The activation of gamma aminobutyric acid(A) receptors in the paraventricular nucleus of the hypothalamus reduces non-contact penile erections in male rats.

Male rats show 4-6 penile erection episodes when put in the presence of an inaccessible receptive female. These non-contact penile erections were reduced dose-dependently by muscimol, a gamma aminobutyric acid (GABA)(A) receptor agonist, when given into the paraventricular nucleus of the hypothalamus (0.1, 0.5, 1 and 2 microg). In contrast, baclofen, a GABA(B) receptor agonist (2 microg) was ineffective. Muscimol reduction of non-contact penile erections was not seen when male rats were pretreated with bicuculline methiodide (2 microg) given 5 min before muscimol into the paraventricular nucleus. Since muscimol injected into the paraventricular nucleus also prevents penile erection induced by drugs (e.g. apomorphine, oxytocin or N-methyl-D-aspartic acid), the present results show that an increased GABAergic activity in the paraventricular nucleus can impair the expression of penile erection induced not only by drugs but also by sexual physiological stimuli.

Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice.

Morphine (10 and 20 mg/kg, s.c.) does not modify dopamine release in the nucleus accumbens of cannabinoid CB(1) knock-out mice under conditions where it dose-dependently stimulates the release of dopamine in the corresponding wild-type mice. These results demonstrate that cannabinoid CB(1) receptors, regulate mesolimbic dopaminergic transmission in brain areas known to be involved in the reinforcing effects of morphine.

CB1 cannabinoid receptor agonist WIN 55,212-2 decreases intravenous cocaine self-administration in rats.

The effect of the CB1 cannabinoid receptor agonist WIN 55,212-2 on intravenous cocaine self-administration (IVSA) in rats was evaluated. Male Long Evans rats were implanted with silastic catheters through the external jugular vein. The IVSA was conducted in 3-h daily sessions with a fixed ratio (FR1) schedule: the experimental apparatus had a nose-poking response-like operandum. Intravenous pre-treatment with WIN 55,212-2 (0.25, 0.5 and 1 mg/kg) to rats self-administering cocaine (0.25 or 0.5 mg/kg/inj) at stable baseline, reduces cocaine intake in a dose-dependent manner. The CB1 receptor antagonist SR 141716A (3 mg/kg i.p.) completely reversed the WIN 55,212-2-induced decrease of cocaine intake. However, pre-treatment of SR 141716A alone (up to dose of 9 mg/kg i.p.) was unable to modify cocaine IVSA. These results indicate that stimulation of CB1 cannabinoid receptors activates rewarding mechanisms which produce reinforcing effects additional to those induced by cocaine.

Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A.

The effect of delta9-tetrahydrocannabinol, the psychoactive principle of marijuana, and [R-(+)-(2,3-dihydro-5-methyl-3-[[4-morpholinylmethyl]pyrol[1,2,3-d e-]-1,4-benzoxazin-6y)(1-naphthalenyl)methanone monomethanesulfonate] (WIN 55,212-2), a synthetic cannabinoid receptor agonist, on the acetylcholine output in the medial-prefrontal cortex and hippocampus was studied by microdialysis in freely moving rats. The administration of delta9-tetrahydrocannabinol (1 and 5 mg/kg i.p.) and WIN 55,212-2 (5 and 10 mg/kg i.p.) produced a long lasting inhibition of acetylcholine release in both areas. The inhibitory effect of delta9-tetrahydrocannabinol and WIN 55,212-2 was suppressed in both areas by the specific cannabinoid CB1 receptor antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3carboxamide]HCl (SR 141716A), at the dose of 0.1 mg/kg i.p., per se ineffective to modify basal acetylcholine release. Most interestingly, SR 141716A alone at higher doses increased acetylcholine release both in the medial-prefrontal cortex (3 mg/kg i.p.) and hippocampus (1 and 3 mg/kg i.p.), suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. Since the inhibitory effect of delta9-tetrahydrocannabinol is produced by doses within those relevant to human use of marijuana, our results suggest that the negative effects of the latter on cognitive processes may be explained by its ability to reduce acetylcholine release in the medial-prefrontal cortex and hippocampus. Conversely, cannabinoid receptor antagonists may offer potential treatments for cognitive deficits.

Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A.

Two synthetic cannabinoids, WIN 55,212-2 {R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinylmethyl]pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate} (5.0 and 10 mg/kg i.p.) and CP 55,940 {[1a,2-(R)-5-(1.1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} {[1a,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} (0.5 and 1.0 mg/kg i.p.), inhibited acetylcholine release in the rat hippocampus. The inhibition was prevented by the cannabinoid receptor antagonist, SR 141716A {N-(piperidin-1-yl)-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide} HCl, at the dose of 0.1 mg/kg i.p. Higher doses of SR 141716A (1.0 and 3.0 mg/kg i.p.) themselves increased hippocampal acetylcholine release, suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. The results also suggest that the negative effects of marijuana on learning and memory may depend on cannabinoid receptor-mediated inhibition of acetylcholine release.

Opposite effects of stress on dopamine release in the limbic system of drug-naive and chronically amphetamine-treated rats.

The effects of repeated amphetamine administration on stress-induced dopamine release in the ventral striatum were examined in male Wistar rats treated with D-amphetamine (1.5 mg/kg; i.p./injection) or saline at 12 h intervals for 14 days. After 12 h as well as 7 days of amphetamine withdrawal, dopamine release was monitored by transverse microdialysis under basal conditions and during exposure to 60 min of restraint stress. Basal dopamine release was significantly suppressed relative to saline-pretreated controls after both 12 h and 7 days of amphetamine withdrawal. In control rats, restraint stress resulted in significantly increased dopamine efflux. In contrast, exposure to this stressor was associated with a significant suppression of dopamine release in rats chronically exposed to amphetamine. This effect was observed at both post-amphetamine test points. The results suggest that chronic amphetamine impairs the dopaminergic response to stress and that this dopaminergic deficit may play a role in stress-induced drug-seeking behavior and relapse.

Reduction of dopamine release and synthesis by repeated amphetamine treatment: role in behavioral sensitization.

Changes in extracellular dopamine concentration in the ventral striatum during repeated amphetamine administration and over the first 7 days of withdrawal were studied by transversal microdialysis in freely moving rats. 2 days after fiber implantation rats were treated with either amphetamine (1.5 mg/kg i.p.) or saline every 12 h for 14 days. In amphetamine-treated rats, the baseline extracellular dopamine concentration, preceding the morning treatment, increased from 0.43 +/- 0.01 on day 1 up to 0.59 +/- 0.02 pmol/40 microliters sample on day 3 of treatment. Thereafter, dopamine fell rapidly on day 5(0.16 +/- 0.01 pmol/40 microliters) and remained at approximately the level reached on day 7(0.11 +/- 0.01 pmol/40 microliters) throughout the treatment and also over the 7 days of withdrawal. In contrast, in control rats, the extracellular dopamine concentration (0.40 +/- 0.01 pmol/40 microliters, on day 1) decreased progressively during the first days of treatment to reach a fairly stable value on day 4 (0.25 +/- 0.01 pmol/40 microliters sample). Thereafter, dopamine remained stable at this level throughout the remaining period of experimentation. Challenge with amphetamine (1.5 mg/kg i.p.) of animals treated with amphetamine for 10 days or withdrawn for 7 days produced a potentiated motor response compared to that in control rats but much less marked dopamine releasing effects. Dopamine synthesis in the ventral striatum, measured as L-dihydroxyphenylalanine formation after blockade of dihydroxyphenylalanine decarboxylase, was found to be reduced by approximately 60% after 2 weeks of amphetamine treatment and in animals withdrawn for 1 day or 7 days. These results indicate that repeated amphetamine treatment causes persistent inhibition of dopamine synthesis and release in the ventral striatum. Such inhibition may be a compensatory response to the repeated stimulation of postsynaptic dopamine receptors by the endogenously released dopamine and also the cause of postsynaptic sensitization to dopamine action.

Chronic morphine increases hippocampal acetylcholine release: possible relevance in drug dependence.

Previous studies have shown that cocaine and amphetamine stimulate acetylcholine release in the hippocampus via an action of endogenously released dopamine on dopamine D1 and D2 receptors. The present study was aimed at clarifying if the property of stimulating hippocampal acetylcholine release was shared by morphine. The acute administration of morphine (10 mg/kg i.p.) failed to modify acetylcholine release in the hippocampus. However, after repeated administration (10 mg/kg i.p. twice daily) morphine acquired the ability to stimulate hippocampal acetylcholine release. Thus, at days 5 and 7 of chronic morphine treatment, a challenge dose of morphine (10 mg/kg i.p.) increased acetylcholine release by 50 and 100%, respectively. Concomitantly with the development of the stimulant property on acetylcholine release, morphine also acquired that of producing behavioural stimulation and lost that of producing sedation and catalepsy. The morphine-induced increase in acetylcholine output was suppressed by the blockade of dopamine D1 receptors with SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine) (0.1 mg/kg s.c.), which also suppressed the morphine-induced motor stimulation. Moreover, repeated morphine administration markedly potentiated the stimulant effect of the dopamine D1/D2 receptor agonist apomorphine (R(-)-10, 11-dihydroxyaporphine) (0.1 or 0.5 mg/kg s.c.) both on hippocampal acetylcholine release and on behaviour. These results may suggest that the enhancement of hippocampal acetylcholine release as well as the development of behavioural sensitisation after chronic morphine could be related to the development of dopamine receptor supersensitivity. Moreover, increased acetylcholine transmission in the hippocampus may play a role in the 'memory' of the rewarding effects of drugs of abuse.

Strain-dependent effects of dopamine agonists on acetylcholine release in the hippocampus: an in vivo study in mice.

The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist cocaine on hippocampal acetylcholine release in mice of the C57BL/6 and DBA/2 inbred strains were investigated using intracerebral microdialysis. The D1 SKF 38393 (10, 20, 30 mg/kg, i.p.), the D2 agonist LY 171555 (0.5, 1, 2 mg/kg, i.p.) and cocaine (5, 10, 15 mg/kg, i.p.) all increased, dose-dependently, acetylcholine release in the hippocampus of C57BL/6 mice. Both the D1 agonist and cocaine did not produce any significant effect in DBA/2 mice. In the latter strain, however, LY 171555 produced a decrease in acetylcholine release that was evident after 60 min from injection of the doses of 0.5 and 1 mg/kg, but not at the dose of 2 mg/kg. The effects observed in C57BL/6 mice as well as those produced by low doses of LY 171555 in the DBA/2 strain were consistent with previous results obtained in rats. The present results indicate major strain-dependent differences in the effects of dopamine agonists on hippocampal acetylcholine release in mice. Moreover, they suggest a complex genotype-related neural organization of dopamine-acetylcholine interactions in the mesolimbic system. Finally, the strain differences in the effects of the dopamine agonists on hippocampal acetylcholine release parallel previously reported strain differences in the effects of these substances on memory consolidation.

Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep-wake cycle in freely moving cats.

The variations of Acetylcholine (ACh) release in the cerebral cortex and dorsal hippocampus were monitored by microdialysis during the electroencephalographically recorded sleep-waking cycle in freely moving cats. The results show a state-dependent variation in ACh output in both the cortex and the hippocampus. ACh release increased by approximately 100% during quiet waking (QW) and by 175% during active waking (AW) as referred to slow wave sleep (SWS) baseline. In contrast, a clear difference between the two areas was observed during REM sleep. During this stage ACh release in the cortex reached approximately the same values observed during QW, while in the hippocampus ACh release rose to about 4-fold the level obtained during SWS or twice that of QW. The results support the idea that the increase in ACh release in the cortex reflects the desynchronized EEG of wakefulness and REM sleep, while the marked increase of ACh during REM in the hippocampus may be related to the sustained theta activity in this area.

Neuroleptics cause stimulation of dopamine D1 receptors and their desensitization after chronic treatment.

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)

Co-dergocrine (Hydergine) regulates striatal and hippocampal acetylcholine release through D2 receptors.

The effect of Co-dergocrine (Hydergine) on acetylcholine (ACh) release in the striatum and hippocampus has been studied by means of brain microdialysis and compared to the effect of SKF 38393 and of LY 171555 selective D1 and D2 dopamine (DA) receptor agonists, respectively. Co-dergocrine (1 and 5 mg kg-1 i.p.) as well as LY 171555 (0.2 and 0.5 mg kg-1 i.p.) decreased the extracellular concentration of ACh in the striatum, whereas SKF 38393 (5 and 10 mg kg-1 i.p.) increased it. On the other hand, Co-dergocrine (1 and 5 mg kg-1), LY 171555 (0.2 and 0.5 mg kg-1) and SKF 38393 (5 and 10 mg kg-1) increased ACh release in the hippocampus in a dose-dependent way. These results show that Co-dergocrine, which is widely used in the treatment of senile mental decline, enhances the release of ACh in the hippocampus in a similar manner to both D1 and D2 DA agonists. This effect might be relevant for the amelioration of cognitive processes. Moreover, our results which demonstrate that Co-dergocrine is able to decrease the release of ACh in the striatum, as are selective D2 agonists, suggest that Co-dergocrine may have a potential therapeutic benefit in Parkinsonian dementia.

Evidence that neuroleptics increase striatal acetylcholine release through stimulation of dopamine D1 receptors.

The relative role of D1 and D2 dopamine receptors in the neuroleptic-induced increase of striatal acetylcholine (ACh) release was investigated using brain microdialysis in freely moving rats. Administration of (-)-sulpiride, haloperidol and clozapine, produced a dose-related increase in ACh release in the striatum. Maximal increase by 52, 45 and 73% over basal values was produced by the dose of 20, 0.25 and 10 mg/kg i.p. of (-)-sulpiride, haloperidol and clozapine, respectively. Administration of the D1 receptor antagonist SCH 23390 (0.1 mg/kg s.c.) decreased ACh output by 30%, completely suppressed the stimulant effect of (-)-sulpiride and haloperidol and only modestly reduced that of clozapine. The inhibitory effect of SCH 23390 vs. (-)-sulpiride or haloperidol-induced ACh output was shared by SCH 39166 (1 mg/kg i.p.), another specific D1 receptor antagonist. On the other hand, SCH 23390 (0.1 mg/kg s.c.) was ineffective in reducing atropine-induced increase in ACh release. A combined treatment with reserpine (5 mg/kg i.p.) and alpha-methyltyrosine (150 mg/kg i.p.), 6 h beforehand, prevented the enhancement of ACh release induced by both (-)-sulpiride and haloperidol, whereas only reduced that by clozapine. The results indicate that neuroleptics increase striatal ACh release by enhancing endogenous extracellular dopamine acting on D1 receptors, and suggest that these receptors play a major physiological role in controlling ACh release in the striatum.