Neuropeptide Y Y1 receptor antagonist BIBP3226 produces conditioned place aversion in rats.

1. Previous studies have shown that the blockade of the neuropeptide Y (NPY) Y1 receptors with N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide (BIBP3226) induces anxiogenic-like reaction in rats tested in elevated plus-maze test. 2. The present study examined whether such a treatment is aversive using place conditioning in a two-compartment apparatus. Locomotor activity was measured in open field test. 3. Pairings with potentially anxiogenic dose of BIBP3226 (5 micrograms/6.5 microliters, i.c.v.) produced a conditioned aversion for the drug-associated place, whereas the locomotor activity in the open field test was not affected by this dose of BIBP3226. 4. These data suggest that the blockade of central NPY Y1 receptors is aversive and provide additional evidence to the hypothesis that the NPY Y1 receptors are involved in the regulation of affective states.

Involvement of opioid mu1-receptors in opioid-induced acceleration of striatal and limbic dopaminergic transmission.

The role of mu1-opioid receptors in the acceleration of cerebral dopaminergic transmission induced by morphine and the putative mu1-opioid agonist, etonitazene, was studied in rats by measuring the tissue levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens. The striatal extracellular concentrations of DA and its metabolites in freely moving rats were estimated as well. Morphine (3 mg/kg) and etonitazene (2.5 microg/kg) increased the striatal and accumbal dopamine metabolism as measured by the tissue ratios of DOPAC/DA and HVA/DA. The mu1-opioid receptor antagonist, naloxonazine (15 mg/kg), significantly antagonized these elevations except the morphine-induced elevation of striatal HVA/DA ratio. Both morphine (3 mg/kg) and etonitazene (1, 2.5, and 5 microg/kg) elevated the striatal extracellular DA, DOPAC, and HVA. Naloxonazine antagonized the effects of morphine and etonitazene on striatal extracellular DA concentration as well as etonitazene's effects on DOPAC and HVA, but not morphine's effects on DOPAC and HVA. As we previously showed concerning morphine, the conditioned place preference induced by etonitazene was inhibited by naloxonazine. These findings emphasize the role of mu1-opioid receptors in opioid reward, in which the mesolimbic dopaminergic system is considered to be importantly involved. Our results clearly show that in addition to the mesolimbic dopaminergic system the mu1-opioid receptors are also involved in the control of nigrostriatal DA release and metabolism. However, the effects of etonitazene on the striatal DA differ from those of morphine, suggesting that the opioid mechanisms regulating these two DA systems differ.

Effects of morphine in rats withdrawn from repeated nifedipine administration.

The effects of withdrawal from repeated nifedipine treatment on morphine-induced analgesia, hyperthermia and catalepsy as well as on cerebral [3H]nitrendipine binding and on morphine-induced changes in striatal and limbic dopamine and 5-hydroxytryptamine metabolism were studied in rats. Repeated administration of nifedipine (5 mg/kg i.p., twice daily for 14 days) decreased [3H]nitrendipine binding in several brain areas of the rats at 24 h after the last dose but did not change the nociceptive response or rectal temperature of the animals. Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment. However, withdrawal from repeated nifedipine treatment failed to affect either the hyperthermia induced by this dose of morphine or the catalepsy and the elevation of dopamine or 5-hydroxytryptamine metabolites induced by 15 mg/kg of morphine. Taken together, these data show that withdrawal from repeated treatment with dihydropyridine calcium channel antagonists selectively reduces the effects of opioids on the nociceptive response.

Involvement of opioid mu 1 receptors in morphine-induced conditioned place preference in rats.

The main purpose of this study was to evaluate the role of mu 1-opioid receptors in morphine reward. Therefore, we studied the ability of a mu 1-selective antagonist, naloxonazine [15 mg/kg intraperitoneally (IP)], to antagonize the conditioned place preference (CPP) induced by morphine [3 mg/kg subcutaneously (SC)]. In addition, effects of naloxonazine on morphine-induced catalepsy (15 mg/kg), analgesia (3 mg/kg), and hyperthermia (3 mg/kg) were studied. For comparison, the effects of a nonselective opioid receptor antagonist, naltrexone (2.5 mg/kg SC), and a selective delta-opioid receptor antagonist, naltrindole (2 mg/kg IP), on CPP induced by morphine were investigated. Morphine-induced CPP was clearly antagonized by pretreatment with naloxonazine and naltrexone (12 h and 20 min prior to morphine, respectively) but not by naltrindole (15 min before morphine). Naloxonazine also antagonized morphine-induced catalepsy and analgesia but not morphine-induced hyperthermia. Naltrindole did not modify morphine-induced catalepsy. These results suggest an active role for mu 1-opioid receptors in morphine reward, whereas morphine-induced hyperthermia does not appear to be mediated by mu 1-opioid receptors. Furthermore, delta-opioid receptors seem to be without significance in morphine-induced reward.

Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice?

Effects of various forms of stress on the GABAA receptor-chloride ionophore complex in the brain of NMRI mice were investigated. Male albino mice were subjected to stress by placing them on small platforms (SP; 3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several stress factors like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. As additional stress control groups we used animals subjected to isolation, large platform (9.0 cm diameter) and repeated swimming stress. SP stress induced an increase in the number of cortical benzodiazepine (BDZ) receptors and a reduction in the GABA-stimulated 36Cl-uptake by brain microsacs, whereas none of these changes could be observed in animals exposed to isolation, swimming or large platform stresses. Furthermore, the amount of GABA-induced stimulation of [3H]flunitrazepam binding was reduced in cortical brain membranes of SP-stressed animals, an effect due to fact that these animals displayed an increase in the basal [3H]flunitrazepam binding, whereas the absolute level of maximally enhanced BDZ binding in the presence of GABA did not differ from those found in controls. Neither basal [3H]muscimol binding or thiopentone sodium-induced stimulation of [3H]flunitrazepam binding were changed in any group of stressed mice. It is proposed that the observed upregulation in the number (Bmax) of cortical BDZ receptors in SP-stressed mice may represent a compensatory response to a stress-induced attenuation of GABAergic neurotransmission.

Behavioural and neurochemical sensitization of morphine-withdrawn rats to quinpirole.

The sensitivity of dopamine D2-like receptors in morphine-withdrawn rats was studied using the selective agonist quinpirole. Morphine was administered twice daily increasing the daily dose from 20 to 50 mg/kg during 7 days. Twenty-four hours after the last morphine administration the rats were given quinpirole (0.01-1 mg/kg) and their behavior was assessed. Withdrawal from repeated morphine treatment enhanced yawning behavior and penile erections induced by small doses (0.01-0.1 mg/kg) as well as the intensity of stereotypy induced by a large dose (1.0 mg/kg) of quinpirole. In the morphine-withdrawn rats the dose of 1 mg/kg of quinpirole caused less yawning than in the control rats, whereas the number of erections induced by this dose was enhanced as compared with the control animals. In the control rats, the striatal and limbic concentrations of dopamine metabolites, 3,4-dihydroxphenylacetic acid (DOPAC), and homovanillic acid (HVA), were not clearly affected by the smallest dose of quinpirole. However, the small dose of quinpirole (0.01 mg/kg) significantly reduced the levels of DOPAC and HVA in the striatum and limbic forebrain of the rats withdrawn from morphine either for 24 or 48 h. These findings indicate that withdrawal from repeated morphine treatment enhances the sensitivity of dopamine D2-like receptors.

Morphine- and cocaine-induced conditioned place preference: effects of quinpirole and preclamol.

The role of dopamine in opioid reward is unresolved. Furthermore, the issue is somewhat unclear regarding cocaine and the place preference paradigm. In the present study we investigated whether the drugs activating dopamine autoreceptors affect cocaine- and morphine-induced place preference in rats. Neither the dopamine D2/D3 receptor agonist, quinpirole (0.05 mg/kg, SC), nor the partial dopamine autoreceptor agonist, preclamol (2 or 8 mg/kg, SC), induced place conditioning by itself. Quinpirole had no significant influence on the place preference induced either by morphine (3 mg/kg, SC) or cocaine (5 mg/kg, IP). Preclamol, when given at the dose of 8 mg/kg SC, significantly attenuated the effect of cocaine but failed to modify the effect of morphine. Our results suggest that the rewarding properties of morphine involve DA-independent mechanisms whereas in the cocaine-induced reward the role of brain DA is critical. Furthermore, as regards place conditioning, we propose that the activation of DA autoreceptors is not sufficient to reliably modify the rewarding effect of cocaine.

Nitric oxide synthesis inhibition attenuates morphine-induced place preference.

Nitric oxide (NO) has been implicated in the actions of opioids. The aim of the present study was to investigate the role of NO in the mechanisms mediating the rewarding effects of morphine. Therefore, the influence of NO synthase inhibitor L-N-nitroarginine (L-NOARG) on morphine-induced place preference in rats was studied. L-NOARG, when given at 20 mg/kg, IP, significantly inhibited the effect of morphine. L-NOARG by itself, when administered at 5 or 20 mg/kg, IP, appeared to have no reliable effect on place conditioning. The results suggest a possible role of NO in the opioid reward process.

Role of dopamine receptors in the dual effect of naloxone on quinpirole-induced yawning in morphine pretreated rats.

The present study was undertaken to determine the state of sensitivity of dopamine D2/D3 receptors involved in the mediation of yawning behaviour at various times following acute morphine administration to rats. Morphine (3.0 mg/kg, s.c.) induced a biphasic effect on locomotor activity: an initial inhibitory phase lasting for about 30 min was after about an hour followed by a phase of locomotor activation lasting for about 60 min. Dopamine D2/D3 receptor agonist quinpirole (0.01-0.1 mg/kg, s.c.) induced yawning behaviour in rats. Morphine given at 15 or 60 min before (inhibitory phase) inhibited the yawning response to quinpirole (0.1 mg/kg) but not when given at 90 or 120 min before (stimulatory phase). Naloxone (1.0 mg/kg) given 10 min before quinpirole restored yawning inhibited by morphine pretreatment during the inhibitory phase (15-60 min after morphine). However, during the morphine-induced stimulatory phase naloxone strongly inhibited the yawning response to quinpirole. D1 receptor antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepin-7-ol hemimaleate] at 0.01 mg/kg did not affect quinpirole-induced yawning or its inhibition by morphine. However, in rats which received morphine 90 min prior to testing yawning, SCH 23390 enhanced quinpirole-induced yawning behaviour as compared with morphine- or saline-pretreated animals. The data obtained in the present study indicate that morphine pretreatment initially induces a lack of responsiveness of the D2/D3 receptors mediating yawning behaviour and subsequently increases their sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)