Disinhibitory effect of phencyclidine in the hippocampus in vitro: PCP receptors implicated

European Journal of Pharmacology, 150 (1988) 67-74

67

Elsevier EJP 50269

Disinhibitory effect of phencyclidine in the hippocampus in vitro: PCP receptors implicated G e r a l d W. B o u r n e , B a r b a r a Esplin a n d R a d a n C a p e k * Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1 Y6, Canada

Received 17 February 1988, accepted 1 March 1988

The effects of phencyclidine (PCP) and two dioxolane stereoisomers, dexoxadrol and levoxadrol, on hippocampal inhibition were compared. Field potentials were recorded in the CA1 pyramidal cell layer in the rat hippocampal slices in vitro. Recurrent inhibition of the population spikes evoked orthodromically by stimulation of the Schaffer collaterals was induced by antidromic conditioning stimulation at appropriate time intervals before the orthodromic stimulation. The drugs were applied by micropressure ejection in concentrations which did not affect the unconditioned population spike. After PCP or dexoxadrol administration, the orthodromically evoked population spike was much less reduced by the antidromic conditioning stimulation than before, suggesting that the recurrent inhibition was diminished. Levoxadrol had only negligible effect. Since dexoxadrol has many PCP-like pharmacological properties but levoxadrol does not, we concluded that PCP attenuates hippocampal recurrent inhibition by activating the PCP receptors. It is suggested that this action results in depression of excitatory synaptic transmission from axon collaterals to the inhibitory interneuron with possible involvement of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor. Phencyclidine (PCP); Dioxolanes (dexoxadrol and levoxadrol); PCP receptors; (Recurrent inhibition, Disinhibition)

1. Introduction

Soon after introduction of phencyclidine (PCP) as i.v. general anesthetic which did not depress blood pressure or respiration, this drug fell into disrepute and had to be withdrawn from clinical use because of psychotomimetic properties and other side effects, such as muscle rigidity, agitation, disorientation, seizures and delirium (Snyder, 1980). Since then, PCP has emerged as a dangerous and wide spread drug of abuse which was said to be everything we were afraid marihuana would turn to be but has not (Stillman and Petersen, 1979).

* To whom all correspondence should be addressed.

The mechanisms by which this drug produces its wide and complex array of clinical symptoms in man and behavioral effects in animals is obscure despite of intense research interest. Investigation into the molecular mechanism of PCP action led to discovery of specific, saturable, reversible, high affinity binding sites in the brain (Vincent et al., 1979; Zukin and Zukin, 1979; Quirion et al., 1981). The good correlation of relative potencies and stereospecifity of PCP analogues in behavioral studies, including discriminative stimulus tests, and in displacing radiolabelled PCP from its binding sites, suggested that these sites may be the receptors mediating the behavioral effects of PCP and other dissociative anesthetics, benzomorphan o opiods and substituted dioxolanes. Several behavioral, ligand binding and biochemical studies

0014-2999/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)

68 suggested that this PCP receptor and the previously described o opioid receptor (Martin et al., 1976) might be the same site (Quirion et al., 1981; Mendelsohn et al., 1985). However, it is now apparent that radiolabelled benzomorphans bind preferentially to a o site whose functional relevance is still obscure and which has a distinct distribution from that of the PCP receptors (Quirion et al., 1987). The hippocampal formation may be an important target for PCP action. The increase in metabolic activity in the hippocampus following administration of PCP, as measured by 2-deoxyglucose uptake, was among the highest found in the brain (Meibach et al., 1979). It contains high density of the PCP receptors (Zukin and Zukin, 1979;) and high concentration of an endogenous PCP like peptide (Quirion et al., 1984). Our electrophysiological study revealed that PCP reduced inhibition of the population spikes in the hippocampal slice preparation (Bourne et al., 1983). This effect was produced by concentrations of PCP which were achieved in the brain after administration of doses producing seizures in rodents and man (Domino, 1964; Bums and Lemer, 1976). Therefore we suggested that PCP induced convulsions may result from such a disinhibitory effect in the hippocampus and possibly other structures. The present study was designed to demonstrate specificity of PCP induced disinhibition and to provide evidence that this effect is mediated by the PCP receptors. To this end, we compared the effects of PCP on recurrent inhibition with those of two dioxolane stereoisomers, dexoxadrol and levoxadrol, in the hippocampal slice preparation. Since dexoxadrol was shown to share many pharmacologic properties with PCP and to displace radiolabelled PCP from brain membranes, while levoxadrol was inactive or much less active (Hampton et al., 1982; Cone et al., 1984), these two stereoisomers are considered chemical probes of choice for studying the effects mediated through PCP receptors (Jacobson et al., 1987). We now report that the disinhibitory effect of PCP in the hippocampus is stereospecific. These results have been presented in a preliminary form (Capek et al., 1987).

2. Materials and methods

2.1. Preparation of slices Slices of the rat hippocampus were prepared as previously described (Bourne et al., 1983). Briefly, male Sprague-Dawley rats were decapitated, the brain removed and the hippocampi dissected in ice-cold oxygenated artificial cerebrospinal fluid (ACSF) of the following composition (in mM): NaC1 124; KC1 4.9; N a H C O 3 25.6; CaC1 z 2.0; K H 2 P O 4 1.2 MgSO 4 1.3; glucose 10. The hippocampus was sliced perpendicular to the longitudinal axis in 425/~m sections using a tissue chopper and the slices were transfered to a recording chamber.

2.2. Stimulation and recording In the recording chamber, the slices were maintained at 36 ° C, the upper surface exposed to a flow of moist 95% 02 and 5% CO 2 and the lower surface resting on a lens paper exposed to the oxygenated ACSF which was perfused through the chamber at a rate of 1 m l / m i n by a pump. After at least 1 h of incubation, field potentials were recorded from the pyramidal cell layer in the CA1 region with a 3 M NaC1 filled glass micropipette (10-20 MI2). They were elicited by stimulating pulses (100 /ts, 3-20 V) delivered through bipolar stimulating electrodes. One was placed in the stratum radiatum to activate the pyramidal cells orthodromically through the excitatory synapses. Another one was positioned in the alveus to activate the cells antidromically through their axons. Recurrent inhibition was tested by the antidromic-orthodromic stimulation paradigm. The intensity of the orthodromic stimulus was adjusted to produce a population spike of about 50% of the maximum. Inhibition of this orthodromically evoked population spike was accomplished by a conditioning antidromic stimulus delivered to the axons 10, 20 or 40 ms before the orthodromic stimulus. The responses were tested every 20 rain. No drugs were applied unless the responses were stable for at least 1 h.

69

2.3. Drugs Phencyclidine hydrochloride and two stereoisomers of dioxolane, dexoxadrol hydrochloride and levoxadrol hydrochloride, were dissolved in A C S F and applied b y micropressure. T h e system used was similar to that described by Palmer and coworkers (1980). The A C S F with or without the drug was ejected from a micropipette having an internal tip diameter of 4 / ~ m by nitrogen at 68.9 kPa (10 p o u n d s per square inch) applied for 0.5 s. The volume exuded from the tip of the micropipette, estimated from the diameter of the drop of fluid measured in mineral oil, was 65.5 pl. The micropipette was positioned about 50 /~m from the recording electrode at the surface of the strat u m pyramidale on the same side as the stimulating electrode in the alveus.

2.4. Data acquisition and analysis I n most experiments, the previously described m i c r o c o m p u t e r based system for data acquisition and analysis (ThrorSt et al., 1984) was used on line. Occasionally, the waveforms were recorded first by a F M tape recorder. The responses were digitized at 12.8 kHz, groups of 10 responses evoked at 0.2 Hz averaged, the averages plotted b y a strip chart recorder and stored on a diskette for further processing. The amplitude of each averaged population spike, defined as the potential difference between the m a x i m u m negativity of the population spike and the m a x i m u m subsequent positivity, was determined b y the computer. The degree of inhibition was quantitatively characterized by the difference between the amplitude of the unconditioned orthodromically evoked p o p u l a t i o n spike and the amplitude of that conditioned by a preceding antidromic stimulus, expressed as percentage of the unconditioned one. A paired t-test was used to evaluate the statistical significance of the drug induced change in this measure at each time interval between the antid r o m i c and o r t h o d r o m i c stimulus.

3. R e s u l t s

Micropressure application of the A C S F without the drug did not alter the amplitude of the ortho-

TABLE 1 Recurrent inhibition of the population spikes before and after micropressure application of the ACSF. Time interval (ms) b

Population spike (%) a Before After c

10 20

20.6±5.9 26.8±5.3 52.4±6.8

16.2±5.2 27.4±5.1 51.2±4.3

a Amplitudes of the orthodromically evoked population spikes conditioned by preceding antidromic stimulation, expressed as percent of the amplitudes of the unconditioned orthodromic population spikes. Each value is the mean + S.E. of six experiments, b Time interval between the antidromic and orthodromic stimuli in ms. c 2 min after pressure application of the ACSF. dromic or antidromic population spike. Neither did it have any effect on the time course of inhibition. This was tested in six experiments. There was no statistically significant difference between the amplitude of population spikes conditioned by preceding antidromic stimuli before and after the A C S F ejection at the three interstimulus intervals tested (table 1). ANTI

PeP

ti

5x1(~5M

t

REcovERy t

ORTHO lOms

2Orris

40ms

,

L_

Fig. 1. The effects of PCP on recurrent inhibition of the population spikes in the CA1 region. Each trace is an average of 10 responses in a typical experiment. Anti, population spikes evoked antidromically by stimulation of the alveus. Ortho, population spikes evoked orthodromically by stimulation of the stratum radiatum. The subsequent population spikes evoked orthodromically were preceded by antidromic stimuli at time intervals given in ms. The drug effect was tested 2 rain after the PCP application by micropressure. Recovery was tested 20 min after the drug application. Calibration: 2 mV; 5 ms.

70

PCP, dexoxadrol or levoxadrol, applied by micropressure in concentrations from 10 -s to 10 -4 M had no effect on the population spikes evoked antidromically or on the unconditioned orthodromically evoked population spikes (fig. 1 and 3). In agreement with our previously reported experiments using bath application (Bourne et al., 1983), PCP reduced recurrent inhibition also when applied by micropressure. As shown in fig. 1, the inhibition of the orthodromically evoked population spike by preceding antidromic stimulation

100

A 10o

PCP Io-sM

~D Q tO

'0 ca C 0

~_ 8O

=

P O O e,,

~

was diminished by PCP (5 × 10 -s M). This disinhibitory effect was maximal 2 rain and the inhibition recovered within 20 min after the drug application. Figure 2 shows a summary of the changes in recurrent inhibition induced by PCP in concentrations 10 -s, 5 × 10 -5 and 10 -4 M. The ratio of the conditioned to unconditioned spikes was statistically significantly increased by the three concentrations of the drug at all stimulus intervals tested. As seen from the displacement of the curves showing the time course of inhibition by the vari-

B

80

i

g 6O

l

I

I

O

=

~. 4 o

40

E

m

x, 2O

20

Stimulus interval - ms

Stimulus interval - ms

lOO

C PCP 10-4M

.o 10

80

60 I ¢D

O.

40

20

10 Stimulus interval - ms

40

Fig. 2. Summary of the PCP effects on recurrent inhibition in the CA1 region. Ordinate, amplitudes of the orthodromic population spikes conditioned by preceding antidromic stimulation, expressed as percent of the amplitude of unconditioned orthodromic population spikes. Abscissa, interval between the antidromic and orthodromic stimuli. Each point is the mean ± S.E., (~r) different from the mean before the drug application for P < 0.05 (©) 10 rain before the drug application; (zx) 2 min and (rl) 20 rain after the drug application. (A) 10-5 M PCP, five experiments; (B) 5 × 1 0 -5 M PCP, five experiments; (C) 10 - 4 M PCP, six experiments.

71

A

PRE-DRUG

ANTI

ORTHO

lOms

20m$

ANTI

40m$

ORTHO

10ms

20ms

40m$

V

DEXOXADROL~--~ ld4M

RECOVERY

LEVOXADROL 1~4M

iL

RCOVRY

Fig. 3. Comparison of the effects of dexoxadrol (A) and levoxadrol (B) on recurrent inhibition of the population spikes in the CA1 region. For details, see legend to fig. 1.

ous concentrations of PCP, the disinhibitory effect of the drug was dose dependent. Dexoxadrol (10 -4 M) also clearly reduced inhibition of the orthodromically evoked population spikes by the conditioning antidromic stimulation (fig. 3). This disinhibitory effect was in all respects similar to that produced by PCP, reaching statisti-

L cal significance at all stimulus intervals tested (fig. 4). In contrast, levoxadrol (10 -4 M) had no effect on recurrent inhibition in most experiments, such as that shown in fig. 3. In a few experiments, only a slight reduction of inhibition was noted. Nevertheless, as the summary of all experiments with

11111

100

B

~xoxadrol

Levoxadrol

"0 @ o

~.

8o

g ao

6o

~ 60

I0 0

~ I "oo

I

~. 4o

20

2'0 Stimulus i n t e r v a l - ms

4'o

1'0

~0

4'0

S t i m u l u s i n t e r v a l - ms

Fig. 4. Summary of the effects of dexoxadrol (A, 10 experiments) and levoxadrol (B, 7 experiments) on recurrent inhibition in the CA1 region. Both drugs were applied by micropressure in 10 -4 M concentration. For details, see legend to fig. 2.

72 levoxadrol in fig. 4 indicates, this drug did not significantly reduce the recurrent inhibition.

4. Discussion

The present study confirms that the effects of PCP, applied by micropressure ejection, on recurrent inhibition in the hippocampus are the same as we reported previously using superfusion with PCP containing ACSF (Bourne et al., 1983). A reduction of inhibition of the orthodromically evoked population spike in the CA1 region was seen in both instances, the concentrations of PCP applied by micropressure were twice as high as those using application in the superfusate. This disinhibitory effect was produced by PCP in concentrations which did not change the unconditioned orthodromically evoked population spikes suggesting that the excitatory synaptic transmission from Schaffer collaterals to CA1 pyramidal cells was not influenced by the drug. It is therefore highly unlikely that the PCP induced increase in the population spikes conditioned by preceding antidromic stimulation was due to an increase in the excitatory drive. The conclusion that such an increase is indicative of reduced inhibition is entirely justified. Furthermore, dexoxadrol which shares many pharmacological properties with PCP, including the behavioral discriminative stimulus properties and the affinity for the PCP receptor had the same disinhibitory effect, while its PCP-like inactive stereoisomer levoxadrol (Hampton et al., 1982; Cone et al., 1984; Jacobson et al., 1987) did not reduce inhibition in the hippocampus. Shortly after our initial report (Bourne et al., 1981), similar findings were obtained in in vivo experiments by Stringer and Guyenet (1982) who reported that PCP reduced the duration of inhibition of the CA1 population spike evoked by stimulation of the contralateral CA3 region in a paired stimulus test. Since this effect was not affected by brainstem transsection, they concluded that this reduction of inhibition resulted from a direct action of PCP on the hippocampal formation. Others (Mueller et al., 1982) found no evidence of any change in inhibition induced by PCP and its two

stereoisomeric analogues in the hippocampal slice preparation. Unlike in our experiments, the drugs produced a pronounced depression of the unconditioned population spikes, which was unrelated to the PCP-like activity of the three compounds. Such a change in the excitatory response against which the inhibitory transmission was tested could account for the discrepancy with our observations with respect to inhibition. The disinhibitory effects of PCP and dexoxadrol cannot be readily explained by the numerous actions these drugs have on cholinergic and monoaminergic synaptic systems or on voltage regulated K + conductance (see Greenberg et al., 1985 for references). It is likely that the locus of PCP action lies within the hippocampal inhibitory circuit, consisting of axon collaterals of the CA1 pyramidal neurons which activate the inhibitory interneurons whose presumably GABA releasing terminals feed back on the pyramidal cells (Curtis et al., 1970). An action on the postsynaptic receptor or the inhibitory transmitter activated conductance is unlikely, since PCP did not change the hyperpolarizing responses of pyramidal cells to iontophoretically applied G A B A (Raja and Guyenet, 1980). Thus PCP appears to reduce inhibition by a depression of GABA release. Such a depression could not result from a reduction of GABA synthesis since PCP was reported either to enhance the activity of the GABA synthesizing enzyme, glutamic acid decarboxylase (Spoerlein et al., 1980), or to have no effect on this enzyme in the hippocampus (Peat and Gibb, 1983). We suggested previously that PCP could reduce the release of GABA by depressing the activity of the inhibitory interneuron (Bourne et al., 1983), similarly as proposed for opioid peptides (Zieglgansberger et al., 1979). The finding that PCP depressed evoked activity of hippocampal cells identified as interneurons (Stringer and Guyenet, 1982) lent support to this interpretation. Activation of the inhibitory interneurons is presumably mediated by an excitatory amino acid neurotransmitter, glutamate or aspartate, released from the terminals of the axon collaterals. A depression of this excitatory synapse could conceivably result in a reduction of activity of the inhibitory interneurons.

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The action of excitatory amino acids on neurons is complex and involves several types of receptors (Watkins and Evans, 1981). It has been recently reported that PCP and other PCP-like drugs produce a non-competitive block of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors (Anis et al., 1983), depress some presumably amino acid mediated synaptic excitatory responses (Lodge and Anis, 1984), produce voltage dependent block of responses to aspartate (Honey et al., 1985) and inhibit the excitatory amino acid induced release of acetylcholine and dopamine in the striatum (Snell and Johnson, 1986). It is thus entirely conceivable that such a PCP receptor mediated non-competitive block of the NMDA preferring glutamate receptor could lead to a depression of GABA release with resulting disinhibition. This suggestion implies that, in the hippocampus, the NMDA preferring amino acid receptors might contribute significantly to synaptic excitation of the inhibitory interneurons by a single afferent volley. By contrast, NMDA receptors contribute very little to synaptic activation of the hippocampal pyramidal cells under such conditions (Collingridge and Bliss, 1987). If any of the PCP multiple effect is accomplished through a block of NMDA receptors, then such an effect should be also produced by the competitive antagonists of this receptor subtype. Indeed, it has been reported that two NMDA antagonists, 2-amino-5-phosphono-pentanoate (APV) (Koek et al., 1986) and 2-amino-7-phosphono-heptanoate (AP7) (Compton et al., 1987), produced behavioral effects similar to those of PCP-like drugs. In preliminary experiments, we have seen that APV can cause a moderate reduction of hippocampal inhibition ((~apek and Esplin, 1987). This observation lends support to the proposed locus of disinhibitory action of PCP.

Acknowledgements This work was supported by a grant from the Medical Research Council of Canada. Phencycfidine was obtained through the courtesy of Health and Welfare Canada, dexoxadrol and levoxadrol was a gift from the Upjohn Company, Kalamazoo, MI, U.S.A.

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