Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates.

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.     

Lack of neuroprotective effect of some sigma ligands in a model of focal cerebral ischemia in the mouse.

The potential neuroprotective effect of seven sigma ligands has been evaluated in a mouse model of focal cerebral ischemia (induced by coagulation of the left middle cerebral artery) and compared to that of known N-methyl-D-aspartate (NMDA) antagonists. When given after the induction of cerebral ischemia, the NMDA receptor antagonists dizocilpine and CGS 19755 and the mixed NMDA antagonist/sigma ligand eliprodil (SL 82.0715) afforded very substantial protection against cortical infarction (92, 44 and 72%, at the doses of 1, 10 and 10 mg/kg, i.p., for dizocilpine, CGS 19755 and eliprodil, respectively). In contrast, none of the sigma ligands investigated--DTG, DMTG, GBR 12909, (+)- and (-)-3-PPP (up to 10 mg/kg), BMY 14802 (up to 30 mg/kg), except haloperidol at a high dose (3 mg/kg)--had neuroprotective effects.     

Effects of CGS 19755 and dizocilpine (MK 801) on delayed time discrimination performance.

The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist dizocilpine (MK 801) on time discrimination and short-term memory were investigated in rats trained on a delayed time discrimination task. In a two-lever operant chamber, pressing one lever was correct and reinforced with a food pellet after presentation of a stimulus light for 2 s (SD(short)); pressing the opposite lever was correct after presentation of a stimulus light for 8 s (SD(long)). CGS 19755 (3.0 mg/kg) attenuated performance, decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimulus and the presentation of the response levers), and increased response latencies (time from 'opportunity to leverpress' to 'actual leverpress'). The highest dose of dizocilpine (0.2 mg/kg) tested also attenuated performance. Further, the number of nose-pokes and response latencies were not altered by any dose of dizocilpine. With increasing delays, saline-injected animals developed a bias towards reporting an occurrence of an SD(long), independent of the actual stimulus presented. This bias was attenuated or even reversed by CGS 19755 (3.0 mg/kg) and (0.2 mg/kg). Our results suggest that NMDA receptors are directly or indirectly involved in time discrimination performance.     

Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.     

CGS-19755 and MK-801 selectively prevent rat striatal cholinergic and gabaergic neuronal degeneration induced by N-methyl-D-aspartate and ibotenate in vivo

Summary The in vivo efficacies and potencies of various excitatory amino acid agonists in inducing cholinergic neuronal degeneration were compared following unilateral injections into the rat striatum. Kainic acid (KA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), ibotenic acid (IBO), and N-methyl-D-aspartic acid (NMDA) all produced dose-related decreases in choline acetyltransferase (ChAT) activity. The relative order of potency was KA>AMPA>IBO>NMDA. Quisqualic acid (QUIS) was about as potent as NMDA, but the maximal decrease in ChAT activity was less (36%). N-acetylaspartyl-L-glutamate (NAAG) did not significantly decrease ChAT activity when up to 1,000 nmoles was injected. Approximate equitoxic doses of agonists were then used to examine the ability of i.p. administered CGS-19755 and MK-801 to prevent in vivo excitatory amino acid-induced cholinergic and GABAergic neuronal degeneration. NMDA-induced decreases in ChAT and glutamic acid decarboxylase (GAD) activities were prevented by CGS-19755 (10–40 mg/kg) and MK-801 (1–10 mg/kg). CGS-19755 (40 mg/kg) and MK-801 (10 mg/kg) did not prevent loss of ChAT or GAD induced by KA or AMPA, but did prevent the degenerative effects of IBO. This study shows that CGS-19755 and MK-801, two NMDA receptor antagonists that act by different mechanisms, are completely selective following systemic administration. Moreover, the in vivo excitotoxic effects of IBO are mediated at NMDA receptor sites that are blocked by these compounds.     

Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on dizocilpine-induced neuropathological changes in rat retrosplenial cortex

In the present study, we examined the effects of LY379268, the group II metabotropic glutamate receptor (mGluR) agonist, on the neuropathological changes in the rat retrosplenial cortex induced by noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). Administration of LY379268 (1, 3, 10 mg/kg, i.p.) reduced dizocilpine (0.5 mg/kg, i.p.)-induced neuropathological changes in the retrosplenial cortex, in a dose-dependent manner. Co-administration of LY379268 (10 mg/kg, i.p.) with group II mGluR antagonist LY341495 (5 mg/kg, i.p.) blocked the effects of LY379268. Furthermore, LY379268 (10 mg/kg, i.p.) significantly reduced the expression of heat shock protein HSP-70, a marker of reversible neuronal injury, in the rat retrosplenial cortex after administration of dizocilpine (0.5 mg/kg, i.p.). Moreover, pretreatment with LY379268 (10 mg/kg, i.p.) significantly suppressed the increase in extracellular acetylcholine (ACh) levels in the retrosplenial cortex induced by administration of dizocilpine (0.5 mg/kg, i.p.). These results suggest that LY379268 has a protective effect on the neurotoxicity in the rat retrosplenial cortex after administration of NMDA receptor antagonists such as dizocilpine.     

N-methyl-D-aspartic acid-induced lethality in mice: selective antagonism by phencyclidine-like drugs

N-Methyl-D-aspartic acid (NMDA) produced a dose-related increase in lethality in mice, with 200 mg/kg (i.p.) effecting 100% lethality. Upon daily dosing, acutely sublethal doses of NMDA produced deaths. This NMDA-induced lethality was stereoselective; N-methyl-L-aspartic acid had no effects at doses as high as 400 mg/kg. Moderate doses of phencyclidine (PCP) and drugs having PCP-like behavioral effects blocked the NMDA-induced lethality. Other classes of psychoactive drugs, including opioids, anticonvulsants and antipsychotics, were ineffective in preventing NMDA-induced lethality. The potency of PCP-like drugs to block the NMDA-induced lethality correlates highly with the dose necessary to produce PCP-like catalepsy and PCP-like discrimination in pigeons. These data support the hypothesis that PCP-like drugs produce many of their effects by impairing the normal functioning of the NMDA-defined excitatory neurotransmitter receptor in the central nervous system.     

Ethanol substitutes for the discriminative stimulus effects of m-chlorophenylpiperazine

Rats were trained to discriminate the 5-HT agonist m-chlorophenylpiperazine (mCPP, 1 mg/kg, i.p.) from saline. Ethanol (0.1 to 1 g/kg, i.p.) partially substituted for the discriminative stimulus effects of 1 mg/kg mCPP. Methysergide (10 mg/kg, i.p.), a 5-HT(1/2) receptor antagonist, blocked the ability of ethanol (1 g/kg) to substitute for mCPP. The largest dose of ethanol markedly reduced response rate. These findings suggest an important role of serotonin receptors in mediating the discriminative stimulus effects of ethanol.     

Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(±)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(±)-SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with α-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 μg, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms.     

Ethanol enhances naloxone sensitization and disrupts morphine discrimination--comparison to dizocilpine and pentobarbital: explanation of enhancing acute and attenuating chronic effects

1. Ethanol affects ligand-gated ion channels as a positive modulator of gamma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartate (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accordingly, we found that ethanol decreased morphine dependence and locomotor sensitization. We now test whether ethanol alters sensitization to the disrupting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered ethanol (1 g/kg; i.p.), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; i.p.), the GABA(A) agonist pentobarbital (PB; 3 mg/kg i.p.), or vehicle with morphine (5 mg/kg s.c.). Separate groups received naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days. Ethanol enhanced the suppressive effects of higher naloxone doses on all three days. DZ and PB altered this behavior differentially by day and naloxone dose. 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/kg; s.c.) on morphine discrimination. Rats, trained to discriminate morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations. Naloxone blocked dose-related responding to morphine, demonstrating pharmacological specificity, and altered response rates. Both ethanol and DZ, but not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiate receptor function followed by secondary NMDA-mediated processes induced by morphine administration.     

The effects of a competitive NMDA receptor antagonist (CGS-19755) on cerebral blood flow and pH in focal ischemia.

We report the effects of intravenous infusion of CGS-19755, a potent competitive N-methyl-D-aspartate (NMDA) antagonist, on local cerebral pH (LCpH) and local CBF (LCBF) in rats with occluded left middle cerebral and common carotid arteries. LCpH and LCBF were determined simultaneously by a double-label autoradiographic technique 4 h after vascular occlusion in three groups: no treatment, carrier infused, and a group receiving CGS-19755 at 10 mg/kg bolus immediately after occlusion followed by infusion at 5 mg kg-1 h-1 for 4 h. Compared with rats receiving carrier, several cortical structures on the side of occlusions showed significantly higher CBF in rats receiving CGS-19755. This drug also corrected the pH in several left cortical structures to values significantly higher than in the rats receiving carrier. The correction in LCpH was not limited to those regions showing significant elevations in LCBF. In the nonoccluded hemisphere, CGS-19755 significantly increased the hemispheric mean blood flow from 122 +/- 17 to 221 +/- 64 ml 100 g-1 min-1 (mean +/- SD of all structures, p less than 0.01) without any changes in LCpH. Cortical but not basal ganglia infarct volume was significantly smaller in rats receiving CGS-19755 than in the carrier-treated group. These results suggest that, at least partially, the neuroprotective effect of CGS-19755 in ischemia may be related to changes in CBF and pH in addition to its antagonist effect on the NMDA receptor.     

Clozapine improves dizocilpine-induced delayed alternation impairment in rats

Summary The effects of systemic administration of dizocilpine (0.16mg/kg, i.p.), clozapine (7.5mg/kg, s.c.) and coadministration of dizocilpine (0.16mg/ kg, i.p.) and clozapine (7.5mg/kg, s.c.) on acquisition of delayed alternation in a T-maze were tested in rats (N=7 per group) on six days with 10 choices per day and animal. Clozapine given alone did not impair delayed alternation learnint, except of the first day. Dizocilpine induced a significant delayed alternation impairment on all days tested. Pretreatment with clozapine significantly improved the dizocilpine-induced impairment. Treatment-induced changes of delayed alternation learning and of locomotor activities showed no correlation. The results demonstrate that clozapine functionally compensated for deficits induced by a blockade of the N-methyl-D-asparatate (NMDA) subtype of glutamate receptors.     

Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [¹⁴C12-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1–3 mg/kg i.v.;n = 20), dizocilpine (0.03–0.3 mg/kg;n = 15), CGS19755 (1–30 mg/kg;n = 15) or saline (2 ml/kg;n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR 115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62–98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively un affected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the F statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional F values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).     

Effects of the serotonin2A/2C receptor agonist and antagonist on phencyclidine-induced dopamine release in rat medial prefrontal cortex

1. Systemic administration of PCP (7.5 mg/kg, i.p.) produced a greater increase in extracellular DA levels in the mPFC than in the STR and NAC, as determined by in vivo microdialysis of awake, freely moving rats. Preferential activation by PCP of prefrontal DA neurons may be, at least in part, the basis for the pathophysiology of PCP-induced psychosis as well as schizophrenia. 2. Recent studies suggest a possible involvement of 5-HT2A receptors in the pathophysiology and treatment of schizophrenia. This study was designed to examine whether and how 5-HT2A receptors modulate PCP-induced DA release in the mPFC. 3. The 5-HT2A/2C receptor agonist (+/-)-DOI (2.5 mg/kg, but not 0.75 mg/kg, i.p.), administered 60 min prior to PCP, significantly attenuated the PCP-induced increase in extracellular DA levels. Pretreatment of the 5-HT2A/2C receptor antagonist ritanserin (1.0 and 5.0 mg/kg, i.p.), administered 60 min prior to PCP, did not influence the PCP-induced increase. When administered alone, neither DOI (2.5 mg/kg) nor ritanserin (1.0 mg/kg) affected basal extracellular DA levels in the mPFC. 4. The NMDA receptor antagonist MK-801 (1.0 mg/kg, i.p.) also increased extracellular DA levels in the mPFC, but this effect was unaffected by pretreatment with DOI (2.5 mg/kg). 5. These results suggest that the stimulation of 5-HT2A/2C receptors may inhibit DA release in the mPFC when it is facilitated by PCP. Other than the NMDA receptor-mediated mechanism may also be involved in the neurochemical interaction between 5-HT2A receptors and PCP in the mPFC.     

Effects of NMDA receptor blockade and nitric oxide synthase inhibition on the acute and chronic actions of Δ9-tetrahydrocannabinol in mice

The present studies examined the hypothesis that the N-methyl- d-aspartate (NMDA) receptor-nitric oxide (NO) pathway might be involved in the acute and chronic actions of Δ⁹-tetrahydrocannabinol (THC). The ability of dizocilpine (MK-801), a competitive NMDA receptor antagonist and N^G-monomethyl- l-arginine (l-NMMA), an inhibitor of NO synthase enzyme to modify the analgesic and hypothermic responses following the acute and chronic treatment of animals with THC was determined in male Swiss-Webster mice. Intraperitoneal administration of THC (5, 10 and 20 mg/kg) produced dose-dependent analgesic and hypothermic effects. MK-801 at 0.1 gg/kg i.p. attenuated the analgesic but not the hypothermic responses to THC (10 and 20 mg/kg, i.p.). The effects of various doses of MK-801 (0.03, 0.1 and 0.3 mg/kg, i.p.) on the analgesic and hypothermic responses to a 10 mg/kg, i.p. dose of THC was also determined. All the doses of MK-801 antogonized the analgesic but not the hypothermic effects of THC. The chronic treatment of animals with THC (10 mg/kg, i.p.) twice daily for 4 days produced tolerance to its analgesic and hypothermic effects. Pretreatment of animals with MK-801 (0.03–0.30 mg/kg, i.p.) did not affect the development of tolerance to the analgesic or the hypothermic action of THC. The pretreatment of animals with l-NMMA (2–8 mg/kg, i.p.), did not alter the analgesic or hypothermic effects of THC. Also, it did not modify the tolerance to its pharmacological actions. It is concluded that non-competitive antagonism of NMDA receptor by MK-801 selectively antagonized the analgesic action of THC and that the mechanisms in the analgesic response and tolerance to THC may be different. Finally, NO does not appear to be involved in the acute or chronic actions of THC.     

The NMDA antagonist dizocilpine (MK-801) reverses haloperidol-induced movement initiation deficits

The present study shows that systemic dopamine receptor blockade impaired movement initiation of rats, trained in a simple reaction time task for rapid initiation of locomotion in response to a combined optic/acoustic cue. Reaction time, movement time and the accelerative force were recorded for each initiation of locomotion. Results indicate a dose-related increase of reaction time following systemic administration of haloperidol (0.1, 0.15, 0.3 mg/kg i.p.). Measures derived from resulting force-time patterns showed a haloperidol-induced decrease (0.15 mg/kg i.p.) of the mean rate of force development, indicating a decreased initial acceleration. These effects were reversed by systemic co-administration of dizocilpine (MK-801) (0.08 mg/kg i.p.), a selective non-competitive N-methyl-D-aspartate (NMDA) antagonist. The haloperidol-induced movement initiation deficits in this task are in part comparable to akinesia seen in Parkinson's disease and their reversal by dizocilpine has implications for the treatment of this disease.     

Efficacy of competitive vs noncompetitive blockade of the NMDA channel following traumatic brain injury

N-methyl-d-aspartate (NMDA) receptor antagonists have been demonstrated widely to be neuroprotective in cerebral ischemia, hypoxia, and traumatic brain injury. However, although noncompetitive NMDA antagonists have typically proven efficacious under all of these conditions, competitive antagonists have not been shown to be beneficial following moderate traumatic brain injury. The present study has used phosphorus magnetic resonance spectroscopy ([³¹P]MRS) to examine the effects of the competitive antagonist cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS-19755) and the noncompetitive antagonist dextromethorphan on biochemical outcome following fluid percussion-induced traumatic brain injury in rats. Five minutes prior to induction of moderate (2.8±0.2 atm) fluid percussion brain injury, animals received either CGS-19755 (10 mg/kg iv), dextromethorphan (10 mg/kg iv), or equal volume saline vehicle. [³¹P]MRS spectra were then acquired for 4 h post-trauma and intracellular pH, free magnesium concentration, cytosolic phosphorylation potential, and oxidative capacity determined. Both CGS-19755-treated animals and saline treated controls demonstrated significant and sustained declines in intracellular free magnesium concentration and bioenergetic status following trauma. In contrast, administration of dextromethorphan significantly attenuated free magnesium decline and improved bioenergetic state during the post-traumatic monitoring period. These results suggest that the neuroprotective actions of NMDA antagonists following traumatic brain injury are associated with attenuation of free magnesium decline and that such actions seem to be preferentially mediated by noncompetitive blockers.     

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1-10 mg/kg, i.p.) produced S-shaped dose-response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.     

Dimemorfan enhances acetylcholine release from rat hippocampal slices

Our previous study reported that an antitussive drug, dimemorfan, attenuates cholinergic dysfunction-induced amnesia in mice and acts like a sigma1 receptor agonist. This study further showed that dimemorfan (30 microM), like the putative sigma1 receptor agonist (+)-SKF-10047 (10 microM), significantly enhanced 25 mM KCl-evoked [3H]acetylcholine release from rat hippocampal but not striatal slices, which was antagonized by a sigma1 receptor antagonist haloperidol (0.3 microM).     

MK-801, phencyclidine (PCP), and PCP-like drugs increase burst firing in rat A10 dopamine neurons: Comparison to competitive NMDA antagonists

Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (±)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 19755 and (±) CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists. © 1993 Wiley-Liss, Inc.