Reduction in 2-deoxy-d-glucose analgesia following acute,but not chronic antidepressant treatment

Acute, but not chronic, antidepressant treatment potentiates the analgesic responses following cold-water swims. The present study evaluated the effects of acute (10 mg/kg) and chronic (10 mg/kg, twice daily over 7 days) pretreatment with desipramine (DMI) upon the analgesic response following 2-deoxy-d-glucose (2dG) in rats as measured by the jump test. Acute, but not chronic, DMI pretreatment significantly reduced 2dG analgesia. These effects are discussed in terms of the heterogeneity of pain-inhibitory responses.     

Glycine and <Emphasis Type="SmallCaps">d</Emphasis>-serine,but not <Emphasis Type="SmallCaps">d</Emphasis>-cycloserine,attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

RATIONALE: Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. OBJECTIVES: We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. RESULTS: High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex. CONCLUSIONS: The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.     

The effect of d-penicillamine of the skeletal development of rat foetuses

Summary Rats received 20, 50 or 100mg/animal d-penicillamine i. p. twice daily on days 15, 16, 17, 18 and 19 of gestation, i. e. a total dose of 200, 500 resp. 1000 mg/animal. At all dosages the number of fetal resorptions did not increasesignificantly. Weight of the 20 day old embryos as well as length of the long bones in the extremities in the 1000 mg-group showed a significant decrease. Numerous skeletal alterations could be observed in the 1000 mg-group such as absence, deformations or incomplete mineralisation of bones. Light microscopic examinations revealed an inhibition of the ossification as well as a decrease of number and size of the trabecula and of the thickness of the perichondrial bone sheath. A swelling of the collagenous fibrils can be demonstrated with the electron microscope. The first apatite crystals aggregate in collagen-free areas. The fusion of these aggregates to homogenously mineralized trabecula is inhibited. In contrast to bones from untreated embryos, mineralized areas show varying content of collagen and apatide crystals. A regular spatial relationship between apatite crystals and collagenous fibrils does not develop. These findings show that even after the so-called critical period malformations can be produced by substances which disturb synthesis and maturation of the mesenchymal intercellular substance.Supported with grants by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 29).     

Neurochemical and behavioural investigations of the NMDA receptor-associated glycine site in the rat striatum: Functional implications for treatment of parkinsonian symptoms

The glutamatergic cortico-striatal and subthalamo-entopeduncular pathways are both overactive in parkinsonism. Previous behavioural investigations have shown that intra-entopeduncular injection of either NMDA-site or glycine-site antagonists results in alleviation of parkinsonian symptoms, although injection of the former is associated with the appearance of anaesthetic-like side effects. These behavioural differences may be mediated by action on different NMDA receptor subtypes. Recent neurochemical and molecular pharmacological studies have indicated the existence of NMDA receptor subtypes which display differential modulation by glycine. In the present study, three potential modes of NMDA antagonism were differentiated in vitro by effects on [³H]-glycine binding to striatal sections. Specific [³H]-glycine binding was totally displaced by the glycine partial agonist (R)-HA-966; the NMDA-site antagonistd-CPP had no effect; and the NMDA-site antagonistd-AP5 displaced [³H]-glycine binding in a subpopulation of glycine sites. The anti-parkinsonian effects of (R)-HA-966,d-CPP andd-AP5 were assessed by intra-striatal injection in reserpine-treated rats and 6-OHDA-lesioned rats. Injection of (R)-HA-966 andd-CPP resulted in alleviation of parkinsonian akinesia, although the latter elicited anaesthetic-like side effects;d-AP5 was ineffective as an anti-parkinsonian agent. (R)-HA-966 was also effective as an anti-parkinsonian agent when administered systemically in the reserpine-treated rat. These data suggest that different classes of NMDA antagonist mediate different behavioural responses within the parkinsonian striatum. The behavioural response produced may depend on the exact nature of the conformational change induced by the antagonist and the location of the subtype most sensitive to that class of compound. Selection of a specific mode of NMDA receptor antagonism or targeting of striatal NMDA receptor subtypes may form the basis of a novel therapeutic approach to Parkinson's disease.     

An acetaldehyde-sequestering agent inhibits appetitive reinforcement and behavioral stimulation induced by ethanol in preweanling rats

Ethanol's motivational consequences have been related to the actions of acetaldehyde, a metabolic product of ethanol oxidation. The present study assessed the role of acetaldehyde in the motivational effects of ethanol on preweanling rats. In Experiment 1 pups (postnatal days 13-14, PD 13-14) were given systemic administration of d-penicillamine (DP, a drug that sequesters acetaldehyde: 0, 25, 50 or 75 mg/kg) before pairings of 1.0 g/kg ethanol and a rough surface (sandpaper, conditioned stimulus, CS). At test, pups given sandpaper-ethanol pairings exhibited greater preference for the CS than unpaired controls, but this preference was not expressed by pups given DP. Pre-training administration of 25 or 50 mg/kg DP completely blocked the expression of ethanol-mediated appetitive conditioning. d-penicillamine did not alter blood ethanol levels. Subsequent experiments revealed that ethanol-induced activation was blocked by central (intra-cisterna magna injections, volume: 1 μl, dose: 0 or 75 μg) but not systemic treatment with DP (0, 25, 50 or 75 mg/kg; ip). These results indicate that: (a) preweanling rats are sensitive to the reinforcing effect of ethanol, and (b) that this effect is associated with the motor activating effect of the drug. These effects seem to be mediated by the first metabolite of ethanol, acetaldehyde.     

Selective potentiations in opioid analgesia following scopolamine pretreatment

The effects of the muscarinic receptor antagonist scopolamine upon analgesia induced by d-ala-d-leu-enkephalin (DADL), beta-endorphin (BEND) and morphine were examined. While scopolamine (10 mg/kg, IP) significantly potentiated the analgesic responses following DADL (40 g, ICV) and morphine (5 mg/kg, SC) on the jump test, it failed to alter significantly BEND (1 g, ICV) analgesia.     

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice

Rationale Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.Objectives The effects of N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, and a combination of a NO precursor l-arginine and l-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.Methods Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, l-NAME (15–60 mg/kg) and l-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.Results Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of l-NAME blocked the development of sensitization to nicotine; and, l-arginine (1 g/kg) pretreatment reversed this effect of l-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of l-NAME inhibited the expression of sensitization to nicotine on day 18; and, l-arginine (1 g/kg) pretreatment reversed this inhibitory effect of l-NAME.Conclusions Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.     

D-cycloserine enhances short-delay, but not long-delay, conditioned taste aversion learning in rats

NMDA receptors have been implicated in conditioned taste aversion (CTA), a form of associative learning with the unique temporal characteristic of associating taste and toxic stimuli across very long delays. d-cycloserine (DCS), an NMDA receptor agonist, has been shown to enhance short-delay CTA learning. Here we examined the interaction of DCS with varying temporal parameters of CTA. DCS (15 mg/kg) administered prior to the pairing of 0.125% saccharin and LiCl (38 mM, 12 ml/kg) enhanced CTA when there was a short delay between the taste-toxin pairing (10 min), but not when there was a long delay (45 min). DCS activity remained at effective levels over the long delay, because DCS administered 60 min prior to a short-delay pairing enhanced CTA. The interaction of DCS with the delay between taste stimulus onset and LiCl injection was investigated by administering DCS and then 5 min access to saccharin 45 min prior to a short-delay pairing of saccharin and LiCl. DCS failed to enhance CTA in rats pre-exposed to saccharin, even with a short delay between the second saccharin exposure and LiCl injection. These results suggest that DCS enhancement of CTA is dependent on mechanisms underlying gustatory processing during long-delay taste-toxin associations.     

Nitric oxide synthesis,epileptic seizures and kindling

Nitric oxide (NO) has been implicated in synaptic changes underlying long-term potentiation and some forms of learning. It is unclear, however, whether NO contributes to long-term changes associated with the kindling of epileptic seizures. In the present study rats were treated, on the first 6 days of kindling, withl-arginine (l-Arg), the endogenous donor from which NO derives, or withl-nitro-arginine (l-No-Arg), a competitive inhibitor of NO synthesis, or with vehicle. Drugs were given in doses previously shown to affect learning or other behaviour.l-Arg (750 mg/kg IP) did not affect kindling or seizure severity.l-No-Arg (100 mg/kg) prolonged the duration of afterdischarges and convulsions on treatment days but did not advance kindling or affect seizures on subsequent days. A second experiment examined the possible rôle of NO in the development of resistance to seizures following prior seizures. Six or more stimuli were administered at 10-min intervals to fully-kindled rats after injection ofl-No-Arg or vehicle. Vehicle-treated rats became progressively more resistant to afterdischarges and convulsions with successive stimulations butl-No-Arg-treated rats failed to do so. Rats injected withl-No-Arg also showed an unexpected high mortality in the ensuing 24 h.l-No-Arg appeared to have no direct effect on the course of kindling but impaired the development of postictal resistance, and increased the duration and lethal after-effects of closely repeated seizures. The results do not support suggestions that antagonists of NO might prove clinically useful as anticonvulsants.     

Formation of dopamine from 3-methoxytyrosine

Summary l-3-Methoxytyrosine-¹⁴C was given intravenously to mice, alone or following inhibitors of monoamine oxidase, catechol-O-methyl transferase or dopa decarboxylase. ¹⁴C-noradrenaline and ¹⁴C-dopamine in brain and heart were determined 2 h after the administration of the labelled compound. The results were very similar to those obtained in previous studies after a small dose of labelled dopa. Therefore, a careful paperchromatographic analysis of the l-3-methoxytyrosine-¹⁴C was made. It was found that 1.5% of the total radioactivity corresponded to dopa. Attempts to make a preparative separation of ¹⁴C-dopa from ¹⁴C-3-methoxytyrosine failed due to the appearance of another labelled impurity interfering with the determination of dopamine. Thus, the question whether dopamine can be formed from 4-methoxytyrosine in vivo could not be definitely answered. However, the serious interference of small amounts of radioactive impurities when working with labelled material in biological systems has been demonstrated once more.     

Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

Rationale A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.Objectives The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.Results PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.Conclusions The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.     

<Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

Rationale Activation of co-agonist N-methyl-d-aspartate (NMDA) and Glycine_B sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function.Objectives This article outlines the complex regulation of activity at Glycine_B/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of Glycine_B/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties.Results Polymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which Glycine_B sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at Glycine_B/NMDA sites, whereas levels of endogenous antagonists are elevated. NMDA receptor open channel blockers, such as phencyclidine, are psychotomimetic in man and in rodents, and antipsychotic agents attenuate certain of their effects. Moreover, mice with genetically invalidated Glycine_B/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, Glycine_B agonists and inhibitors of glycine reuptake have been found to potentiate the ability of conventional antipsychotics to improve negative and, albeit modestly, cognitive and positive symptoms. In contrast, therapeutic effects of clozapine are not reinforced, likely since clozapine itself enhances activity at NMDA receptors.Conclusions Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine_B sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine_B sites alone improves psychotic states.     

Pre- and postjunctional actions of endothelin in the rat iris sphincter preparation

Effects of endothelins (ETs) were studied in the rat iris sphincter preparation. Three peptides (ET1, ET-2 and ET-3) caused contractile responses, and the rank order of agonist potency was: ET-1 = ET-2 > ET-3. The concentration-response curve to ET-1 was shifted to the right by the ET_A receptor antagonist cyclo [d-Asp-l-Pro-d-Val-l-Leu-d-Trp] (BQ-123: 10^–7 M), the pA₂ value of which was 7.41 ± 0.09 (n = 4).ET-1 and ET-3, at the concentration of 10^–9 M, potentiated cholinergic contractions evoked by electrical field stimulation (5 and 20 Hz) without affecting the postjunctional sensitivity to carbachol. This potentiating effect was not influenced by BQ-123 (10^–6 M). The ET-evoked percentage increase in the stimulation-induced contraction observed at 5 Hz was significantly greater than that at 20 Hz. A release of immunoreactive ET was detected when the preparation was stimulated at 20 Hz (1.81 ± 0.36 pg/sphincter n = 6). ET release evoked by 20 Hz stimulation was completely abolished by tetrodotoxin (10^–7 M).In conclusion, ET interacts with two different receptor types, ET_A and non-ET_A receptors (probably ET_B) which exist post- and presynaptically at cholinergic neuroeffector junctions of the rat iris preparation. Stimulation of ET_A receptor results in a direct muscle contraction and non-ET_A receptor activation facilitates the acetylcholine output from cholinergic nerve endings. It is suggested that ET released from a tetrodotoxin-sensitive site is involved in the modulation of acetylcholine release in the rat iris sphincter preparation. Correspondence to: I. Takayanagi at the above address     

Association l-Dopa,désipramine et inhibiteur de la décarboxylase dans le traitement de la dépression

The use of l-Dopa in the treatment of depressions has been suggested by pharmacological hypotheses and by observations made during the treatment of Parkinson's disease. The authors discuss the first results of their experiences using a combination of l-Dopa, a decarboxylase inhibitor, and desipramine. Some types of depression were rapidly relieved by such treatment, while those types associated with anxiety and agitation did not respond.

     

The effect of l-dopa on young patients with simple schizophrenia,treated with neuroleptic drugs

Thirteen out of 18 young out-patients with simple schizophrenia under neuroleptic treatment completed a double-blind cross-over trial with Madopar® [l-Dopa + benserazid (a peripheral decarboxylase inhibitor)] and placebo. Nine patients were given 900 mg l-Dopa + 225 mg benserazid daily, 1 patient received 600 mg l-Dopa + 150 mg benserazid, and 3 patients, 300 mg l-Dopa + 75 mg benserazid. In these doses, l-Dopa was effective against emotional withdrawal, blunted affect, tendency to isolation and apathy, without inducing or aggravating productive, accessory symptoms. The activity score, according to the specific activity-withdrawal scale, was significantly increased (P<0.05), whereas the total BPRS score (Brief Psychiatric Rating Scale) was slightly, but significantly reduced (P<0.05). In cases where l-Dopa had to be limited to 600 and 300 mg daily, a tendency to anxiety, distortion of thinking, and a sense of unreality were observed, depending on the dose of l-Dopa. In no case were gastrointestinal, cardiovascular or neurological sideeffects observed.     

Demethylation of l-3-methoxytyrosine in vivo

Summary After administration of purified l-¹⁴C-3-methoxytyrosine (l-¹⁴C-3-MTO) to rats, the fractions of labelled amino acids, catecholamines and phenolcarboxylic acids of urine and brain have been separated by column chromatography. Prior to performing the quantitative determinations, the individual metabolites of each urinary fraction and of the cerebral catecholamine fraction were isolated by paper chromatography using different systems. Susbtantial amounts of ¹⁴C-3,4-dihydroxyphenylacetic acid (¹⁴C-DOPAC) as well as some ¹⁴C-3,4-dihydroxyphenylalanine (¹⁴C-DOPA) and traces of dopamine (DA) appeared in the urine. Furthermore, small amounts of ¹⁴C-DA and ¹⁴C-norepinephrine were found in the brain with two different chromatographic systems. The urinary excretion of ¹⁴C-DOPAC and ¹⁴C-DA was increased by pretreatment with dopacetamide, an inhibitor of catechol-3-O-methyl-transferase. A possible contamination of the l-¹⁴C-3-MTO with traces of l-¹⁴C-DOPA as a major source of the dihydroxylated metabolites has been ruled out. It is concluded that part of l-3-MTO undergoes demethylation in vivo and that the finding of DA in brain and urine after administration of l-3-MTO is not an artifact.     

Ionically Fixed Polymeric Nanoparticles as a Novel Drug Carrier

Purpose

In this study, we have prepared a novel polymeric drug delivery system comprised of ionically fixed polymeric nanoparticles (IFPN) and investigated their potential as a drug carrier for the passive targeting of water-insoluble anticancer drugs.

Materials and Methods

For this purpose, the physicochemical characteristics of the IFPN were investigated by comparing them with conventional polymeric micelles. IFPN containing paclitaxel were prepared and evaluated for in vitro stability and in vivo pharmacokinetics.

Results

The IFPN were successfully fabricated using a monomethoxypolyethylene glycol-polylactide (mPEG-PLA) diblock copolymer and a sodium salt of d,l-poly(lactic acid) (d,l-PLACOONa) upon the addition of CaCl₂. The transmittance of the IFPN solution was much lower than that of a polymeric micelle solution at the same polymer concentration implicating an increase in the number of appreciable particles. The particle size of the IFPN was approximately 20～30 nm which is in the range of particle sizes that facilitate sterile filtration using a membrane filter. The IFPN also have a regular spherical shape with a narrow size distribution. The zeta potential of the IFPN was almost neutral, similar to that of the polymeric micelles. In contrast, mixed micelles with a combination of mPEG-PLA and d,l-PLACOONa prior to the addition of Ca²⁺ showed a negative charge (?17 mV), possibly due to the carboxyl anion of polylactic acid exposed on the surface of the micelles. The IFPN formulation was highly kinetically stable in aqueous medium compared to the polymeric micelle formulation. The molecular weight of d,l-PLACOONa in the IFPN and the mPEG-PLA/d,l-PLACOONa molar ratio had a great influence upon the kinetic stability of the IFPN. Pharmacokinetic studies showed that the area under the concentration vs time curve (AUC) of IFPN in blood was statistically higher (about two times) when compared with that of Cremophor EL-based formulation (Taxol^® equivalent) or polymeric micelle formulation.

Conclusions

The results suggests that the IFPN were retained in the circulation long enough to play a significant role as a drug carrier in the bloodstream, possibly resulting in improved therapeutic efficiency. Therefore, the IFPN are expected to be a promising novel polymeric nanoparticulate system for passive tumor targeting of water-insoluble anticancer drugs including paclitaxel.     

Glutamate: its role in learning,memory, and the aging brain

l-Glutamate is the most abundant of a group of endogenous amino acids in the mammalian central nervous system which presumably function as excitatory neurotransmitters and under abnormal conditions may behave as neurotoxins. As neurotransmitters, these compounds are thought to play an important role in functions of learning and memory. As neurotoxins, they are believed to be involved in the pathogenesis of a variety of neurodegenerative disorders in which cognition is impaired. Moreover, brain structures which are considered anatomical substrata for learning and memory may be particularly vulnerable to the neurotoxic actions of these excitatory amino acids, especially in the elderly who are also the segment of the population most susceptible to impairments of mnemonic function. This paper is a review of data concerning the role of excitatory amino acids in the processes of learning and memory and in the pathogenesis and treatment of disorders thereof.     

The amino acid <Emphasis Type="SmallCaps">l</Emphasis>-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice

Rationale The cognitive and attentional deficits observed in schizophrenic patients are now considered central to the pathophysiology of the disorder. These deficits include an inability to filter sensory input as measured by, e.g., prepulse inhibition (PPI) reflex. Administration of phencyclidine (PCP), a drug that can induce a schizophrenia-like psychosis in humans, disrupts PPI in experimental animals. In rodents, this PCP-induced deficit can be blocked by pretreatment with nitric oxide (NO) synthase inhibitors. This suggests that some of the behavioral effects of PCP are mediated via NO. The substrate for in vivo NO production is l-arginine, and active transport of l-arginine via the cationic amino acid transporter may serve as a regulatory mechanism in NO production. Objectives The aim of the present study was to study the effects of l-arginine transport inhibition, using acute and repeated l-lysine treatment, on PCP-induced disruption of PPI in mice. Results Subchronic, and to some extent acute, pretreatment with l-lysine blocked a PCP-induced deficit in PPI without affecting basal PPI. Conclusions l-lysine has been shown to block l-arginine transport in vitro, most likely via a competitive blockade and down regulation of cationic amino acid transporters. However, the importance of l-arginine transport as a regulatory mechanism in NO production in vivo is still not clear. The present results lend further support to the notion that some of the effects of PCP in the central nervous system are mediated via NO and that l-arginine transport may play a role in the regulation of NO production in the brain.     

Morphine,d-Pen2,d-Pen5 enkephalin and U50,488H differentially affect the locomotor activity and behaviours induced by quinpirole in guinea-pigs

The effects of morphined-Pen²,d-Pen⁵ enkephalin (DPDPE) and U50,488H on the behavioural syndrome elicited by the dopamine (DA) D-2 agonist quinpirole, were investigated. Morphine (1, 5 and 15 mg/kg SC) and morphine administered intracerebroventricularly (ICV) (2×5 µl, 10^–3 M; total dose = 10 nmol) produced piloerection and sedation. DPDPE-ICV (2×5 µl and 2×10 µl, 10–³ M; total doses = 10 and 20 nmol) produced piloerection and sedation similar to morphine. U50,488H (1 mg/kg SC) induced locomotor activity and some stereotyped behaviour, whereas U50,488H (5 and 10 mg/kg SC) induced muscle rigidity and dystonic-like movements. The locomotor and behavioural response elicited by quinpirole (3 mg/kg IP) was attenuated in guinea-pigs pretreated with morphine (1, 5 and 15 mg/kg SC), morphine-ICV (2 × 5 µl, 10–³ M), and DPDPE-ICV (2 × 5 µl and 2 × 10 µl, 10^–3 M). These effects were reversed by naloxone (15 mg/kg SC). U50,488H (1 mg/kg SC) increased the quinpirole-induced locomotor activity, whereas U50,488H (5 and 10 mg/kg SC) decreased the locomotor activity and stereotyped behaviours produced by quinpirole. These results indicate that the gross behavioural effects of mu, delta and kappa opioids differ in guinea-pigs compared to other rodent species, and suggest differential involvement of these opioid receptor subtypes with DA D-2 receptor-mediated activity.