Action of phencyclidine on synaptic transmission in the hippocampus

A neurophysiological investigation of the effects of phencyclidine (PCP) and ketamine on synaptic transmission was carried out at the level of two excitatory connections of the hippocampal formation: the interhippocampal projections from contralateral CA3 (cCA3) to CA1 and the entorhino-dentate pathway.In urethane-anesthetized rats PCP i.v. produced a moderate depression of the population EPSP elicited in the stratum radiatum of CA1 by cCA3 stimulations (16–40%) and a large decrease (up to 97%) of the amplitude of the corresponding population spike recorded at the level of the CA1 pyramidal cell bodies (ED₅₀:1.83 mg/kg).Single-unit analysis of CA1 pyramidal cell activation triggered by cCA3 stimulations indicated that i.v. PCP did not decrease the amplitude of individual action potentials suggesting that the decrease in the size of the population spike was due to a decrease in the number of CA1 pyramidal cells activated by the stimulus. Moreover, PCP administered i.v. in the same dose range (0.6-4.0 mg/kg) reduced the maintained activity of CA1 pyramidal cells and their excitation by iontophoretically applied glutamate or ACh.Similar effects on both field potentials and single-unit activity in the CA1 area were also observed following the administration of larger i.v. doses of ketamine (ED₅₀: 7.2 mg/kg), but the effects of the latter drug were of considerably shorter duration than those of PCP.     

(±)CPP, an NMDA receptor antagonist, blocks the induction of commissural-CA3 LTP in the anesthetized rat

Commissural CA3-CA3 (cCA3) long-term potentiation (LTP) was investigated in the anesthetized rat treated with the highly selective NMDA-receptor antagonist , -3[(±)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP). Intraperitoneal injections of CPP did not significantly affect baseline test responses for either field EPSP slope or amplitude measures but did reduce LTP in a dose-dependent manner, with 3.2 mg/kg as the lowest effective dose. EPSP variability following tetanization was also significantly reduced in both the 3.2 mg/kg and 10.0 mg/kg groups. We interpret these results to suggest that a 3.2 mg/kg dose of CPP may be sufficient for studying the behavioral effects of this NMDA receptor antagonist.     

MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain

Summary We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive³H-glutamate binding in CA₁ of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (O.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA-sensitive glutamate receptor binding in CA₁ of hippocampus and kainate binding in CA₃ and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801.     

Phencyclidine blockade of sodium and potassium channels in neuroblastoma cells

Voltage-clamp experiments with N1E 115 neuroblastoma cells showed that the phenyclidine (PCP) is an efficient blocker of both the K⁺ channel (EC₅₀ = 2.6 μM) and the Na⁺ channel (EC₅₀ = 9.2 μM). Results are also presented for two derivatives of PCP.     

Schizophrenia‐related endophenotypes in heterozygous neuregulin‐1 ‘knockout’ mice

Neuregulin‐1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N‐methyl‐d ‐aspartate receptor antagonists MK‐801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK‐801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N‐acetylaspartate and GABA were determined using high‐performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor‐activating effects of acute PCP. Subchronic MK‐801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance‐related behaviours observed in vehicle‐treated mutants. No phenotypic differences were demonstrated in N‐acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia‐relevant processes including the effects of psychotomimetic N‐methyl‐d ‐aspartate receptor antagonists.     

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24–48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments. Synapse 29:14–28, 1998. © 1998 Wiley-Liss, Inc.     

[H]TCP: a new tool with high affinity for the PCP receptor in rat brain

PCP binding sites have previously been demonstrated in the central nervous system with [³H]PCP. We now describe the binding properties to rat brain membranes of [³H]TCP, a PCP derivative. It is very advantageous to use [³H]TCP instead of [³H]PCP for the 3 following reasons: (i) it has a better affinity (K_d = 7.4nM) for PCP binding sites than PCP itself; (ii) it dissociates slowly from its binding sites (t1/2= 20min); (iii) the non-specific binding component obtained with [³H]TCP is much lower than that found with [³H]PCP.     

Specific Binding of [H] phencyclidine in rat central nervous tissue: further characterization and technical considerations

The interaction of phencyclidine (PCP) with its specific receptor sites in the central nervous system has been further characterized. Kinetic association and dissociation rate constants of 2.9 × 10⁶ M⁻¹ and 4.8 × 10⁻¹ were determined, yielding a kinetic K_D of 1.6 × 10⁻⁷ M, in agreement with the K_D previously determined at equilibrium. Permissible separation time of 13 s was calculated from the kinetic data, well above the actual separation time of less than 10 s in the rapid filtration assay. Presoaking of filters in 0.01% poly-l-lysine eliminated displacable [³H]PCP adsorption to filter material. Binding data obtained via centrifigation assays was identical to that obtained with the rapid filtration method. Stereospecificity of the PCP receptor was demonstrated by the finding that (+)-ketamine is four-fold more potent than (−)-ketamine in displacing specifically bound [³H]PCP. Several proteolytic enzymes including trypsin, papain and thermolysin potently inactivated PCP receptors. Detailed regional distribution studies showed highest density of PCP receptors in subicular cortex and hippocampus, intermediate levels in hypothalamus, striatum, frontal cortex and cerebellum, lower levels in brainstem and spinal cord, and negligible levels in corpus callosum, a white- matter control area. Benzomorphan opiates with PCP-like behavioral effects interact with the PCP receptor. These data support the pharmacological relevance of the PCP receptor site as demonstrated by the rapid filtration method.     

Subchronic treatment with phencyclidine in adolescence leads to impaired exploratory behavior in adult rats without altering social interaction or N‐methyl‐D‐aspartate receptor binding levels

Although both the onset of schizophrenia and human phencyclidine (PCP) abuse typically present within the interval from adolescence to early adulthood, the majority of preclinical research employing the PCP model of schizophrenia has been conducted on neonatal or adult animals. The present study was designed to evaluate the behavioral and neurochemical sequelae of subchronic exposure to PCP in adolescence. Male 35–42‐day‐old Sprague Dawley rats were subcutaneously administered either saline (10 ml · kg^?1) or PCP hydrochloride (10 mg · kg^?1) once daily for a period of 14 days (n = 6/group). The animals were allowed to withdraw from treatment for 2 weeks, and their social and exploratory behaviors were subsequently assessed in adulthood by using the social interaction test. To examine the effects of adolescent PCP administration on the regulation of N‐methyl‐D‐aspartate receptors (NMDARs), quantitative autoradiography was performed on brain sections of adult, control and PCP‐withdrawn rats by using 20 nM ³H‐MK‐801. Prior subchronic exposure to PCP in adolescence had no enduring effects on the reciprocal contact and noncontact social behavior of adult rats. Spontaneous rearing in response to the novel testing arena and time spent investigating its walls and floor were reduced in PCP‐withdrawn animals compared with control. The long‐term behavioral effects of PCP occurred in the absence of persistent deficits in spontaneous locomotion or self‐grooming activity and were not mediated by altered NMDAR density. Our results document differential effects of adolescent PCP administration on the social and exploratory behaviors of adult rats, suggesting that distinct neurobiological mechanisms are involved in mediating these behaviors. © 2014 Wiley Periodicals, Inc.     

Reduced expression of synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia

Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)—a N‐methyl‐D‐aspartate (NMDA) receptor antagonist—induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well‐known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini‐pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper‐locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre‐pulse inhibition (p < 0.0001) in comparison to saline‐treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer‐term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.     

GABA-dependent generation of ectopic action potentials in the rat hippocampus

Intracellular recordings from CA3 pyramidal cells of rat hippocampus in a slice preparation revealed the occurrence of interictal epileptiform discharges and synchronous GABA-mediated potentials during application of 4-aminopyridine (4AP, 50 μm ). The synchronous GABA-mediated potential consisted of a sequence of early hyperpolarization, long-lasting depolarization (LLD), and late hyperpolarization. Action potentials of variable amplitude occurred at the peak of the early hyperpolarization and during the LLD rising phase (48 of 64 cells); they were not prevented by membrane hyperpolarization and displayed inflections that were reminiscent of the initial segment-somatodendritic (IS-SD) fractionation. Interictal discharges were blocked by excitatory amino acid receptor antagonists, while both GABA-mediated potentials and action potentials of variable amplitude continued to occur (n = 10). The latter events were still recorded in the presence of the GABA_B receptor antagonist CGP-35348 (0.5–1 mm , n = 4), but were abolished by the GABA_A receptor antagonist bicuculline methiodide (BMI, 10 μm , n = 5). Localized application of BMI (20 μm , n = 6) or tetrodotoxin (TTX, 5 μm , n = 3) to the CA1 stratum radiatum blocked the variable amplitude action potentials; these effects were not seen when BMI (n = 4) or TTX (n = 4) were applied to the CA3 stratum radiatum, although both procedures made LLDs disappear. Our findings indicate that action potentials of variable amplitude recorded from CA3 pyramidal cells in the 4AP model are generated at or near the terminal region of the Schaffer collaterals and that they represent TTX-sensitive ectopic events. These action potentials are generated at this site by a BMI-sensitive (and thus GABA_A-mediated) mechanism. We propose that the ectopic action potentials reflect an increased excitability of axon terminals that is presumably caused by [K⁺]_o elevations associated with the 4AP-induced synchronous GABA-mediated potential.     

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

Summary Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK-801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.     

Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp70 in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp70 induction. Rimcazole binds predominately to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominately to sigma-1 sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200–260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 μm) and presence of the hsp70 gene protein product, HSP70, was determined immunocytochemically. (+)-3-PPP significantly (p < 0.05) diminished the ability of rimcazole to inhibit PCP hsp70 induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (80mg/kg, IP) given in an analogous manner did not diminished the ability of rimcazole to inhibit PCP hsp70 induction.     

Enhancement of dendritic persistent Na<Superscript>+</Superscript> currents by mGluR5 leads to an advancement of spike timing with an increase in temporal precision

Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to transform their input into output action potential is primarily determined by intrinsic excitability. Particularly, plastic changes in intrinsic excitability represent the cellular substrate for spatial memory formation in CA1 pyramidal neurons (CA1-PNs). Here, we report that synaptically activated mGluR5-signaling can modulate the intrinsic excitability of CA1-PNs. Specifically, high-frequency stimulation at CA3-CA1 synapses increased firing rate and advanced spike onset with an improvement of temporal precision. These changes are mediated by mGluR5 activation that induces cADPR/RyR-dependent Ca²⁺ release in the dendrites of CA1-PNs, which in turn causes an increase in persistent Na⁺ currents (I_Na,P) in the dendrites. When group I mGluRs in CA1-PNs are globally activated pharmacologically, afterdepolarization (ADP) generation as well as increased firing rate are observed. These effects are abolished by inhibiting mGluR5/cADPR/RyR-dependent Ca²⁺ release. However, the increase in firing rate, but not the generation of ADP is affected by inhibiting I_Na,P. The differences between local and global activation of mGluR5-signaling in CA1-PNs indicates that mGluR5-dependent modulation of intrinsic excitability is highly compartmentalized and a variety of ion channels are recruited upon their differential subcellular localizations. As mGluR5 activation is induced by physiologically plausible brief high-frequency stimulation at CA3-CA1 synapses, our results suggest that mGluR5-induced enhancement of dendritic I_Na,P in CA1-PNs may provide important implications for our understanding about place field formation in the hippocampus.     

Involvement of the serotonergic system in the anxiolytic-like effect caused by m-trifluoromethyl-diphenyl diselenide in mice

The organoselenium compound diphenyl diselenide (PhSe)₂ has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented some toxic effects. m-Trifluoromethyl-diphenyl diselenide (m–CF₃–C₆H₄Se)₂, a structural analog of (PhSe)₂, has proven to be antipsychotic and antioxidant in mice. The present study was designed to investigate the anxiolytic-like effect of (m–CF₃–C₆H₄Se)₂ in female mice, employing light/dark box and elevated plus-maze (EPM) tests. The involvement of 5-hydroxytryptamine (5-HT) receptors and monoamine oxidase (MAO) activity in the anxiolytic-like effect was also evaluated. (m–CF₃–C₆H₄Se)₂ (0.1, 10 and 100 mg/kg, p.o.) did not affect locomotor activity as evaluated in the open-field test (OFT). (m–CF₃–C₆H₄Se)₂ at the dose of 100 mg/kg produced an anxiolytic-like action, both in light–dark box and the EPM tests. To evaluate the role of 5-HT receptors in the anxiolytic-like effect of (m–CF₃–C₆H₄Se)₂, a selective 5-HT_1A receptor antagonist, WAY100635 (0.1 mg/kg, s.c.), a non-selective 5-HT_2A/2C receptor antagonist, ritanserin (2 mg/kg, i.p.) and a selective 5-HT₃ receptor antagonist, ondansetron (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic-like effect of (m–CF₃–C₆H₄Se)₂. (m–CF₃–C₆H₄Se)₂, at the dose of 100 mg/kg, inhibited the MAO-A activity in mice brain. Taken together these data demonstrated that the anxiolytic-like effect caused by (m–CF₃–C₆H₄Se)₂ seems to be mediated by the involvement of the serotonergic system.     

Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment

Summary Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [³H]MK801. Chronic PCP treatment increased [³H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.     

The nitric oxide synthase inhibitor. L-NAME, blocks certain phencyclidine-induced but not amphetamine-induced effects on behaviour and brain biochemistry in the rat

1. 1. The present experiments examined the effects of the nitric oxide synthase (NOS) inhibitor, N^G-nitro-L-arginine methyl ester (L-NAME), on some behavioural and biochemical effects of phencyclidine (PCP) and d-amphetamine (AMPH) in rats. Observation of behaviour was performed using a subjective scoring system.

2. 2. PCP (4 mg/kg) increased locomotor activity, rearing, sniffing, grooming and stereotyped behaviour, and decreased stillness. PCP also increased forepaw myoclonus, forepaw treading, head weaving, licking and chewing behaviour. Most of these behaviours were significantly suppressed by pretreatment with L-NAME (10 mg/kg).

3. 3. AMPH (1 mg/kg) exerted different effects on behaviour. It increased locomotor activity, rearing, sniffing, and stereotyped behaviour, and decreased stillness and grooming, but failed to affect the other behavioural items observed. Pretreatment with L-NAME did not counteract these effects.

4. 4. Ex vivo biochemical analysis indicated that PCP increased the tissue concentration of the dopamine (DA) metabolites, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), in the ventral striatum (i.e., the nucleus accumbens and olfactory tubercles) and frontal cortex but not in the dorsal striatum. DA was not significantly affected in any of these regions. Furthermore, PCP increased the tissue concentration of the serotonin (5-HT) metabolite, 5-hydroxyindole acetic acid (5-HIAA), in a similar manner, while 5-HT was not affected. These biochemical effects were significantly counteracted by pretreatment with L-NAME.

5. 5. AMPH decreased tissue DOPAC concentration in the dorsal striatum, an effect which was not sensitive to pretreatment with L-NAME. However, the combined treatment with L-NAME and AMPH increased tissue DA concentration in all three regions investigated.

6. 6. The neurochemical and behavioural effects of PCP and AMPH were further investigated in an experimental model which allowed measurement of prepulse inhibition (PPI) of acoustic startle in parallel with in vivo microdialysis sampling of extracellular DA concentration in the brain of awake, freely moving animals.

7. 7. Both PCP (2 mg/kg) and AMPH (2 mg/kg) caused a significant decrease in PPI of similar magnitude and duration. These behavioural effects were accompanied by a significant increase in extracellular DA concentration in the nucleus accumbens (PCP: 213 ± 21% of basal concentration; AMPH: 563±117%).

8. 8. The decrease in PPI caused by PCP was blocked by pretreatment with L-NAME, but the change in DA concentration was not. Neither of these measures were significantly affected by L-NAME in AMPH-treated rats.

9. 9. In conclusion, this study shows that several behavioural and biochemical effects of PCP are prevented by pretreatment with the NOS inhibitor, L-NAME, while the effects of AMPH are less sensitive to this pretreatment. These observations emphasise the involvement of nitric oxide in the pharmacological effects of PCP.

     

Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study

In a putative model of acute phencyclidine (PCP)-induced psychosis we evaluated effects of the drug on locomotor activity (LMA) and immediate early gene (IEG) induction in the rat using two routes of drug administration, intraperitoneal (i.p.) and subcutaneous (s.c.). Adult male rats received saline or PCP (1.0-5.0 mg/kg) either i.p or s.c. and were assessed for LMA for 60 min. At the end of the LMA testing animals were culled and blood and brain samples were collected for PCP concentration analysis. Separate cohorts of animals received 5.0 mg/kg PCP (i.p. or s.c.) and were used to investigate (1) the pharmacokinetics of PCP or (2) induction of IEG (Arc, c-fos, BDNF, junB, Krox-20, sgk-1, NURR1, fra-2, Krox-24, and egr-3) mRNA expression in the prefrontal cortex (PFC). Administration of PCP resulted in locomotor hyperactivity which was more robust and longer-lasting in animals dosed s.c. compared to i.p.-treated-animals. Differences in hyperlocomotion were paralleled by higher concentrations of PCP in the blood and in the brain of s.c.-treated animals compared to i.p.-treated animals. The differences in the concentration of PCP between the two routes of administration were detected 30 min after dosing and persisted for up to 4 h. Administration of PCP via the s.c. route resulted in induction of more IEGs and consistently larger magnitudes of induction than that via the i.p. route. Therefore, we have outlined the dosing conditions to induce rapid and robust effect of acute PCP on behaviour, gene induction, and pharmacokinetic profile, to allow investigation of this as a potential animal model of acute psychosis.     

Anoxia-induced depolarization in CA1 hippocampal neurons: role of Na-dependent mechanisms

We have previously shown that (1) removal of extracellular sodium (Na⁺) reduces the anoxia-induced depolarization in neurons in brain-slice preparations and (2) amiloride, which blocks Na⁺-dependent exchangers, prevents anoxic injury in cultured neocortical neurons. Since anoxia-induced depolarization has been linked to neuronal injury, we have examined in this study the role of Na⁺-dependent exchangers and voltage-gated Na⁺ channels in the maintenance of membrane properties of CA1 neurons at rest and during acute hypoxia. We recorded intracellularly from CA1 neurons in hippocampal slices, monitored V_m and measured input resistance (R_m) with periodic injections of negative current. We found that tetrodotoxin (TTX, 1 μM) hyperpolarized CA1 neurons at rest and significantly attenuated both the rate of depolarization (ΔV_m/dt) and the rate of decline of R_m (ΔR_m/dt) by about 60% during the early phase of hypoxia. The effect of TTX was dose-dependent. Amiloride (1 mM) decreased V_m and increased R_m in the resting condition but changed little the effect of hypoxia on neuronal function. Benzamil and 5-(N-ethyl-N-isopropyl)-2′,4′-amiloride (EIPA), two specific inhibitors of Na⁺ dependent exchangers, were similar to amiloride in their effect. We conclude that neuronal membrane properties are better maintained during anoxia by reducing the activity of TTX-sensitive channels and not by the action of Na⁺-dependent exchangers.