beta-Phenylethylamine modulates acetylcholine release in the rat striatum: involvement of a dopamine D(2) receptor mechanism

We examined the effects of beta-phenylethylamine on striatal acetylcholine release in freely moving rats using in vivo microdialysis. beta-Phenylethylamine at 12.5 mg/kg, i.p. did not affect acetylcholine release in the striatum, whereas 25 and 50 mg/kg, i.p. immediately induced an increase in acetylcholine release in the striatum at 15-45 min. This increase following intraperitoneal administration of beta-phenylethylamine (25 mg/kg) was not affected by locally applied SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 10 microM), a dopamine D(1) receptor antagonist, nor by raclopride (10 microM), a dopamine D(2) receptor antagonist. The increased release of acetylcholine induced by beta-phenylethylamine was suppressed by local infusion of tetrodotoxin (1 microM). In contrast, the extracellular acetylcholine level in the striatum was significantly decreased by local application of beta-phenylethylamine (10 and 100 microM) in the striatum via a microdialysis probe. The decrease was completely blocked by local co-application of raclopride (10 microM). The beta-phenylethylamine-induced decrease in striatal acetylcholine release was not affected by co-perfusion with SCH-23390 (10 microM). These results indicate that systemic administration of beta-phenylethylamine increases acetylcholine release, whereas locally applied beta-phenylethylamine decreases striatal acetylcholine release in freely moving rats. Furthermore, the dopaminergic system, through the dopamine D(2) receptor, is involved in the locally applied beta-phenylethylamine-induced decrease in acetylcholine in the striatum.     

Effects of morphine on release of acetylcholine in the rat striatum: an in vivo microdialysis study

Summary We examined the effect of morphine on the release of acetylcholine (ACh) in the striatum of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 3.01 ± 0.51 pmol/30 l/15 min in the presence of neostigmine (10 M). Tetrodotoxin (1 M), a selective blocker of voltage-dependent Na⁺ channels, rapidly decreased the release of ACh in the striatal perfusates. Morphine at a dose of 10 mg/kg (i.p.) caused a reduction of ACh release in the striatum at 90–150 min. However, a lower dose of morphine (5 mg/kg, i.p.) did not affect ACh release in the striatum. The reduction following intraperitoneal administration of morphine was abolished by naloxone (1.0 mg/kg).After microinjection of the neurotoxin 6-hydroxydopamine (6 g/3 l, 7 days before) in the substantia nigra, the morphine (10 mg/kg)-induced decrease of ACh was attenuated, and a similar result occurred following reserpine (2 mg/kg, i.p.) 24 h before combined with -methyl-p-tyrosine (300 mg/kg, i. p.) 2.5 h before.These findings indicate that morphine exerts an inhibitory influence on striatal ACh release in freely moving rats and that this inhibitory effect is mediated by the nigro-striatal dopaminergic system.Correspondence to K. Taguchi at the above address     

Effect of [1,3-di-n-butyl-7-(2-oxopropyl)-xanthine] (denbufylline), a low Km phosphodiesterase inhibitor, on striatal acetylcholine release in the rat: analysis using cerebral microdialysis

Effect of oral and intraperitoneal administrations of [1,3-di-n-butyl-7-(2-oxopropyl)-xanthine] (denbufylline) on acetylcholine (ACh) content and release in the rat striatum was investigated. Denbufylline (3, 10 and 30 mg/kg, p.o.) decreased striatal ACh contents in a dose-dependent manner. Denbufylline administration (30 mg/kg, i.p.) produced no significant change in the spontaneous release of ACh, while it increased a high potassium-evoked ACh release in the striatum. These results suggest that denbufylline may be a drug inducing the increased release of ACh in the brain.     

Cocaine releases limbic acetylcholine through endogenous dopamine action on D1 receptors.

Cocaine (10 and 20 mg/kg i.p.) enhanced the extracellular concentration of acetylcholine (ACh) in the ventral striatum of freely moving rats. The enhancement was prevented both by dopamine (DA) D1 receptor blockade with SCH 23390 (0.1 mg/kg s.c.) and by depletion of endogenous DA after coadministration of reserpine (5 mg/kg i.p.) and alpha-methyltyrosine (alpha-MT) (150 mg/kg i.p.). In contrast, blockade of DA D2 receptors with (-)-sulpiride (20 mg/kg i.p.) did not prevent the cocaine-induced increase in ACh release. These results indicate that the cocaine-induced stimulation of ACh release is mediated by an action of DA on D1 receptors, and suggest that the enhancement of ACh release might play a functional role in the central effects of cocaine. Moreover, DA depletion after reserpine + alpha-MT or D1 receptor blockade with SCH 23390 led to a comparable decrease of baseline ACh release, suggesting that striatal cholinergic interneurons are under D1 receptor-mediated facilitatory dopaminergic control.     

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum

The administration of high doses of methamphetamine causes the degeneration of striatal dopaminergic fibers in the brains of rodents, and oxidative stress appears to be one of the main factors of neurotoxicity. This study examined whether edaravone, a radical scavenger, protects against methamphetamine-induced neurotoxicity in mice. Methamphetamine treatment (4 mg/kg, s.c. x 4 with 2 h intervals) showed striatal dopaminergic degeneration as observed by decreases in dopamine levels and tyrosine hydroxylase immunoreactivity in the striatum. The neurotoxicity was reduced by edaravone (3 mg/kg, i.p.), when it was administered four times 30 min before methamphetamine at 2 h intervals and additionally four times after methamphetamine at 12 h intervals. An immunohistochemical study showed that methamphetamine increased 3-nitrotyrosine immunoreactivity, an in vivo marker of peroxynitrite production, and activated microglia and astrocytes in the striatum. Edaravone blocked the increase in 3-nitrotyrosine immunoreactivity and the activation of astrocytes, but it did not affect the activation of microglia. Edaravone did not affect methamphetamine-induced hyperthermia and striatal dopamine release. These results suggest that edaravone protects against methamphetamine-induced neurotoxicity in the striatum by blocking peroxynitrite production. This study also suggests that methamphetamine activates microglia in a radical-independent mechanism.     

Reversal of methamphetamine-induced behavioral sensitization by repeated administration of a dopamine D1 receptor agonist

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D₁ receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0 mg/kg, i.p.) to rats once every 3 days for a total of 5 times (days 1–13) induced the enhancement of locomotor activity after MAP challenge (0.5 mg/kg, i.p.) on day 20, verifying the development of behavioral sensitization. The MAP-sensitized rats then received a dopamine D₁ agonist, R-(+)-SKF38393 (3.0 mg/kg, i.p.), once a day for 7 consecutive days (days 21–27). Behavioral analysis on days 30 and 41 revealed that the enhanced locomotor activity was reversed by repeated R-(+)-SKF38393 administration. Moreover, repeated R-(+)-SKF38393 administration reversed the increased dopamine release in the striatum after MAP challenge on day 41. Thus, repeated administration of the dopamine D₁ receptor agonist induces the reversal of established behavioral sensitization to MAP and of increased dopamine release in the striatum, lasting for at least 2 weeks. Dopamine D₁ receptor agonists may be useful therapeutic agents for the treatment of psychostimulant addiction.     

Intravenous administration of ecstasy (3,4-methylendioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo

The effect of intravenous administration of 3,4-methylendioxymethamphetamine (MDMA), in a range of doses (0.32-3.2 mg/kg) that have been shown to maintain self-administration behaviour in rats, on in vivo acetylcholine release from rat prefrontal cortex and dorsal striatum was studied by means of microdialysis with vertical concentric probes. Intravenous administration of MDMA dose-dependently increased basal acetylcholine release from the prefrontal cortex to 57+/-21%, 98+/-20%, 102+/-7% and 141+/-14% above baseline, at doses of 0.32, 0.64, 1.0 and 3.2 mg/kg, respectively. MDMA also stimulated striatal acetylcholine release at the dose of 3.2 mg/kg i.v. (the maximal increase being 32+/-3% above baseline) while at the dose of 1 mg/kg i.v., MDMA failed to affect basal acetylcholine output. Administration of MDMA also dose-dependently stimulated behaviour. The results of the present study show that MDMA affects measures of central cholinergic neurotransmission in vivo and suggest that at least some of the psychomotor stimulant actions of MDMA might be positively coupled with an increase in prefrontal cortical and striatal acetylcholine release.     

Effect of pentylenetetrazol on carbaryl-induced changes in striatal catecholamines

Administration of pentylenetetrazol (PTZ) (60 mg/kg, s.c.) to normal or carbaryl (200 mg/kg, p.o.) treated adult male albino rats produced characteristic changes in the steady-state levels of striatal dopamine (DA), noradrenaline (NA) and homovanillic acid (HVA) at different time intervals (0.5, 1.0 and 2.0 hr). The elevation of striatal NA level was found to be more pronounced with PTZ than that produced by carbaryl. Treatment of rats with PTZ alone caused a significant elevation of DA levels only at 2.0 hr without any significant change in the level of HVA at any time interval. Carbaryl which did not have any significant effect on striatal DA level produced an elevation of HVA at 0.5 hr and 1.0 hr in striatum. The simultaneous administration of PTZ and carbaryl, under similar conditions, caused a marked reduction in the level of NA at 0.5 hr and DA at 1.0 hr without any significant effect on (i) both the amine levels at 2.0 hr and (ii) HVA level at any of the time intervals. Measurement of (a) alpha-methyl-p-tyrosine (alpha-MpT) (250 mg/kg, i.p.) induced depletion of striatal DA and NA, (b) FLA-63 (25 mg/kg, i.p.) induced disappearance of NA, (c) pargyline (75 mg/kg, i.p.) induced reduction and probenecid (200 mg/kg, i.p.) induced accumulation of striatal HVA in the presence or absence of PTZ and/or carbaryl revealed that: (1) PTZ or carbaryl alone caused a significant increase in the turnover of striatal DA; (2) the turnover of striatal NA was significantly increased after PTZ treatment but not after carbaryl administration; (3) the simultaneous administration of carbaryl and PTZ, on the other hand, attenuated (a) PTZ- or carbaryl-induced increase in metabolic activity of the striatal dopaminergic system, and (b) the enhanced anabolic activity of striatal noradrenergic system caused by PTZ, but failed to affect the enhanced utilization of striatal NA induced by PTZ alone.     

Dopaminergic regulation of striatal cholinergic interneurons: an in vivo microdialysis study

Summary In vivo microdialysis was used to study the putative inhibitory effects of dopamine on cholinergic interneurons in the striatum of conscious rats. The dopamine receptor agonists apomorphine (0.3 and 3 mg/kg, s.c.) and (±)N-0437 (1.4 mg/kg, s.c.) decreased interstitial concentrations of acetylcholine while increasing those of choline. In contrast, the dopamine receptor antagonists haloperidol (0.1 and 1 mg/kg, i.p.) and (±)sulpiride (20 mg/kg, i.p.) enhanced striatal acetylcholine output but had little effect on choline. Previously, a lack of effect of these drugs on striatal acetylcholine was reported. The main methodological difference between these studies was that the calcium concentration of the microdialysis perfusion solution was 3.4 mM in the former study versus 1.2 mM in the present experiments. The results of this study reemphasize the importance of the calcium concentration in determining the effects of drugs on central neurotransmitter release, and confirm a role of dopamine in the regulation of striatal cholinergic interneurons.Send offprint requests to G. Damsma at the present address     

Inhibitory effects of the psychoactive drug modafinil on γ-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig

Summary The effects of modafmil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3–30 mg/kg s. c. modafmil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i. p.) but not prazosin (0.14 mg/kg, i. p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT₂ receptors, since the action of modafmil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT₂ antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafmil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafmil at least in the striatum. The reduction of cortical GABA outflow via 5-HTZ receptors by modafmil is probably related to some of its actions on the central nervous system including behavioural effects. Send offprint requests to K. Fuxe at the above address     

Fluphenazine-induced decline in striatal acetylcholine content is not abolished by exogenous choline

Experiments were conducted in rats, to examine the extent to which the significant decline in striatal acetylcholine content induced by fluphenazine (0.5 mg/kg, s.c.) can be reversed by systemic administration of exogenous choline. Choline chloride (200 mg/kg, i.p.) was administered either at the same time as fluphenazine (or saline, in the case of controls); 40 min later; 30min prior to administration of fluphenazine or saline; and on three consecutive 20-min intervals in the same animal, at 0, 20, and 40min following fluphenazine or saline treatment. Striatal choline and acetylcholine levels were subsequently analyzed by gas chromatography. In all cases choline administration failed either to elevate significantly striatal acetylcholine levels in the control animals, or to block the fluphenazine-induced fall in acetylcholine levels. These data suggest that, under the basal or drug-treated conditions investigated in these studies, the availability of choline from the periphery may not be rate-limiting for striatal acetylcholine synthesis.     

Behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor

The antimicrobial agent oxolinic acid, injected i.p. in mice, induced a dose dependent increase in locomotor activity. This stimulation culminated at the 32 mg/kg dose and became smaller for higher doses (64–128 mg/kg). When opposed to increasing doses (50–100–200 μg/kg i.p.) of haloperidol (D2 dopamine receptor antagonist), the stimulant locomotor effect of 32 mg/kg oxolinic acid was not significantly reversed. On the contrary increasing doses (7.5–15–30 μg/kg s.c.) of SCH 23390 (D1 dopamine receptor antagonist) inhibited the stimulant locomotor effect. In mice made completely akinetic by a pretreatment with reserpine (4 mg/kg s.c., 18 h before testing), dexamphetamine (2 mg/kg s.c.) reversed this akinesia and even displayed a stimulant activity, similar to that observed in mice not treated by reserpine. On the contrary, oxolinic acid (32 mg/kg) did not reverse the reserpine induced akinesia and even opposed the reversion induced by dexamphetamine. In a synaptosomal fraction prepared from striatum of rats, oxolinic acid inhibited the ³H dopamine uptake with an IC₅₀=4.3±0.6×10⁻⁶ M. Finally, in mice injected i.v. with a tracer dose of ³H WIN 35428 (1 μCi) (a dopamine uptake blocker), 32 mg/kg oxolinic acid, i.p. administered, reduced by about 50% the specific binding of the radioligand to striatal dopamine carriers. It is concluded that the stimulant locomotor effect of oxolinic acid depends on the blockade of the neuronal dopamine uptake complex.     

Effect of cholecystokinin on acetylcholine turnover and dopamine release in the rat striatum and cortex

The effect of sulfated cholecystokinin (CCK-8S) on acetylcholine turnover (TRACh) and dopamine (DA) release in the rat cerebral cortex and striatum was studied in unanaesthetized animals in vivo. CCK-8S (1 mg/kg s.c.) decreased TRACh in the fronto-parietal cortex but not in the striatum. This effect was prevented by peripheral (10 mg/kg i.p.) but not central (1 microgram i.v.t.) administration of the peripheral CCK receptor antagonist CR 1409. In a separate study, CCK-8S decreased 3-methoxytyramine (3-MT) levels (an index of DA release) in the fronto-parietal cortex and in the striatum. CR 1409 appeared to have a partial agonist action, reducing cortical and striatal 3-MT levels, and only partially reversing the effect of CCK-8S in the striatum. These data indicate that peripheral administration of CCK-8S decrease TRACh in the cortex but not in the striatum and that this action is mediated by peripheral-type CCK receptors possibly located outside the CNS. CCK-8S also reduces DA release in the cortex and in the striatum, and this effect appears to be mediated by a mechanism of action different from that modulating cortical TRACh.     

Effect of anticholinergic drugs on striatal acetylcholine release and motor activity in freely moving rats studied by brain microdialysis

We have studied effects of intraperitoneal administration of anticholinergic drugs on striatal acetylcholine release in association with motor activity in freely moving rats using brain microdialysis. A low dose of atropine (2.5 mg/kg) increased striatal acetylcholine release. A high dose of atropine (5 mg/kg) or scopolamine (2.5, 5 and 10 mg/kg) increased both striatal acetylcholine release and motor activity, while its quaternary ammonium compounds, atropine methylbromide (5 and 10 mg/kg) and methscopolamine bromide (5 and 10 mg/kg), increased striatal acetylcholine release without motor excitation. Scopolamine (2.5 mg/kg) produced no significant change in striatal acetylcholine content 4 hr after the injection followed by perfusion. These results suggest that anticholinergic drugs cause an increase in striatal acetylcholine release which does not always result in the increase of motor activity.     

Reversal by [D-Ala2,D-Leu5]enkephalin of the dopamine transporter loss caused by methamphetamine.

A single administration of 40 mg/kg (i.p.) of methamphetamine caused a loss of dopamine transporter in the striatum of albino Swiss (CD-1) mouse for at least 3 weeks. The administration of a single dose of [D-Ala2,D-Leu5]enkephalin (DADLE) (18 mg/kg, i.p.), given at day 14 after the administration of methamphetamine, caused a significant, transient restoration of dopamine transporter level in the striatum. These results suggest that delta-opioid peptide DADLE is able to reverse the neuronal damage caused by methamphetamine.     

Effects of adenosine A1- and A2A-receptor agonists on enhancement of dopamine release from the striatum in methamphetamine-sensitized rats.

We report here both adenosine A1- and A2A-receptor agonists inhibit the expression of methamphetamine (MAP)-induced behavioral sensitization in rats. Animals were treated with MAP (1.0 mg/kg, i.p.) every 3 days with a total of 5 administrations. The augmentation of dopamine release from the striatum was demonstrated by MAP re-administration (0.5 mg/kg, i.p.) after 7-day withdrawal by microdialysis. The augmentation of dopamine release was inhibited by pre-treatment not with N6-cyclohexyladenosine (0.01 mg/kg, i.p.) but by with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxy-amide adenosine (0.1 mg/kg, i.p.). These results suggested that adenosine A1 and A2A receptors play an inhibitory role in sensitization via different mechanisms.     

Effects of the l isomer of fenfluramine on dopamine mechanisms in rat brain: further studies

Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg/kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5-20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the l isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.     

Tolerance to the procholinergic action of the D1 receptor full agonist dihydrexidine

Rationale It has been well established that dopamine D1 receptor agonists increase acetylcholine (ACh) release in the brain, an effect that has been suggested to contribute to their procognitive properties. Objectives We sought to examine whether the ACh-releasing action of the D1 receptor full agonist dihydrexidine HCl (DHX) is altered after repeated administration. Results DHX dose-dependently (3, 9, 18, and 36 mg/kg, i.p.) increased ACh efflux in the hippocampus of freely moving rats through D1 receptor stimulation, as the D1 receptor antagonist SCH 23390 (0.3 mg/kg, i.p.) abolished the effect of DHX (18 mg/kg, i.p.). Daily injections of DHX (18 mg/kg, i.p.) over 14 days did not significantly affect basal hippocampal ACh concentrations, but they significantly curtailed the stimulatory action of a challenge injection of DHX (18 mg/kg, i.p.) on ACh efflux. Conclusions Tolerance to the procholinergic action of DHX develops with repeated administration.     

Local modulation of the 5-HT release in the dorsal striatum of the rat: an in vivo microdialysis study

Using in vivo microdialysis in freely moving rats, we examined the involvement of major striatal transmitters on the local modulation of the 5-HT release. Tetrodotoxin reduced the striatal 5-HT output to 15–20% of baseline. The selective 5-HT_1B receptor agonist CP 93129 (50 μM) reduced (50%) and the 5-HT_2A/2C receptor agonist DOI (1–100 μM) increased (220%) the 5-HT output. Neither GABA nor baclofen (100 nM–100 μM) altered the 5-HT output. The glutamate reuptake inhibitor -trans-PDC (1–4 mM) raised 5-HT to 280% of baseline. This effect was not antagonized by the NMDA receptor antagonist MK-801 (0.5 mg/kg i.p.). Local MK-801 (10–100 μM) did not significantly alter the 5-HT output. Finally, neither carbachol (10–100 μM) nor quipirole (10 μM–1 mM) affected 5-HT. These data suggest that the striatal 5-HT release is influenced by local serotonergic and glutamatergic (but not GABAergic) inputs.