Effect of phencyclidines on hippocampal pyramidal cells

Phencyclidine (PCP) and several behaviorally active or inactive structural analogs were administered i.v. to urethane-anesthetized rats in order to determine their effects on CA1 pyramidal cell discharges elicited by contralateral CA3 (cCA3) stimulation.PCP and the behaviorally active m-amino derivative (m-NH₂PCP) depressed, in a dose-dependent manner, the amplitude of the population spike evoked in CA1 by a cCA3 stimulation (ED 50s: 0.9 mg/kg for PCP, 0.5 mg/kg for m-NH₂ PCP). However, the behaviorally inactive derivatives m-nitro (m-NO₂ PCP) and PCP methyliodide (PCP CH₃I) were ineffective up to 10 mg/kg.PCP (0.1–0.3 mg/kg i.v.) also decreased the duration of inhibition of CA1 discharges in a paired-stimulus paradigm; this was in contrast to the effects of thiopental and diazepam.In midcollicular-transected, urethane-anesthetized rats, the inhibitory effect of PCP on cCA3-CA1 transmission was not observed but the drug was still as effective as in intact rats in the paired-stimulus paradigm.In animals subjected to 6-hydroxydopamine lesions of the hippocampal noradrenergic innervation (average 85%) decrease in NE content), the potency of PCP in inhibiting cCA3-CA1 transmission was the same as in a group of sham-operated controls.These results suggest the following conclusions: (i) PCP exerts at least 2 separate types of effects in CA1, both of which result from a central action of the drug; (ii) PCP decreases the monosynaptic excitation of CA1 pyramidal cells and this action requires the integrity of brainstem afferents; (iii) PCP may decrease recurrent inhibition or afterhyperpolarization in CA1 via a mechanism which is independent of these connections and, therefore, could result from a direct action of the drug at the level of the hippocampus; (iv) finally, no evidence was found to suggest that the noradrenergic innervation of the hippocampus is critically involved in the action of PCP on CA1 discharges.     

Changes of neuronal transmission in the hippocampus after transient ischemia in spontaneously hypertensive rats and the protective effects of MK-801.

BACKGROUND AND PURPOSE: I studied the mechanism of postischemic neuronal degeneration in the hippocampus by an electrophysiological method. METHODS: Sequential changes of field potentials evoked by perforant path stimulation in the dentate gyrus and the CA1 region of the hippocampus were evaluated in spontaneously hypertensive rats up to 7 days after transient global ischemia induced by bilateral occlusion of the carotid arteries for 20 minutes after electrocauterization of the vertebral arteries. Animals were treated with vehicle or the excitotoxin antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10 amine (MK-801, 2 mg/kg or 5 mg/kg) intraperitoneally 30 minutes before ischemia. RESULTS: Complete recovery of the population spike was observed in the dentate gyrus within 24 hours after recirculation, followed by a gradual reduction of population spike amplitude. In contrast, population spike in the CA1 region showed partial recovery 24 hours after recirculation, and an abrupt reduction of population spike amplitude occurred on day 2. There was no significant enhancement of population spike amplitude in either region throughout the experiment. Interneuronal recurrent inhibition in the dentate gyrus was enhanced on day 4, and ischemic changes were apparent in the CA1 pyramidal cells on day 7. Pretreatment with 5 mg/kg MK-801 prevented field potential and pathological changes completely in the dentate gyrus and partially in the CA1 region. CONCLUSIONS: My results indicate that pathological changes of the CA1 pyramidal neurons after transient ischemia may not be the result of postischemic overstimulation. However, neuronal transmission in the CA1 region may be persistently impaired during or after transient ischemia.     

Pentobarbital-like electroencephalographic rubral rhythm induced by ketamine in rabbits

1. The effects caused by the dissociative anaesthetic drugs (PCP, KT), the sigmaopiates (SKF 10.047, cyclazocine), and the mixed excitatory amino acid antagonist CCP on the electrical activity of the red nucleus in rabbits were compared with PB. 2. Ketamine (10 mg/kg, i.v.) induced the appearance of a pentobarbital-like EEG synusoidal rhythm characterized by an increase in amplitude and a decrease in frequency of the basal electrical activity at the red nucleus level. 3. Both pentobarbital and ketamine induced rhythms were blocked by the GABA-antagonist pentylenetetrazol at the subconvulsant dose of 10 mg/kg, i.v. 4. Phencyclidine, SKF 10.047, cyclazocine, and the mixed excitatory amino acid antagonist CCP failed to affect the basal electrical activity of the red nucleus. 5. These data indicate an interaction of ketamine on the GABA neurotransmission at the level of cerebello-rubral pathways which the other PCP/sigma opiates did not present.     

Noradrenergic responses in rat hippocampus: Evidence for mediation by α and β receptors in the in vitro slice

The effect of perfused norepinephrine (NE) on evoked potentials in CA1 of the in vitro rat hippocampus was examined. Weak and variable effects on population spike amplitude were observed, with lower doses of NE generally producing excitations and higher doses more often producing inhibitions. Clonidine, an α-receptor agonist, produced a dose-dependent inhibition of population spike amplitude; this inhibition was effectively antagonized by the α-antagonist, phentolamine. Isoproterenol (ISO), a β-agonist, produced marked increases in population spike amplitude which could be antagonized by timolol, a β-receptor antagonist. Phentolamine did not antagonize the excitations produced by ISO, and timolol had no effect on the inhibitions seen with clonidine. After pretreatment with either phentolamine or timolol, NE perfusion elicited robust and consistent elevations or reductions in the population spike, respectively. A potent cyclic AMP derivative, 8-p-chlorophenylthio cyclic AMP, produced large increases in population spike amplitude which appeared similar to the responses seen with β-agonists. No changes in field EPSP amplitudes were observed with any of the drugs tested. Taken together, these results suggest that NE may interact with α-adrenergic receptors to decrease pyramidal cell excitability, and with β-adrenergic receptors to increase pyramidal cell excitability; the β-effect may involve cAMP.     

Noradrenergic responses in rat hippocampus: evidence for medication by alpha and beta receptors in the in vitro slice

The effect of perfused norepinephrine (NE) on evoked potentials in CA1 of the in vitro rat hippocampus was examined. Weak and variable effects on population spike amplitude were observed, with lower doses of NE generally producing excitations and higher doses more often producing inhibitions. Clonidine, an alpha-receptor agonist, produced a dose-dependent inhibition of population spike amplitude; this inhibition was effectively antagonized by the alpha-antagonist, phentolamine. Isoproterenol (ISO), a beta-agonist, produced marked increases in population spike amplitude which could be antagonized by timolol, a beta-receptor antagonist. Phentolamine did not antagonize the excitations produced by ISO, and timolol had no effect on the inhibitions seen with clonidine. After pretreatment with either phentolamine or timolol, NE perfusion elicited robust and consistent elevations or reductions in the population spike, respectively. A potent cyclic AMP derivative, 8-p-chlorophenylthio cyclic AMP, produced large increases in population spike amplitude which appeared similar to the responses seen with beta-agonists. No changes in field EPSP amplitudes were observed with any of the drugs tested. Taken together, these results suggest that NE may interact with alpha-adrenergic receptors to decrease pyramidal cell excitability, and the beta-adrenergic receptors to increase pyramidal cell excitability; the beta-effect may involve cAMP.     

Blockade of long-term potentiation by phencyclidine and sigma opiates in the hippocampus in vivo and in vitro

Long-term potentiation (LTP) of synaptic transmission in the rat hippocampus in vivo and in vitro, was studied using field potentials. Pretreatment with phencyclidine (PCP) or 'sigma' opiates blocked LTP in vivo while mu and kappa opiates and the antagonist naloxone were ineffective. Scopolamine (20 mg/kg i.p.) neither prevented LTP nor antagonized the LTP-blocking effect of PCP. In vitro, PCP up to 100 microM did not alter synaptic activation of CA1 pyramidal cells by stratum radiatum stimulation but blocked LTP in a dose-dependent manner (ED50: 3 microM). The sigma opiate, cyclazocine, also prevented the induction of LTP in vitro while morphine and procaine were ineffective.     

Haloperidol Prevents Ketamine- and Phencyclidine-Induced HSP70 Protein Expression but Not Microglial Activation

NoncompetitiveN-methyl- -aspartate (NMDA) receptor antagonists, including ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20-day-old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80–140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adult rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.     

5-Hydroxytryptamine increases excitability of CA1 hippocampal pyramidal cells.

In the presence of spiperone to block the 5-HT1A-mediated inhibition of pyramidal cell activity, 5-hydroxytryptamine (serotonin, 5-HT) produces a rapid transient increase in amplitude of the extracellularly recorded population spike from area CA1 of the hippocampus. Intracellular recording techniques in area CA1 of rat hippocampal slices were used to identify the ionic mechanism and to characterize the 5-HT receptor mediating this excitatory response to 5-HT. Most of the experiments were conducted in the presence of spiperone to block the 5HT1A hyperpolarization. Since spiperone also has high affinity for 5-HT2 receptors, any response mediated by 5-HT2 receptors would also be blocked. Bath perfusion of the slice with 5-HT increased the rectification of pyramidal cells in the subthreshold region, increased the resistance, and increased the amplitude of subthreshold excitatory postsynaptic potentials (EPSPs) to initiate spike firing. The 5-HT2,1C-selective agonist DOI mimicked this effect of 5-HT, and the 5-HT2,1C antagonist ketanserin (1 microM) blocked the effect of DOI. There was no change in the amplitude of the slow afterhyperpolarization (sAHP) or the amplitude of evoked inhibitory postsynaptic potentials (IPSPs). The increase in rectification and EPSP amplitude by 5-HT occurred even in the presence of the 5-HT4-selective antagonist BRL 24924 to prevent the decrease in amplitude of the sAHP by 5-HT. We conclude that 5-HT produces a fast excitatory response by increasing subthreshold conductance in CA1 hippocampal pyramidal cells. The identity of the receptor mediating this response was not conclusively identified, but resembled the 5-HT1C receptor.     

Long-lasting facilitation of a synaptic potential following tetanization in the in vitro hippocampal slice.

Field potentials evoked by stimulation of afferent fibers in stratum radiatum were recorded in the CA1 region of the hippocampal slice maintained in vitro. Stimulation rates of 3-50/sec produced a large increase in amplitude of the population spike in CA1. This increase was maintained for several hours after the tetanization. The facilitation phenomenon appeared to be specific to the synapse of stratum radiatum afferents onto CA1 pyramidal cells since: (1) stimulation outside the radiatum layer did not produce the effect, (2) antidromic field potentials recorded in CA3 were unchanged, (3) EPSP threshold in CA1 was unchanged, and (4) alveus tetanization did not produce a facilitatory effect.     

A specific effect of morphine on evoked activity in the rat hippocampal slice

The effect of morphine (0.5-50 microM) was examined on CA1 field potentials in the tranverse hippocampal slice. Morphine consistently produced an augmentation of evoked activity manifest as (i) a decrease in the threshold for generation of a population spike and (ii) generation of an additional population spike(s) whose amplitude was proportional to the position of the sampled response on its input/output curve. Both of these opiate effects were stereospecific and naloxone-reversible. Additional population spikes occurred in opiate medium with either orthodromic or antidromic activation of the pyramidal cells, and the antidromic effect was abolished when synaptic transmission was blocked, suggesting that morphine did not act directly upon the pyramidal cells. Recordings of population EPSPs in the dendrites of the pyramidal cells showed no changes due to opiate exposure near threshold. Opiate effects were mimicked by the gamma-aminobutyric acid (GABA) antagonist picrotoxin, and were partially to fully reversed by GABA itself, suggesting that disinhibition of pyramidal cells might be involved as a mechanism in this opiate effect. The data are evidence for a specific primary effect of morphine within the hippocampus in spite of the low numbers of opiate receptors in this brain region.