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.     

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.     

Effect of monoamine precursors on the forced-swimming test in mice

The antidepressant properties of monoamine precursors were evaluated by the forced-swimming test for mice developed by Porsolt et al. DOPA but not 5-hydroxy-tryptophan (5HTP) shortened immobility at doses that did not increase locomotor activity. Although l-threo-dihydroxyphenylserine (DOPS), an artificial norepinephrine (NE) precursor, did not change immobility in intact mice, DOPS significantly reduced immobility in mice pretreated with the selective NE neurotoxin DSP4. These results suggest possible antidepressant properties of DOPA and DOPS, the latter of which may act as an antidepressant in a certain NE-depleting condition.     

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     

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.     

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.     

<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.     

Patterns of acetylation of procainamide and procainamide-derived p-aminobenzoic acid in man

Summary The metabolism of orally administered procainamide has been studied in fast and slow acetylators of sulphadimidine. Although the overall excretion in 6 hours of procainamide and its metabolites was similar in both groups, the excretion ofn-acetylprocainamide by the fast acetylator group was much higher (40.9 mg vs 14.9 mg); individual values showed a bimodal distribution. In contrast, no difference between the two groups in totaln-acetyl-p-aminobenzoic acid was detected, the percentages ofn-acetyl-PABA being distributed unimodally. The plasma half-life of procainamide was shorter in the fast acetylator group (2.2 hr vs 3.9 hr).Preliminary results presented at the Sixth International Congress of Pharmacology, Helsinki, 1975Supported in part by a grant from Merrell International Research Center     

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.     

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.     

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.     

Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role ofd-Ala2-d-Leu5-enkephalin (DADL) and dynorphin A(1-13)

The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001–30 g), depending upon ligand and animal, by morphine, by themu-selective peptides DAGO[d-Ala²-NMePhe⁴-Gly(ol)-enkephalin] and FK33824[d-Ala²,NMePhe⁴-Met(O)⁵-(ol)-enkephalin], and by thedelta-selective peptide, DADL[d-Ala²,d-Leu⁵enkephalin]. The order of relative potency of these substances was: FK33824>DAGO>morphine>DADL. In contrast, DPLPE[d-Pen²,l-Pen⁵)enkephalin], which has much greaterdelta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1–10 g), akappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 g DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 g dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings thatmu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.     

Amphetamine-induced perseverative behavior in a radial arm maze following DSP4 or 6-OHDA pretreatemnt

Mice permitted to explore an 8-arm radial maze tended to visit those arms least recently entered. Treatment with d-amphetamine engendered a perseverative tendency, wherein mice repeatedly visited two arms of the maze. Administration of the norepinephrine (NE) neurotoxin, N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP4), appreciably reduced NE in the hippocampus and cortex, moderately reduced NE in the locus coeruleus, and had only a small effect on hypothalamic NE. The DSP4 treatment resulted in a decrease of locomotor activity among amphetaminetreated mice, coupled with an increase of stereotyped response patterns. Although the NE depletion did not affect the pattern of exploration that mice ordinarily displayed, DSP4 appreciably increased the perseverative tendency provoked by amphetamine. Reduction of dopamine (DA) and NE by intraventricular administration of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), antagonized the effects of amphetamine, such that the frequency of alternation responses was increased and the proportion of perseverative responses was reduced. The effectiveness of the 6-OHDA treatment in antagonizing the amphetamine-induced perseveration was not reduced among mice that were pretreated with desmethylimipramine, which resulted in partial prevention of the NE reduction by 6-OHDA administration. It is suggested that DA neuronal activity contributes to the amphetamineprovoked perseveration, whereas NE stimulation modifies the perseverative tendency by influencing exploration or habituation.     

N-acetyl-S-(2-hydroxyethyl)-L-cysteine as a potential tool in biological monitoring studies?

In mammalian species, including man, N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-HEMA) is a common urinary metabolite of a large number of structurally different xenobiotic chemicals. It is a common urinary end product of glutathione pathway metabolism of a variety of chemicals possessing electrophilic properties and, in most cases, also a genotoxic potential. Five different chemically reactive intermediates, with different electrophilic properties, may be involved in the formation of 2-HEMA. An inventory of chemicals known to lead to the formation of 2-HEMA, or based on their chemical structure expected to do so, is presented. Furthermore, an attempt is made to evaluate the possibilities and limitations in terms of the potential use of urinary 2-HEMA as a tool in biomonitoring studies. Two other related, sulfur-containing urinary metabolites, i. e. N-acetyl-(S-carboxymethyl)-L-cysteine and thio-diacetic acid, are proposed as possible alternatives to urinary 2-HEMA. It is suggested that 2-HEMA might be seen as a potentially useful and sensitive signal parameter for the assessment of exposure of animals and man to a variety of electrophilic and therefore potentially toxic xenobiotic chemicals.     

Similarities and differences between d-ALA2 MET5 enkephalin amide and morphine in the induction of tolerance to their effects on catalepsy and on dopamine metabolism in the rat brain

Summary Rats were made tolerant to morphine or to DALA, a synthetic analogue of met-enkephalin, by prolonged exposure to these compounds. Tolerance was assessed by evaluating the resistance of the treated rats to present catalepsy after an acute dose of the opiates. Both morphine and DALA induced tolerance and cross-tolerance to the cataleptic effect. Acute administration of morphine and DALA increased the concentration of DOPAC in striatum, limbic area and s.nigra of control rats. This increase was not present when morphine was given acutely to chronically morphine-treated rats, indicating that these animals were tolerant to this effect. Chronically morphine-treated rats given DALA presented partial tolerance to the biochemical effect of the peptide in limbic area and in s.nigra but not in striatum, indicating that only in certain areas was crosstolerance produced by chronic morphine. When DALA was administered at different doses to chronically DALA treated rats, the peptide induced rise in DA catabolite was similar to that produced in control animals, so clearly there was no tolerance to this biochemical effect. In these animals cross tolerance to morphine's effect on DA metabolism was present in s.nigra but not in the other two areas, indicating that s.nigra is particularly sensitive to opiate-induced tolerance on DA metabolism.Supported by CNR-ROME Grant no. CT81.00258.04     

Possible involvement of l-arginine-nitric oxide pathway in modulating regional blood flow to brown adipose tissue of rats

To evaluate whether the l-arginine-nitric oxide (NO) pathway is involved in the regulation of regional blood flow to brown adipose tissue (BAT), the effects of two specific NO synthase inhibitors, N^G-nitro-l-arginine methyl ester (l-NAME) and N^G-monomethyl-l-arginine (l-NMMA), on the blood flow to interscapular brown adipose tissue (IBAT) were studied in urethane-anesthetized rats. Regional blood flow in MAT was measured with laser-Doppler flowmetry.An intravenous injection of l-NAME and l-NMMA, but not of either d-enantiomer, caused a transient and dose-dependent increase in IBAT blood flow. Dose-response curves for these NO synthase inhibitors showed that l-NAME was more potent than l-NMMA in increasing IBAT blood flow. We also observed a concomitant pressor effect accompanied by a slight decrease in heart rate following intravenous injection of l-NAME and l-NMMA. An elevation of IBAT blood flow and blood pressure induced by both l-NAME and l-NMMA was reversed by l-arginine in an enantiomerically specific manner. The increase in IBAT blood flow induced by NO synthase inhibitors was of shorter duration and less sensitive to l-arginine than the increase in blood pressure.Our results show that the WAY blood flow is increased by inhibition of NO synthase and that the response of IBAT vasculature to NO synthase inhibitors is different from that of the resistance vessels which regulate blood pressure. The involvement of l-arginine-NO pathways in modulating microcirculation in IBAT is suggested. Correspondence to: Y. Uchida at the above address     

Propriétés différentielles d'un inhibiteur de la décarboxylase envers la l-Dopa et le l-5-HTP. Données polygraphiques et biochimiques

This study, comparing polygraphic data and biochemical dosages with a short term rabbit EEG recording technique, shows that Ro 4602 does not have the same quantitative (or even qualitative) effect whether combined with l-Dopa or l-5-HTP. Thus minimal and optimal doses of this inhibitor of the decarboxylase are not the same for the two precursors. Using equimolar doses, clinical effects on the whole appeared to be much more evident with the association Ro 4602-l-5-HTP than with Ro 4602-l-Dopa.

     

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.