stimulation enhances acoustic startle amplitude and indicate that a previous report failed to find an effect of apomorphine on startle because startle was only measured 40 min after injection.     

An examination of the putative sigma-receptor in the mouse isolated vas deferens.

1. The effects of several ligands which interact with the sigma-binding site were studied on the electrically-evoked (0.1 Hz) neurogenic twitch contractions of the mouse isolated vas deferens. 2. (+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) (10(-8) - 10(-5) M), inhibited the neurogenic twitch contractions. This inhibitory action was unaffected by naloxone (10(-6)M), idazoxan (10(-6)M), cocaine (10(-6)M) or tyramine (10(-4)-3 x 10(-4)M), but was abolished by the dopamine D2-antagonist, sulpiride (10(-6)M). Therefore, in order to study the potentiating actions of sigma ligands, sulpiride (10(-6)M) was used to prevent any inhibitory actions mediated via dopamine D2-receptors. 3. In the presence of sulpiride (10(-6)M), haloperidol (10(-6)-10(-5)M), (+)-3-PPP (10(-6)-3 x 10(-4) M) and (+)-N-allyl-N-normetazocine [+)-SKF 10,047) (10(-5)-10(-4)M) each reversibly potentiated the neurogenic twitch contractions in a concentration-dependent manner. The rank order of potency was haloperidol greater than (+)-3-PPP greater than (+)-SKF 10,047. 4. The stereoisomers of 3-PPP displayed stereoselectivity with (+)-3-PPP being more potent than (-)-3-PPP. 5. At a concentration that did not potentiate the twitch contractions, (3 x 10(-7)M), haloperidol did not antagonize the potentiating action of (+)-3-PPP (3 x 10(-5)M). 6. 1,3-Di-O-tolyguanidine (DTG) (10(-8)-10(-5)M) had no effect on the amplitude of twitch contractions and did not affect the potentiating action of (+)-3-PPP (10(-5)-3 x 10(-5)M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the phosphodiesterase inhibitor rolipram on the acoustic startle response in rats

Systemic administration of the phosphodiesterase inhibitor rolipram (0.05–10.0 mg/kg, IP) produced a rapid and dose-related increase in the amplitude of the acoustic startle response in rats. The (−) isomer was more potent than the (+) isomer in enhancing startle amplitude. Rolipram increased startle responses that were elicited by brief electrical stimulation of the ventral cochlear nucleus or nucleus reticularis pontis caudalis, two brainstem relay nuclei of the startle neural circuit. A low (5 μg) dose of rolipram produced an excitatory effect on startle following spinal (lumbar intrathecal) infusion but not following supraspinal (lateral ventricle) infusion. Rolipram (0.5 mg/kg, IP) excitation of startle was not blocked by drugs which differentially disrupt the release of monoamines (DSP4, reserpine + alpha-methylpara-tyrosine, reserpine + para-chloro-phenylalanine) or by drugs which differentially block monoamine receptors (haloperidol, prazosin, idazoxan, cinanserin, or cyproheptadine). The marked increase in startle seen following systemic rolipram injection is attributable, at least in part, on an action in the lumbar spinal cord that directly or indirectly facilitates neural transmission along the reticulospinal component of the startle reflex neural pathway. The startle reflex should be a useful behavioral test system for studying the mechanism of action of rolipram and related compounds purported to selectively inhibit calmodulin-independent forms of phosphodiesterase.     

Discriminative stimulus effects of a low dose of apomorphine in the rat

The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other directacting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation.     

On the mode of action of six putative dopamine receptor agonists on suppression of exploratory behaviour in rats

The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereotyped behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose response curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.     

Selective sigma receptor agonist and antagonist affect dopamine neuronal activity

Extracellular recording techniques were used to study the effects of the selective sigma receptor agonist (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and selective sigma receptor antagonist BMY 14802 on dopamine (DA) neurons of the substantia nigra. Intravenous administration of (+)-3-PPP produced a dose-dependent inhibition of DA neuron firing rate. Complete inhibition of DA neurons produced by (+)-3-PPP could be completely reversed by administration of BMY 14802. Also, pretreatment with BMY 14802 shifted the (+)-3-PPP dose response curve to the right. These data 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.     

Antagonist Effects of the Enantiomers of 3-PPP towards α1-Adrenoceptors Coupled to Inositol Phospholipid Breakdown in the Rat Cerebral Cortex

Abstract: The effects of the two enantiomers of 3-PPP upon α₁-adrenergic and muscarinic receptors coupled to the inositol phospholipid (PI) breakdown response have been investigated. 3-PPP(-) and 3-PPP(+) were found to antagonize the noradrenaline (10 μM) - stimulated PI breakdown in rat cerebral cortical miniprisms with IC50 values of 18 and 61 μM, respectively. The dopamine receptor antagonists haloperidol and raclopride were also antagonists, with IC50 values of 0.4 and 25 μM, respectively. 3-PPP(-) and raclopride were found further to act as competitive antagonists, with pA₂ values of 6.03 and 5.44, respectively. 3-PPP(-), 3-PPP(+) and haloperidol also antagonized the muscarinic receptor-mediated carbachol (50 μM) - stimulated PI breakdown in cortical miniprisms, albeit at high concentrations (IC50 values of 91, 170 and 28 μM, respectively) whereas raclopride produced only 24% inhibition at the highest concentration tested (100 μM).