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The present study was aimed at identifying the receptor systems involved in the mediation of the sedative/hypnotic effect of gamma-hydroxybutyric acid (GHB) in DBA mice. Administration of the putative antagonist of the GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382; 50-500 mg/kg, i.p.), significantly increased the duration of loss of righting reflex induced by GHB (1000 mg/kg, i.p.). In contrast, the GABA(B) receptor antagonists, (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; 25-100 mg/kg, i.p.) and (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381; 12.5-150 mg/kg, i.p.), completely prevented the sedative/hypnotic effect of GHB. SCH 50911 (100 and 300 mg/kg, i.p.) was also capable to readily reverse the sedative/hypnotic effect of GHB (1000 mg/kg, i.p.) in mice that had lost the righting reflex. SCH 50911 (100 mg/kg, i.p.) also completely abolished the sedative/hypnotic effect of the GABA(B) receptor agonist, baclofen. These results indicate that the sedative/hypnotic effect of GHB is mediated by the stimulation of GABA(B) receptors and add further support to the hypothesis that the GABA(B) receptor constitutes a central site of action of GHB.

The effect of cyclo-oxygenase inhibitors, indomethacin and nimesulide, on the action of i.v. morphine on dopamine neurons projecting to the nucleus Accumbens was studied using standard extracellular recording techniques coupled with antidromic identification in unanesthetized rats. The i.v. administration of either nimesulide (3 mg/kg) or indomethacin (3.5 mg/kg) per se did not affect the firing rate of mesolimbic dopamine cells. In contrast, the subsequent administration of morphine (0.25-2 mg/kg i.v.) potently increased the firing rate of mesolimbic dopamine neurons in cyclo-oxygenase inhibitor-pretreated rats as compared with saline-pretreated rats. The maximal enhancement of basal firing rate at the highest dose of morphine tested was 92%, 80% and 47%, for nimesulide-, indomethacin-, and saline-treated rats, respectively. Our results indicate that the effect of morphine on mesolimbic dopamine cells is potentiated by blocking cyclo-oxygenase activity and suggest that the modulation of cyclo-oxygenase pathway in dopamine cells might be involved in the cellular mechanisms of the rewarding actions of morphine.

Alcohol administration (1 g/kg, i.p.) increased the levels of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) in the cerebral cortex and hippocampus both in alcohol-naive Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats (two rat lines selectively bred for alcohol preference and non-preference, respectively). However, the increase reached several fold higher levels in sP than in sNP rats (6-24 vs. 2-11 fold the basal levels, respectively). Since the two neurosteroids are the most potent endogenous positive modulators of GABA(A) receptors and elicit anxiolytic and rewarding effects, while voluntary alcohol consumption produces anxiolytic and rewarding effects in sP but not in sNP rats, the results suggest that the neurosteroids may play a role in the anxiolytic and rewarding effects of alcohol in sP rats.

Delta(9)-Tetrahydrocannabinol (1 and 5 mg/kg, i.p.) produced, dose-dependently, antinociceptive effects using hot plate and tail flick tests in rats. These effects were suppressed not only by the cannabinoid CB(1) receptor antagonist SR 141716A (0.5 mg/kg; i.p.) but also by the dopamine D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg; i.p.) and S(-)-raclopride (1.5 and 3 mg/kg; i.p.). Conversely, Delta(9)-tetrahydrocannabinol antinociceptive effects were potentiated by the dopamine D(2) receptor agonists (-)-quinpirole (0.025 mg/kg, s.c.) and (+)-bromocriptine (0.5 and 1 mg/kg; i.p.). Our results indicate that the antinociceptive effects of Delta(9)-tetrahydrocannabinol are mediated by the concomitant activation of cannabinoid CB(1) and dopamine D(2) receptors and that dopamine D(2) receptor agonists may be useful in improving the analgesic effects of cannabinoids.

Gamma-Hydroxybutyrate (GHB) has been shown to mimic different central actions of ethanol, to suppress alcohol withdrawal syndrome, and to reduce alcohol consumption both in rats and in humans. The aim of the present study was to determine if GHB shared with alcohol the ability to inhibit glutamate action at both NMDA and AMPA/kainate receptors. The NMDA or the AMPA/kainate receptors-mediated postsynaptic potentials were evoked in CA1 pyramidal neurons by stimulation of Schaffer-collateral commissural fibers in the presence of CGP 35348, bicuculline to block the GABA(B) and GABA(A) receptors, and 10 microM 6,7-dinitroquinoxaline-2,3-dione (DNQX) or 30 microM DL-2-amino-5-phosphonovalerate (d-APV) to block AMPA/kainate or NMDA receptors, respectively. GHB (600 microM) produced a depression of both NMDA and AMPA/kainate receptors-mediated excitatory postsynaptic potentials with recovery on washout. The GHB receptors antagonist, NCS-382, at the concentration of 500 microM had no effect per se on these responses but prevented the depressant effect of GHB (600 microM) on the NMDA and AMPA/kainate-mediated responses. In the paired-pulse experiments, GHB (600 microM) depressed the amplitude of the first and the second evoked AMPA/kainate excitatory postsynaptic potentials, and significantly increased the paired-pulse facilitation (PPF). These results suggest that GHB inhibits excitatory synaptic transmission at Schaffer-collateral commissural-pyramidal neurons synapses by decreasing the probability of release of glutamate.

The present study was designed to determine if cannabinoids share with other drugs of abuse the ability to stimulate mesolimbic dopaminergic neurons and if this effect is mediated by cannabinoid receptors. To this end, the effects of the prototypical cannabinoid, delta9 tetrahydrocannabinol ¿(-)-trans-(6aR,10aR)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl- 3-pentyl-6H-dibenzo[b,d]pyran-1-ol¿, and the two highly potent synthetic cannabinoids, ¿(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl]pyrrolo[1,2,3-d e]-1,4-benzoxazin-6-yl, +(1-naphtalenyl)methanone¿ WIN 55,212-2 and ¿(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl )-cicloexan-1-ol¿ CP 55,940, on the spontaneous discharge rate of meso-accumbens dopamine (A10 dopamine) neurons were studied in rats. The intravenous administration of delta9-tetrahydrocannabinol, WIN 55,212-2 and CP 55,940 (0.0625-1.0 mg/kg) produced a dose-dependent increase in the spontaneous firing of A10 dopamine neurons both in non-anesthetized and anesthetized rats, with a maximal percent increase of 120, 187 and 155 in non-anesthetized and 33, 102 and 52, respectively, in anesthetized rats. The stimulant response to cannabinoids was suppressed by the specific cannabinoid receptor antagonist ¿N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide¿ SR 141716A, indicating a cannabinoid receptor-mediated effect. These findings support the contention that cannabinoids regulate mesolimbic dopamine transmission and may help to explain the addictive properties of marijuana.

The present study describes the induction of gamma-hydroxybutyric acid (GHB) preference over water in rats. GHB solution (1% w/v in water) was initially offered as the sole fluid available for 14 consecutive days. Subsequently, rats were given a free choice of GHB solution and tap water for 20 consecutive weeks. Under the free-choice regimen, all rats showed periods of preference for GHB solution over water and periods of voluntary abstinence from GHB. On GHB-preference days, GHB was ingested at pharmacologically relevant doses. GHB intake occurred in 2-3 discrete episodes during the nocturnal phase. The development of an animal model of GHB self-administration may constitute a useful tool in the investigation of the neurobiological substrates of GHB-reinforcing properties.

In the present study, the development of tolerance to the motor impairing effects of gamma-hydroxybutyric acid (GHBA) and ethanol was compared (Experiment 1). Rats were required to perform a motor coordination task daily shortly after ethanol (3.5 g/kg) and GHBA (1.0 g/kg) administration for 9 consecutive days. Tolerance to the motor impairing effects of ethanol and GHBA developed to a similar extent but with different patterns. On the tenth day, the presence of cross-tolerance to the motor impairing effects of GHBA and ethanol was assessed (Experiment 2). Administration of 1.0 g/kg GHBA produced a significantly lower impairment in ethanol-tolerant rats than in ethanol-naive rats. Similarly, administration of 3.5 g/kg ethanol induced a significantly lower impairment in GHBA-tolerant rats than in GHBA-naive rats. The presence of cross-tolerance between GHBA and ethanol is discussed in terms of common pathways of neuroadaptation to chronic GHBA and ethanol.

The effect of the dihydropyridine Ca2+ channel antagonist, isradipine, on ethanol discrimination was assessed in rats trained to discriminate 1.5 g/kg ethanol from water in a T-maze, food-reinforced drug discrimination procedure. Pretreatment with isradipine (0, 1.0, 3.0 and 5.0 mg/kg i.p.) resulted in a dose-dependent blockade of ethanol discrimination. The results of the present study suggest that L-type Ca2+ channels are involved in the mediation of ethanol discriminative stimulus effects.

Chronic treatment with neuroleptics has been reported to induce a status of depolarization inactivation of the majority of midbrain dopamine neurons. The present study was aimed at determining whether general anesthesia might be a contributory cause of depolarization inactivation of substantia nigra dopamine neurons. In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 days) produced a marked reduction (about 80%) in the number of spontaneously active dopamine neurons. However, when neuronal sampling was performed in unanesthetized rats, chronic administration of haloperidol (daily for 21-28 days) failed to reduce the incidence of active dopaminergic neurons. The results suggest that depolarization inactivation of dopamine neurons is not present in the intact animal but is probably produced during the neuronal sampling procedure as a consequence of neuroleptic-induced hyperexcitability of dopamine neurons combined with their stimulation by general anesthetics.

Recent evidence indicates that the neuroleptic-induced increase of in vivo acetylcholine output in the striatum does not depend on the relief of cholinergic neurons from the inhibitory control by dopamine, but on increased dopamine output onto dopamine D1 receptors. The present microdialysis study was aimed at finding if the neuroleptic-induced increase in striatal acetylcholine release persists after chronic treatment, and how it is correlated with dopamine output. Rats were chronically treated with the dopamine D2 receptor antagonists, haloperidol and (-)-sulpiride (0.5 mg/kg and 50 mg/kg i.p., respectively, daily, for 30 days). The stimulant effect of both neuroleptics on striatal dopamine release persisted unaltered throughout the chronic treatment (by about 100% over basal values). In contrast, the enhancing effects of haloperidol and (-)-sulpiride on striatal acetylcholine release remained unchanged up to day 12 of treatment. Thereafter, tolerance developed, so that both neuroleptics became totally ineffective on day 30 of treatment. Both on day 1 and 30, the neuroleptic-induced dopamine release was reversed by gamma-butyrolactone (gamma-hydroxybutyric acid lactone), suggesting that this effect is mediated by enhanced neuronal activity. On day 1 and day 10, the neuroleptic-induced acetylcholine release was antagonized by the blockade of dopamine D1 receptors with SCH 39166 (trans-(-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b- hexahydro-7-methyl-5H-benzo[d]napht[2,1-b]azepine-12-ol, hydrochloride) (0.5 mg/kg i.p.). SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride) (5 mg/kg i.p.) increased acetylcholine release by about 50% in control rats and in rats treated with (-)-sulpiride or haloperidol for up to 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the effect of two selective dopamine D1 receptor agonists, SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl) and A68930 ((1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman.HCl), and that of imipramine in the behavioural despair model of depression. The dopamine D1 receptor agonists and imipramine showed an anti-immobility effect. Moreover we found that the 'antidepressant' effect of imipramine in the behavioural despair test was antagonized by SCH 23390, a selective dopamine D1 receptor blocker. The results further support the hypothesis that dopamine D1 receptor stimulation plays an important role in the mechanism of action of antidepressants and suggest that dopamine D1 receptor agonists might be considered as potential antidepressant drugs.

Abecarnil (0.1-1 mg/kg i.p.), a new anxioselective and anticonvulsant ligand of benzodiazepine receptors, like diazepam (2.5-10 mg/kg i.p.) inhibited in a dose-dependent manner the basal release of acetylcholine in the hippocampus of freely moving rats. In contrast, whereas diazepam inhibited the basal output of dopamine in the prefrontal cortex, abecarnil had no such effect. The effects of both abecarnil and diazepam were antagonized by prior treatment with flumazenil at a dose (1 mg/kg i.p.) that per se had no effect on acetylcholine or dopamine release. The results suggest that abecarnil has different intrinsic efficacies at gamma-aminobutyric acid type A (GABAA) receptors involved in the regulation of acetylcholine release in the hippocampus and dopamine release in the prefrontal cortex, two brain areas important in cognitive function and emotional state, respectively.

The present study examined the effect of naloxone on ethanol- and gamma-hydroxybutyric acid-induced narcosis in mice and the changes induced by these drugs on striatal dopamine metabolism. The results show that naloxone (1-10 mg/kg s.c.) markedly reduced ethanol-induced narcosis but failed to modify the duration of sleep induced by gamma-hydroxybutyrate. Naloxone (10 mg/kg) modified neither ethanol- nor gamma-hydroxybutyrate-induced changes in striatal dopamine and dihydroxyphenylacetic acid (DOPAC) content. The results suggest that gamma-hydroxybutyrate- and ethanol-induced narcosis are mediated by different mechanisms and that opioid receptors are not involved in the changes in dopamine metabolism induced by these compounds.

The effect of acute administration of ethanol on the release of 5-hydroxytryptamine (5-HT) in the frontal cortex of "Sardinian alcohol preferring" rats, "Sardinian non-preferring" rats and control rats was investigated using in vivo microdialysis. At the dosage of 2.5 g/kg i.p. ethanol increased the level of 5-HT in the dialysate by approximately 80 +/- 20% of basal values in the Sardinian alcohol preferring rats whereas no effect was observed in Sardinian non-preferring and control rats.

Chronic treatment with imipramine enhanced the locomotor stimulant response to quinpirole (0.3 mg/kg s.c.), a dopamine D2/D3 receptor agonist. Chronic, but not acute, blockade of the NMDA receptor with the non-competitive antagonist MK-801 (0.3 mg/kg i.p.) prevented the imipramine-induced potentiation of the quinpirole effect. The results suggest that NMDA receptors play a role in the development of supersensitivity to dopamine receptor agonists produced by chronic antidepressant treatment.

Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movements (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administration of the specific dopamine D1, receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were totally suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, alpha-methyl-tyrosine (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D1 agonist, SKF 38393. The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon D1 receptors.

The stimulatory effect of cocaine on locomotor activity and on dopamine efflux from the ventral striatum was studied in rats chronically treated with the antidepressant imipramine. Chronic imipramine (20 mg/kg per day for 3 weeks) potentiated by about 2-fold cocaine-stimulated motor activity and extracellular dopamine concentrations. The results indicate that chronic imipramine facilitates mesolimbic dopamine neurotransmission by potentiating the mechanism which is thought to mediate the rewarding effects of cocaine.

The effect of different calcium antagonists on cocaine-induced dopamine (DA) release in the striatum, as measured by brain microdialysis in freely moving rats, and on cocaine-induced motor stimulation was studied. While two dihydropyridine calcium antagonists, nimodipine (20 mg/kg) and isradipine (2.5 mg/kg), prevented cocaine-induced DA release and motor stimulation, the diphenylalkylamine-type calcium antagonist flunarizine (20 mg/kg) strongly potentiated both effects of cocaine. Moreover, two calcium antagonists, verapamil (20 mg/kg) and diltiazem (20 mg/kg), were ineffective. The results indicate that various classes of calcium antagonists differ in their interaction with the effects of cocaine in the CNS and suggest that dihydropyridine calcium channel antagonists might be clinically useful for the treatment of cocaine abuse.

Pretreatment with flunarizine (20 mg/kg), a diphenylalkylamine calcium channel antagonist, markedly potentiated cocaine (10 mg/kg)-induced dopamine (DA) output from the ventral striatum, as measured by microdialysis in freely moving rats. Moreover, flunarizine enhanced cocaine-induced motor stimulation. Pretreatment with the D2 receptor antagonist (-)-sulpiride (25 mg/kg) potentiated cocaine-induced DA output but, unlike flunarizine, inhibited cocaine-induced motor stimulation. When added to striatal membrane preparations, flunarizine displaced [3H]spiperone binding with a Ki of about 100 nM. Since recent evidence indicates that the effects of cocaine are calcium-dependent and are prevented by dihydropyridine calcium antagonists, these findings suggest that the paradoxical potentiating effect of flunarizine is probably due to an interaction with the DA system and is not due to its calcium antagonist property.

The effect of the dopamine (DA) agonist, apomorphine, on oxytocin concentrations in the hypothalamus, hippocampus, septum and plasma was studied in male rats. Apomorphine dose dependently increased the concentration of oxytocin in the plasma and hippocampus, the minimal effective dose being 80 micrograms/kg s.c., which induced a 65% increase in plasma and a 45% increase in the hippocampus. The maximal effect (210 and 125% above controls) was induced with 240 micrograms/kg s.c. In contrast, there was a significant decrease (32%) in the oxytocin concentration in the hypothalamus, but only after the highest doses of apomorphine, while no change was found in the septum. The apomorphine effect in the hippocampus and hypothalamus was prevented by the mixed DA D-1/D-2 receptor blocker, haloperidol (0.3 mg/kg i.p.), and by the DA D-2 receptor blocker, (-)-sulpiride (20 mg/kg i.p.), but not by the DA D-1 receptor blocker, SCH 23390 (0.2 mg/kg s.c.). Similar effects were found in plasma, although SCH 23390 inhibited the apomorphine effect by 45%. Our results suggest that apomorphine stimulates oxytocinergic transmission in male rats and provide biochemical support for the hypothesis that a DA-oxytocin link exists in the central nervous system.

We considered the drug-induced circling behaviour of rats monolaterally lesioned with kainic acid (KA) as a marker of the dopamine (DA) concentration in the synaptic space. D-Amphetamine produced a dose-related increase in the DA concentration of the dialysate from an intact striatum and a proportional number of ipsilateral circlings. Pargyline or L-dihydroxyphenylalanine (L-Dopa), alone or in combination with benserazide, increased the concentration of DA to a similar or even higher level than d-amphetamine, but failed to elicit a circling response. Apomorphine given after these drugs at the peak of DA accumulation always induced circling behaviour. The results suggest that released DA may undergo different inactivation processes before reaching the dialysis probe, and that these processes may be differentially affected by drug treatments. Alternatively, it may be suggested that DA can be released into the synaptic space, in a functional manner, or into the interstitial fluid, from where it cannot reach the synaptic receptors.