Some 40 years ago phencyclidine (PCP) was developed as the prototype of a proposed new class of ‘dissociative’ general anesthetics, so called because it induced a marked dissociation from the environment without complete loss of consciousness. In the earliest clinical trials of PCP anesthesia, it was observed that as many as half the subjects experienced severe psychotic reactions during and beyond emergence. This striking clinical observation at once marked the failure of PCP as a suitable general anesthetic, and the beginning of a remarkable new era in basic and clinical neuroscience which can serve as an example of the interaction between clinical observation and basic science. At once, clinical researchers turned their focus upon the characterization of the PCP-induced psychosis, and recognized striking similarities between PCP-induced symptoms and signs and both the negative and positive symptoms of schizophrenia, proposing the PCP psychosis as a new model of that illness. Several years later PCP suddenly emerged as a major drug of abuse, with the result that emergency rooms and psychiatric inpatient units were observing and treating large numbers of these patients, in many of whom a diagnosis of schizophrenia could not be ruled out until toxicological analyses were performed. This natural experiment yielded a huge amount of additional data, and contributed a strong public-health based impetus to research into the nature and treatment of PCP intoxication.

Actions of antagonists for excitatory amino-acid (EAA) receptors on extracellularly and intracellularly recorded responses of layer II/III cells to electrical stimulation of the underlying white matter were studied in a slice preparation of rat's visual cortex. Antagonists used were 2-amino-5-phosphonovalerate (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which are selective antagonists for EAA receptors of N-methyl-D-aspartate (NMDA) and quisqualate/kainate (non-NMDA) type, respectively. In extracellular recordings, it was found that responses of almost all of the cells were suppressed by CNQX. In contrast, sensitivity to APV was different between cells with short- and long-latency responses; 81% of the former responses were not suppressed by APV, while about a half of the latter were suppressed. Excitatory postsynaptic potentials (EPSPs) evoked by white-matter stimulation were recorded intracellularly from 42 neurons. Most of polysynaptically elicited EPSPs were sensitive to APV, whereas the majority of monosynaptic EPSPs were not. CNQX almost completely suppressed EPSPs irrespective of monosynaptically or polysynaptically evoked, but in some cases slow EPSPs with low amplitude were spared. These CNQX-resistant EPSPs were elicited polysynaptically and had an anomalous voltage dependence, a characteristic of NMDA receptors. It is suggested that non-NMDA receptors contribute dominantly to first-order synaptic transmission while NMDA receptors participate substantially in second-order transmission so as to serve as a booster of outputs from visual cortex.

We have employed two paradigms to investigate the mechanisms of contrast gain control in cat striate cortex. In the first paradigm, optimal drifting gratings were presented in three consecutive periods. The contrast was near threshold in the first and third periods and accompanied by iontophoretic pulses of glutamate or glutamate receptor (GluR) agonists. The contrast was set to evoke a higher firing rate in the second period. Although both visual and iontophoretic conditions were identical in the first and third periods, responses to glutamate, N-methyl-D-aspartic acid (NMDA), and (1S, 3R)-1-Aminocyclopentane-1, 3-dicarboxylic acid (ACPD) were reduced following the adapting interval. (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses were not reduced. Administration of ionotropic GluR antagonists did not affect adaptation to the high-contrast grating. The metabotropic GluR antagonist (±)-α-Methyl-4-carboxyphenylglycine (MCPG), which acts at presynaptic glutamate autoreceptors, decreased the degree of adaptation exhibited by striate cells. In a second paradigm, contrast response functions (CRFs) were obtained at various adapting contrasts and least-squares fits to a hyperbolic ratio equation generated for each adapting level. Similar to previous reports, DL-2-amino-5-phosphonovaleric acid (APV) reduced the slope of the CRF and increased the responsiveness of the cells but did not affect the semisaturation constant, σ, or the exponent of the CRF, n. Only MCPG significantly altered the distribution of σ and n for 19 cells. The effect on α suggests that this drug can interfere with the cell's ability to shift its operating point to match the adapting contrast. These results suggest the involvement of a presynaptic mechanism for contrast adaptation. The decrease in neuronal responsiveness immediately following the high-contrast period may reflect an additional, postsynaptic effect in which there is a decrease in the NMDA-mediated component of the visual response.

We used an in vitro preparation of the ferret lateral geniculate nucleus (LGN) to examine the role of the NMDA class of excitatory amino acid (EAA) receptors in retinogeniculate transmission. Intracellular recordings revealed that blockade of NMDA receptors both shortened the time course and reduced the amplitude of fast and slow components of excitatory postsynaptic potentials (EPSPs) evoked by optic tract stimulation. The amplitude and width of the EPSPs mediated by NMDA receptors increased as membrane potential was depolarized towards spike threshold. Individual LGN cells were influenced to varying extents by blockade of NMDA receptors; NMDA and non-NMDA receptor blockade together attenuated severely the entire retinogeniculate EPSP. The dependence of all components of retinogeniculate EPSPs (and action potentials) on NMDA receptor activation supports the hypothesis that the NMDA receptor participates in fast (<10 ms) synaptic events underlying conventional retinogeniculate transmission. The voltage dependence of the NMDA receptor-gated conductance suggests strongly that the transmission of retinal information through the LGN is subject to modulation by extraretinal inputs that affect the membrane potential of LGN neurons.

We have developed an optical method to monitor the activity of the ON and OFF channels in the anuran retina. The change in the fraction of near infrared that is transmitted transversely through the retina in an eyecup slice is monitored during stimulation by visible, green light. Near-infrared transmission increases both at the onset and at the termination of a step stimulus. This “ON/OFF” response is maximal in the neural retina. Sodium L-aspartate, which blocks the light-evoked activity of post-photoreceptor neurons, abolishes the “ON/OFF” response. L-AP4, used as a selective blocker of the ON channel, reduces the “ON” component and has little or no effect on the “OFF” component. The “ON” and “OFF” processes observed optically are distinct from those that generate the b– and d–waves of the electroretinogram, and the “ON” and “OFF” components may be superior to the b– and d–waves as indicators of ON and OFF channel activity. The optical method is almost as simple as electroretinography and has the advantage that responses can be spatially localized with ease.

A subpopulation of cells developing in dissociated neuronal cultures prepared from 8-day-old embryonic chick retinae can be identified as putative in vitro counterparts of GABAergic amacrine cells by immunocytochemical and autoradiographic markers and by their electrophysiological responses to transmitter agonists. In the present study, transmitter-gated conductances expressed by these neurons were examined using the whole-cell patch-clamp technique. At negative holding potentials, the excitatory amino acid agonists N-methyl-D-aspartate (NMDA), kainate quisqualate, and glutamate induced inward currents with reversal potentials close to 0 mV in most of the cells selected for recording. NMDA-evoked responses were selectively blocked by the noncompetitive inhibitor MK 801 and by Mg2+ (in a voltage-dependent manner) and were potentiated in the presence of submicromolar concentrations of glycine. Glutamate apparently interacted with both NMDA and non-NMDA type receptors. All cells tested responded to the inhibitory transmitters GABA and glycine. Both inhibitory agonists could be shown to activate chloride conductances. Responses to GABA and glycine were specifically inhibited in the presence of bicuculline and strychnine, respectively. Thus, GABAergic neurons in retinal cultures express at least two different excitatory amino acid receptors–NMDA and non-NMDA–and two different inhibitory amino acid receptors–the GABAA and the glycine receptor. The results demonstrate the ability of the cultured neurons to develop an apparently mature phenotype and contribute to the understanding of the functional properties of GABAergic amacrine cells in the vertebrate retina.

Whole-cell recordings were obtained from retinal ganglion cells of the tiger salamander (Ambystoma tigrinum) in a superfused slice preparation to evaluate contributions of NMDA (N-methyl-D-aspartate) and KA/AMPA (kainate/α-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid) receptors to excitatory postsynaptic potentials (EPSPs) of retinal ganglion cells. Synaptic activation of retinal ganglion cells was achieved through the use of a brief pressure pulse of hyperosmotic Ringer (Ringer + sucrose) delivered through a microelectrode visually placed in the inner plexiform layer while whole-cell recordings were obtained from adjacent cells in the ganglion cell layer. Separation of NMDA and KA/AMPA excitatory postsynaptic currents (EPSCs) was achieved through the application of the antagonists NBQX and D-AP7, while inhibitory currents were blocked by strychnine and picrotoxin. Simple addition of the two independent EPSCs showed, most often, that the sum of the KA/AMPA and NMDA currents was less than the control response, but in some cases the sum of the two currents exceeded the magnitude of the control response. Neither result was consistent with expectations based on voltage-clamp principles and the assumption that the two currents were independent; for this reason, we considered the possibility of nonlinear interactions between KA/AMPA and NMDA receptors. Computer simulations were carried out to evaluate the summation experiments. We used both an equivalent cylinder model and a more realistic, compartmental model of a ganglion cell constrained by a passive leakage conductance, a linear KA/AMPA synaptic current, and a nonlinear NMDA current based on the well-known, voltage-sensitive Mg2+ block. Computer simulation studies suggest that the hypo- and hyper-summation of NMDA and KA/AMPA currents, observed physiologically, can be accounted for by a failure to adequately space clamp the neuron. Clamp failure leads to enhanced NMDA currents as the ion channels are relieved of the Mg2+ block; their contribution is thus exaggerated depending on the magnitude of the conductance change and the spatial location of the synaptic input.

Although excitotoxins derived from acidic amino acids are known to damage neurons in the inner nuclear and ganglion cell layers of the retina, little is known about their effects on photoreceptors. This study examines the acute and long-term effects of excitotoxins on photoreceptors of the chick retina. The zinc-iodide-osmium (ZIO) technique, which darkly labels a substantial subpopulation of synaptic vesicles in normal photoreceptor terminals, was used to supplement routine electron microscopy. Two-day-old chicks received a single intraocular injection of either 10, 50, or 200 nmoles kainic acid (KA), 200 nmoles N-methyl-D-aspartic acid (NMDA), or 200 nmoles quisqualic acid (QUIS), and were allowed to survive for either 6 h, 7 d, or 21 d. At 6 h, following exposure to 10, 50, and 200 nmoles KA, there was swelling and disruption of photoreceptor lamellae of the outer segments. At 7- and 21-d survival, 50 and 200 nmoles KA resulted in rounded, condensed synaptic terminals, which contained a high density of synaptic vesicles. However, there was complete loss of ZIO-positive vesicles within these photoreceptors. Outer segments were still disrupted, although small patches of lamellae were evident, suggestive of regeneration. Following exposure to QUIS, there was extensive swelling of outer segment lamellae at 6 h survival. Synaptic ribbons in terminals were also swollen. At longer survival periods, QUIS exposure resulted in a reduction of ZIO-positive vesicles, as well as swollen lamellae in outer segments. NMDA exposure, at either short or long-term survival, did not alter photoreceptor morphology, including the pattern of ZIO stain. The prolonged effects of KA, and to a lesser extent QUIS, on photoreceptors suggests that these drugs have a long-term effect on photoreceptor function. The ZIO technique provides a novel and potentially useful approach for identification of damaged photoreceptors.

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl-D-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow.

Background and objective Increased glutamate concentration in the cerebrospinal fluid has been reported in severely head–injured patients, suggesting that an excessive release of glutamate may be involved in the process of neuronal damage. Ischaemic damage after subdural haematoma has been reported to be reduced by glutamate (N-methyl-D-aspartate: NMDA) receptor antagonists such as dizocilpine and CGS 19755; even though these drugs were given 20–30 min after insult. Excessive release of excitatory amino acids may produce the neural damage after subdural haematoma and NMDA receptor antagonists may become valuable therapeutic drugs. This study compared the effects of ketamine and dizocilpine, on intracranial pressure and histopathological changes after acute subdural haematoma produced by an injection of autologous blood (150 μL) in rats.

Methods The control (n =9), ketamine (n =9) and dizocilpine (n =9) groups, respectively, received saline, ketamine (total dose: 210 mgkg−1) or dizocilpine (total dose: 1.0 mgkg−1) from 0.5 to 8 h after acute subdural haematoma. A silicone group (n =9) had the same volume of silicone injected subdurally.

Results The volume of ischaemic damage in the silicone group (1.3±1.2mm3) was significantly smaller than in the control group (11.9±3.8mm3). Ketamine and dizocilpine did not increase intracranial pressure. Dizocilpine significantly decreased the volume of ischaemic damage (6.1±3.8mm3). Ketamine failed to significantly decrease damage (7.8±5.0mm3).

Conclusions These results suggest that the factors elicited by the clotted blood contribute to the ischaemic damage after subdural haematoma, and that the glutamate receptor antagonist dizocilpine reduces the damage, while ketamine shows only a trend reduction of the damage.

The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors – therefore opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature.

The excitatory amino acid glutamate has been shown to be toxic to a number of neuronal cell types both in vitro and in vivo. It has also been shown to be capable of controlling the development of neurons grown in vitro. Using time-lapse video microscopy techniques the effects of glutamate on the rate of neurite outgrowth and growth cone motility were examined on cultured mouse spinal cord neurons. Concentrations in the range of 1 to 100 µM caused a significant inhibition of neurite outgrowth and concentrations of 10 and 100 µM significantly inhibited growth cone activity. In addition it was shown that the kainate/AMPA receptor antagonist (±)3-(2-carbvoxypiperazin-4-yl)-propyl-l-phosphonic acid, but not the NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione, was capable of blocking the inhibitory actions of glutamate on both outgrowth and motility. These results show that, at least in the culture system employed, glutamate might have a role in regulating neuronal development and function.

The precise mechanisms underlying secondary brain damage after traumatic injury to the central nervous system (CNS) are not well understood, and delayed neuronal injury may result from pathological changes in neurotransmitter release, synthesis or generation of endogenous autodestructive neurochemicals and/or inflammatory mediators, or alterations in endogenous protective or trophic factors. Recent identification of such factors and the elucidation of the timing of the neurochemical cascade following CNS injury provides a window of opportunity for therapeutic intervention with pharmacological compounds which modify synthesis, release, receptor binding or physiological activity of neurotoxic factors. A number of recent experimental studies have reported that pharmacological modification of the post-traumatic neurochemical milieu can promote functional recovery in a variety of animal models of CNS trauma. This paper summarizes recent work suggesting that pharmacological manipulation of several key neurotransmitter and neurochemical systems can attenuate neuronal damage and improve functional outcome associated with traumatic brain injury.