Differential effects of pyrethroid insecticides on extracellular dopamine in the striatum of freely moving rats

In order to obtain a more complete understanding of pyrethroid neurotoxicity, effects of the pyrethroid insecticides, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II) on extracellular levels of dopamine (DA) and its metabolites in the striatum of conscious rats were studied by in vivo microdialysis. Rats were treated i.p. with pyrethroids or vehicle. Allethrin had a dual effect on DA release. The increase in the extracellular level of striatal DA by 10 mg/kg allethrin reached a maximum of 178% of baseline but 20 and 60 mg/kg inhibited DA release to 63% and 52% of baseline with a peak effect at 60-80 min after injection. Cyhalothrin 10, 20 and 60 mg/kg inhibited DA release to 65%, 56% and 45% of basal release, respectively, with a peak time of inhibition 40-80 min past injection. Deltamethrin (10 and 20 mg/kg) increased DA release to maximum of 187% and 252% of basal release whereas 60 mg/kg first reduced the efflux for 40 min to 50% of basal release and then increased the efflux to a maximum of 344% of basal release with a peak time of 120 min. Local infusion of 1 microM tetrodotoxin, a Na(+) blocker through the dialysis probe completely prevented the effect of allethrin (10 and 60 mg/kg), cyhalothrin (60 mg/kg) and deltamethrin (20 mg/kg) on DA release but only partially blocked the effects of 60 mg/kg deltamethrin. The effect of deltamethrin (60 mg/kg) on DA release was completely prevented by local infusion of 10 microM nimodipine, an L-type Ca(++) channel blocker. All three pyrethroids did not alter the extracellular levels of DOPAC, 3-MT and HVA except that 20 and 60 mg/kg of allethrin and cyhalothrin increased 3-MT levels. Effect of the pyrethroids on synaptosomal DA uptake was also examined. The DA uptake was decreased in rats exposed to 60 mg/kg of allethrin and cyhalothrin but was increased in rats exposed to 60 mg/kg of deltamethrin. Our results demonstrate that striatal DA release and DA uptake are differentially affected by type I and the two type II pyrethroids indicating that dopaminergic circuitry, striatal DA in particular, may be a pyrethroid target and that pyrethroids may be acting on striatal DA by multiple mechanisms.     

Different effects of fenfluramine isomers and metabolites on extracellular 5-HIAA in nucleus accumbens and hippocampus of freely moving rats

The effects of optical isomers of fenfluramine and their metabolites, d- and l-norfenfluramine on the serotonergic system were studied in the nucleus accumbens and hippocampus of freely moving rats by in vivo voltammetry. Both isomers and the metabolites induced a slow, sustained decrease in 5HIAA but only d-fenfluramine and its metabolite, d-norfenfluramine, increased the 5HIAA levels in nucleus accumbens shortly after injection, the increase being greater after the metabolite. No effect could be detected in the hippocampus after the higher dose of d-fenfluramine.     

Systemic morphine simultaneously decreases extracellular acetylcholine and increases dopamine in the nucleus accumbens of freely moving rats.

Microdialysis was used to measure extracellular levels of acetylcholine (ACh) and dopamine (DA) simultaneously in the nucleus accumbens (NAC) of freely moving rats. Systemic injection of morphine (20 mg/kg) significantly decreased ACh (30%, p less than .01) while it increased DA (55%, p less than .01). The effects of morphine were eliminated by naloxone. The results confirm that morphine increases DA and in addition, demonstrate an inhibitory influence of this opiate on extracellular levels of ACh in the NAC.     

Focal bicuculline increases extracellular dopamine concentration in the nucleus accumbens of freely moving rats as measured by in vivo microdialysis

Donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride)) is a centrally acting acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, its inhibitory effect on the activity of cholinesterase ex vivo was evaluated in the brain, plasma, erythrocytes, heart, small intestine, liver and pectoral muscle of young adult as well as aged rats, in comparison with that of tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride). In aged animals, cholinesterase activity in heart, small intestine and pectoral muscle was lower, whereas that in plasma and liver was higher than in young rats. Both groups showed the highest levels in the brain. Donepezil, at doses of 1.25, 2.5 and 5 mg/kg, p.o., inhibited brain, plasma, erythrocyte, liver and pectoral muscle cholinesterase activity in young rats in a dose-dependent manner but had less effect on cholinesterase activity in heart and small intestine. In aged animals, inhibition of cholinesterase activity in the brain, erythrocytes and pectoral muscle by donepezil was more potent than that in young animals. Tacrine, at doses of 5, 10 and 20 mg/kg, p.o., dose-dependently inhibited cholinesterase activity in all tissues of both young and aged animals, but most potently in heart, small intestine and liver. The inhibition of cholinesterase activity by tacrine in the brain, plasma, erythrocytes, heart and liver was more potent in aged rats than in tissues of young rats. Brain and plasma concentrations of unchanged donepezil and tacrine were measured in the same animals as used for the cholinesterase inhibition study. Brain and plasma concentrations of donepezil and tacrine were higher in aged than in young animals. It is concluded that the inhibitory effects of donepezil and tacrine on cholinesterase activity are greater in aged than in young rats, owing to differences in the tissue concentrations of these compounds between young and aged animals. It is also suggested that the effect of donepezil on cholinesterase activity is more tissue-selective than that of tacrine.     

Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis

This study examined the acute effects of the novel antidepressant drug, bupropion, on extracellular concentrations of dopamine (DA), its metabolites, and the serotonin metabolite 5-HIAA in the striatum and nucleus accumbens using on-line microdialysis in freely moving rats. Bupropion HCl (10, 25, and 100 mg/kg intraperitoneally) increased extracellular striatal DA in a dose- and time-dependent manner; 1 mg/kg did not affect extracellular DA. The maximal response occurred within the first 20 minutes (+76%, +164%, and +443% for each dose, respectively) followed by a gradual decrease to a stable but elevated level for the next 2 hours. This neurochemical response was strongly associated with bupropion-induced stereotyped behavior during the first hour but not during the subsequent 2 hours. Bupropion decreased DOPAC concentrations, increased 5-HIAA, and had variable effects on homovanillic acid (HVA) (decreases with 10 mg/kg and increases with 25 and 100 mg/kg). The increase in extracellular DA after bupropion (25 mg/kg) was blocked by tetrodotoxin and was therefore action-potential-dependent. Bupropion produced similar neurochemical responses in the striatum and the nucleus accumbens. These results suggest that increases in DA transmission contribute to the behavioral effects of bupropion and are consistent with a role for DA in the antidepressant effects of this drug. The partial dissociation between DA release and stereotyped behavior suggests that the relationship between neurotransmitter release and behavior may be complex.     

On the mechanism of levosimendan-induced dopamine release in the striatum of freely moving rats

The Ca(2+) sensitizer levosimendan (LEV) improves myocardial contractility by enhancing the sensitivity of the contractile apparatus to Ca(2+). In addition, LEV promotes Ca(2+) entry through L-type channels in human cardiac myocytes. In this study, which was performed using microdialysis, infusion of LEV at 0.25 microM for 160 min increased dopamine (DA) concentrations (up to fivefold baseline) in dialysates from the striatum of freely moving rats. Ca(2+) omission from the perfusion fluid abolished baseline DA release and greatly decreased LEV-induced DA release. Reintroduction of Ca(2+) in the perfusion fluid restored LEV-induced DA release. Chelation of intracellular Ca(2+) by co-infusing 1,2-bis (o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM, 0.2 mM) did not affect basal DA release and scarcely affected LEV-induced increases in dialysate DA. In addition, co-infusion of the L-type (Ca(v) 1.1-1.3) voltage-sensitive Ca(2+)-channel inhibitor nifedipine failed to inhibit LEV-induced increases in dialysate DA, which, in contrast, was inhibited by co-infusion of the N-type (Ca(v) 2.2) voltage-sensitive Ca(2+)-channel inhibitor omega-conotoxin GVIA. We conclude that LEV promotes striatal extracellular Ca(2+) entry through N-type Ca(2+) channels with a consequent increase in DA release.     

Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone

The neurosteroid allopregnanolone is a potent and efficacious modulator of γ-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 μg in 5 μl) on basal and stress-induced changes in the extracellular concentrations of dopamine were investigated by microdialysis in various brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 μg in 5 μl). Allopregnanolone reduced (by a maximum of 65 to 75%) basal dopamine content in the prefrontal cortex and nucleus accumbens in a dose-dependent manner, but had no effect on dopamine output in the striatum. Allopregnanolone (10 to 15 μg) also completely prevented the increase in extracellular dopamine concentrations in the nucleus accumbens and cerebral cortex induced by foot-shock stress. Midazolam reduced basal dopamine content in all three brain regions studied as well as the stress- induced increase in dopamine content in the nucleus accumbens and cerebral cortex with a greater potency than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of dopaminergic transmission in the rat cerebral cortex and nucleus accumbens, two brain areas which are important in the regulation of emotional processes. These agents do not appear to affect striatal dopaminergic transmission which modulates motor function.     

The effects of systemically administered taurine and N-pivaloyltaurine on striatal extracellular dopamine and taurine in freely moving rats

The second most abundant cerebral amino acid, taurine, is widely consumed in the so-called "energy drinks". Therefore, its possible actions on the brain are of great interest. In the present experiments taurine was given intraperitoneally to rats in order to study if it can be administered systemically in large enough amounts to alter cerebral dopaminergic transmission or to induce hypothermia. In addition, the effects of subcutaneously administered lipophilic taurine analogue, N-pivaloyltaurine, were studied. The extracellular striatal taurine and dopamine concentrations were estimated using in vivo microdialysis in awake and freely moving rats, and the rectal temperatures were measured. Taurine at the total dose of 45 mmol/kg i.p. led to a maximally 8-fold increased striatal extracellular taurine concentration, induced a long-lasting hypothermia, and significantly reduced the striatal extracellular dopamine concentration. The latter effect was strengthened by co-treatment with reuptake inhibitor nomifensine. N-pivaloyltaurine (15 mmol/kg in total, s.c.) only slightly elevated the striatal extracellular taurine concentration, failed to alter the rectal temperature, and in contrast to taurine somewhat elevated the striatal extracellular dopamine concentration suggesting a different mechanism or locus of action from that of taurine. Finally, our experiments using brain microdialysis confirmed the earlier findings that taurine is slowly eliminated from the brain. The results clearly indicate that systemically given taurine enters the brain in concentrations that induce pharmacological effects.     

Comparison of changes in the EEG of freely moving rats induced by enciprazine, buspirone and diazepam

The effect of enciprazine, buspirone and diazepam was investigated on the cortical electrical activity in freely-moving rats. Enciprazine (5 mg/kg, i.p.) and buspirone (5 mg/kg, i.p.) induced comparable changes, consisting in decreases of mean power values in delta and theta and increases in alpha and beta EEG frequency bands. Regarding only a particular area of the brain or particular frequency bands, these two compounds could not be clearly separated from each other. Changes in frequency bands induced by O-methoxy-phenyl-piperazine (5 mg/kg i.p.) (D 15157), the presumed main metabolite of enciprazine, were dose-related to that caused by the parent compound. The second metabolite (R,S)-1-4-(1-methoxy-4-hydroxy-phenyl)piperazin-1-yl-3-(3,4,5- trimethoxyphenoxy)propan-2-ol-dihydrochloride (D 20092) (5 mg/kg i.p.) evoked only minimal changes in the different frequency bands of the rats. The power spectra did not significantly differ from those seen in animals treated with saline. The action of diazepam (2 mg/kg i.p.) was characterized by decreases in alpha and delta frequency bands, accompanied by marked increases in fast beta waves. The marked frequency shifts caused by buspirone and enciprazine could clearly be differentiated from the EEG changes evoked by the minor tranquilizer, diazepam.     

Differential effects of 3-PPP enantiomers on extracellular dopamine concentration in the caudate-putamen and nucleus accumbens of rats

The ability of the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine) to modify the extracellular concentration of dopamine (DA) in the caudate-putamen and the nucleus accumbens of awake rats was assessed using intracranial microdialysis. The enantiomers and the racemate were directly infused at 3 incremental concentrations (1–100 M) or systemically administered by subcutaneous injection (10 mg/kg). Both systemic administration and direct infusion of (–)3-PPP at the highest concentration (100 M) significantly increased extracellular DA in both brain regions. This increase was also seen in the presence of higher extracellular DA levels following reuptake inhibition by nomifensine (10 M). In contrast to the effects of (–)3-PPP, systemic administration of both (+)3-PPP and (±)3-PPP decreased DA levels. Infusion of (±)3-PPP led to slight increases in DA levels in both brain regions at the highest concentration (100 M), while (+)3-PPP at 100 M also produced a significant increase in the caudate-putamen, but not in the nucleus accumbens. However, in the presence of nomifensine-induced elevations in extracellular DA, (+)3-PPP produced a significant decrease in DA concentrations in both brain regions. These results support previous findings that the enantiomers of 3-PPP show unique profiles in their in vivo effects on DA terminal functions. Furthermore, these effects are dependent on the mode of 3-PPP administration, the brain region in which DA overflow is measured, and the level of basal extracellular DA. Correspondence to: R. E. See at the above address     

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core

Rationale Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (d-amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% l-amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for d-amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between d-amphetamine and l-amphetamine have not been well characterized.Objectives To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes.Results The presence of l-amphetamine in the d,l-amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The d,l-amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When l-amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of d,l-amphetamine.Conclusions These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that l-amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.     

Effect of ginseng total saponin on extracellular dopamine release elicited by local infusion of nicotine into the striatum of freely moving rats

We investigated the effect of ginseng total saponin (GTS) on nicotine-induced dopamine (DA) release in the striatum of freely moving rats using an in vivo microdialysis technique. In order to further characterize the mechanism by which GTS affects DA release, the effect of GTS on K(+)-induced DA release was also examined. Local infusion of nicotine (1, 5, and 10 mM) into the striatum produced a dose-dependent increase in extracellular DA in dialysate samples (maximal response = 154.0 +/- 10.8%, 308.1 +/- 55.7%, and 499.9 +/- 77.9% over basal levels, respectively). GTS (100 mg/kg i.p.) had no effect on basal levels of extracellular DA. However, GTS inhibited maximal DA release induced by intrastriatal infusion of nicotine (1, 5, and 10 mM) by 35.3%, 36.6%, and 58.5%, respectively. Intra-striatal infusion of high K+ solution (100 mM) produced an increase in extracellular DA in the striatum (maximal response = 796.6 +/- 98.8% over basal levels). However, GTS had no effect on the K(+)-induced increase in extracellular DA. The present study demonstrated that GTS inhibited striatal DA release stimulated by local infusion of nicotine. This may reflect the blocking effect of GTS on the striatum-related behavior induced by nicotine as well as other psychostimulants. The results also suggest that GTS may act on presynaptic nicotinic acetylcholine receptors or receptor-operated Na+ channels in dopaminergic nerve terminals, but not on voltage-sensitive ion channels.     

Effect of conditioning with d-amphetamine on the extracellular concentration of dopamine and its metabolites in the striatum of behaving rats

The effect of classical conditioning with d-amphetamine on the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving rats was studied using microdialysis. This was done in order to test, whether there occurred alterations in DA release as conditioned responses in the striatum. The first series of experiments studied the acute effects of d-amphetamine on the concentration of DA and its metabolites DOPAC and HVA. d-Amphetamine (2 mg/kg, s.c.) increased extracellular DA and decreased DOPAC and HVA. Behaviorally, it led to stereotyped locomotor activation and sniffing. In principle, these observations confirmed earlier findings. In a second series, conditioned responses to d-amphetamine were studied. Rats were implanted with guide cannulas prior conditioning experiments started. For conditioning experiments, the rats were divided into three groups: conditioned group, pseudoconditioned group and a drug-naive control group. After 7 daily training sessions with d-amphetamine (2 mg/kg), on the 8th day, the test day, rats were injected with saline and exposed to the conditional stimuli, while they were observed for their stereotyped, conditioned response. Additionally, microdialysis was performed in order to observe possible changes in the extracellular transmitter or metabolite concentrations. Conditioning with amphetamine led to conditioned stereotypic behavior. In comparison with the pseudoconditioned rats, there was an increase in DA release as conditioned response to amphetamine. In pseudoconditioned rats. DOPAC and HVA were slightly higher than in both other groups. DOPAC and HVA were lower in rats conditioned to d-amphetamine when compared with the pseudoconditioned ones. The results suggest that with regard to DA release, the conditioned responses to d-amphetamine mimicked the acute pharmacological responses. The same is valid for the DA metabolites, although in the opposite direction — they mimicked decreases. Furthermore, the conditioned DA responses to d-amphetamine might contribute to conditioned behavioral responses observed in these experiments. Correspondence to: K. Kuschinsky at the above address     

Role of GABAA receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats

In vivo microdialysis was used to study the effects of the locally applied GABA(A) receptor agonist muscimol and GABA(A) receptor antagonist bicuculline on the basal dopamine efflux as well as on the endomorphin-1- and endomorphin-2-induced dopamine efflux in the nucleus accumbens of freely moving rats. Muscimol (2500 pmol) and bicuculline (5 and 10 nmol) increased basal dopamine efflux. Bicuculline (50 pmol) inhibited the muscimol (2500 pmol)-induced dopamine efflux. Muscimol (250 pmol), but not bicuculline (50 and 500 pmol), enhanced the endomorphin-1 (25 nmol)-induced dopamine efflux. Bicuculline (50 pmol) counteracted the muscimol (250 pmol)-induced increase of the endomorphin-1-elicited dopamine efflux. Neither muscimol (25 and 250 pmol) nor bicuculline (50 and 500 pmol) affected the endomorphin-2 (25 nmol)-induced dopamine efflux. The doses mentioned are the total amount of drug over the infusion period (25 or 50 min) that varied across the drugs. The finding that muscimol and bicuculline increased basal dopamine efflux may imply that these drugs acted at different sites. It is suggested that (1) muscimol acts at GABA(A) receptors on GABA-ergic neurons that exert an inhibitory control of dopaminergic neurons and, accordingly, disinhibits these dopaminergic neurons, and that (2) bicuculline acts directly at GABA(A) receptors on dopaminergic neurons and, accordingly, removes the inhibitory control of these dopaminergic neurons. The finding that an agonist, but not antagonist, of GABA(A) receptors enhanced the endomorphin-1's effects might indicate that endomorphin-1 produced a floor effect at the level of GABA(A) receptors located on presynaptic, dopaminergic terminals. Finally, the present results support our earlier reported notion that endomorphin-1 and endomorphin-2 increase accumbal dopamine efflux by different mechanisms.     

Neurotensin effects on evoked release of dopamine in slices from striatum,nucleus accumbens and prefrontal cortex in rat

Summary The effects of neurotensin (NT) on the K⁺-evoked release of endogenous and tritiated dopamine in striatum and on ³H-dopamine in slices from nucleus accumbens and prefrontal cortex were investigated. In striatum, NT (1–1000 nM) elicited a dose-dependent increase in endogenous and ³H-dopamine release. The dose-response curves were comparable with the two methods. Concerning the comparison of NT modulation of ³H-dopamine release in the three cerebral structures, the peptide induced a more marked effect in striatum with a maximal effect of 150% increase. In accumbens, NT (1–1000 nM) potentiated the K⁺-evoked 3H-dopamine release, but in contrast with striatum, the plateau corresponded to a 50% increase. In prefrontal cortex, NT (1–1000 nM) induced small but significant effects, with a maximal increase of 50% at 100 nM. Acetyl-NT (8–13) displayed an action similar to the natural peptide while NT (1–8) did not exhibit any effect, suggesting that the action of NT involved a receptor. The presence of tetrodotoxin did not alter the facilitating effects of NT in the three structures, indicating that interneurons were not involved in the action of NT. The comparison of the effects of NT showed that in terms of efficacy, NT induced an increase in dopamine release more marked in striatum than in nucleus accumbens and prefrontal cortex. These results are consistent with differences in NT receptors localization in these three dopaminergic structures. Send offprint request to: A. Boireau     

Analysis of S-nitroso-N-acetylpenicillamine effects on dopamine release in the striatum of freely moving rats: role of endogenous ascorbic acid and oxidative stress

1. We showed previously that interaction between NO and iron(II), both released following decomposition of sodium nitroprusside (SNP), accounted for the late SNP-induced dopamine (DA) increase in dialysates from the striatum of freely moving rats. 2. In this study, intrastriatal infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) (0.2 mM for 180 min) induced a moderate increase in dialysate DA and decreases in ascorbic acid dialysate concentrations; in contrast, SNAP 1 mM infusion induced a long-lasting decrease in both DA and ascorbic acid dialysate concentrations. 3-Methoxy-tyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and uric acid levels were unaffected. 3. Co-infusion of ferrous sulphate [iron(II), 1 mM for 40 min] with SNAP either 1 or 0.2 mM (for 180 min), produced a significant increase in both DA and 3-MT dialysate concentrations, but it did not affect decreases in dialysate ascorbic acid levels. All other dialysate neurochemicals were unaffected. 4. Co-infusion of ascorbic acid (0.1 mM) with SNAP (1 mM) for 180 min did not modify SNAP-induced decreases in dialysate DA levels. In contrast, co-infusion of uric acid (1 mM) reversed SNAP-induced decreases in dialysate DA; co-infusion of a superoxide dismutase mimetic delayed SNAP-induced DA decreases for a short period, while co-infusion of the antioxidant N-acetylcysteine (NAC, 0.1 mM) significantly increased dialysate DA. 5. The results of this study show that SNAP induces concentration-related changes in DA dialysate levels. At higher concentrations, SNAP induces non-enzymatic DA oxidation, which is inhibited by uric acid and NAC; ascorbic acid failed to protect dialysate DA from oxidation, probably owing to its promoting effect on SNAP decomposition; exogenous iron(II) may react with NO generated from SNAP decomposition, with a consequent increase in dialysate DA and 3-MT, therefore mimicking SNP effects on striatal DA release.     

Role of GABA B receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats

In vivo microdialysis was used to study the effects of the locally applied GABA B receptor antagonist 2-hydroxysaclofen and GABA B receptor agonist baclofen on the basal dopamine efflux as well as on the endomorphin-1- and endomorphin-2-induced dopamine efflux in the nucleus accumbens of freely moving rats. 2-Hydroxysaclofen (100 and 500 nmol) increased basal dopamine efflux. Baclofen (2.5 and 5 nmol) failed to affect basal dopamine efflux. 2-Hydroxysaclofen (1 and 10 nmol) which did not alter the basal dopamine efflux, enhanced the endomorphin-1 (25 nmol)-induced dopamine efflux. Baclofen (2.5 and 5 nmol) failed to affect endomorphin-1 (25 nmol)-induced dopamine efflux, but it counteracted the 2-hydroxysaclofen-induced increase of the endomorphin-1-elicited dopamine efflux. Neither 2-hydroxysaclofen (10 nmol) nor baclofen (5 nmol) affected the endomorphin-2 (25 nmol)-induced dopamine efflux. The doses mentioned are the total amount of drug over the infusion period that varied across the drugs (25 or 50 min). These results suggest that accumbal GABA B receptor plays an inhibitory role on the basal as well as the endomorphin-1-elicited accumbal dopamine efflux. The present results support our earlier reported notion that endomorphin-1 and endomorphin-2 increase accumbal dopamine efflux by different mechanisms. Finally, it is suggested that a decrease of endogenous accumbal GABA reduces the accumbal GABA B receptor-mediated GABA-ergic inhibition, enhancing thereby the accumbal dopamine efflux.     

The effect of repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in freely moving rats

Evidence exists that modulation of neuronal activity in nucleus accumbens shell region may re-establish normal function in various neuropsychiatric conditions such as drug-withdrawal, obsessive–compulsive disorder, depression and chronic pain. Here, we study the effects of acute repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in awake and freely moving rats using in vivo microdialysis. To scale the biochemical results to the induced electric field in the rat brain, we obtained a realistic simulation of the stimulation scenario using a finite element model. Applying 20 Hz repetitive transcranial magnetic stimulation in 6 trains of 50 stimuli with 280 μs pulse width at a magnetic field strength of 130% of the individual motor threshold, dopamine as well as serotonin outflow in the nucleus accumbens shell significantly increased compared to sham stimulation. Since the electric field decays rapidly with depth in the rat brain, we can conclude that the modulation in neurotransmitter outflow from the nucleus accumbens shell is presumably a remote effect of cortical stimulation.     

动态监测清醒自由活动大鼠纹状体细胞外液乙酰胆碱和胆碱水平的方法

目的　建立动态监测正常清醒自由活动大鼠纹状体细胞外液中乙酰胆碱 (ACh)和胆碱 (Ch)水平的方法。方法　应用脑内微透析与高效液相色谱 (HPLC ) 柱后固定化酶反应器 (IMER ) 电化学检测法 (ED)相结合的技术 ,动态监测正常清醒自由活动大鼠纹状体细胞外液中ACh和Ch水平。结果　大鼠纹状体细胞外液中ACh和Ch浓度在灌流开始时较高 ,然后逐渐降低 ,ACh在灌流进行 2 4 0min后达到较稳定水平 ;Ch浓度则在灌流的 4 5 0min内持续下降。HPLC IMER ED检测ACh和Ch的极限可达 15 0fmol,且至少在 0 12 5～ 1 0 μmol·L-1的范围内线性关系良好。结论　HPLC IMER ED是一种灵敏且可靠的测定ACh和Ch的方法 ,和微透析技术相结合可以动态监测清醒自由活动大鼠脑内细胞外液中ACh和Ch的水平。     

Neuroleptic-like effects of the l-isomer of fenfluramine on striatal dopamine release in freely moving rats

l-Fenfluramine (l-F) was studied for its ability to release dopamine (DA) and its metabolites in freely moving rats through the trans-striatal dialysis technique. l-F's effect on striatal DA release was also studied in animals made tolerant to the effect of haloperidol by chronic treatment (1 mg/kg i.p. twice daily for 11 days and 48 hr wash-out) with the neuroleptic or pretreated with 300 mg/kg i.p. gamma-butyrolactone (GBL). Five and 10 mg/kg l-F dose-dependently increased the release of DA and its metabolites with a pattern of effects similar to that observed with neuroleptic drugs. The dose of 20 mg/kg l-F had the same effect as 10 mg/kg. Repeated haloperidol treatment reduced the basal release of DA and its metabolites and a much smaller amount of DA and metabolites was released by l-F (10 mg/kg i.p.) and haloperidol (0.1 mg/kg i.p.) in animals treated with haloperidol than in controls. GBL 300 mg/kg i.p. reduced basal DA release by about 50%. When 10 mg/kg l-F, 0.1 mg/kg haloperidol and 0.25 mg/kg d-amphetamine were injected i.p. 40 min after GBL, l-F and haloperidol did not significantly raise DA release in GBL-treated rats whereas a significant effect was observed at various times after d-amphetamine. The data show that l-F resembles haloperidol in its ability to release DA and its metabolites from the corpus striatum of freely moving rats. The cross-tolerance between haloperidol and l-F for their effect on DA release suggests that a common site is involved in the mechanism of these drugs.