Amount Of Extracellular Dopamine Research Articles

Sex Differences in Dopamine‐ and Vesicular Monoamine‐Transporter Functions

Men and women differ with regard to their use of, and responses to, methamphetamine (MA). Analogous sex differences with regard to MA are observed in animal models. In this report, data from a series of experiments that focus upon dopamine transporter (DAT) and vesicular monoamine transporter2 (VMAT2) function are reviewed by way of providing some understanding for these sex differences to MA. The amount of dopamine (DA) recovered after infusion of DA into superfused striatal tissue was greater in females and an accentuated amount of extracellular DA was obtained from females after infusion of the DAT-blocking drug, nomifensine. These data suggest a higher level of DAT activity in females. To evaluate the implications of this sex difference in DAT function as related to MA, the amount of DA evoked by an infusion of MA into superfused striatal tissue was tested and found to be significantly greater in males. In contrast, potassium chloride-stimulated DA release was greater in females. The results of these DA-evoked experiments imply that the greater DAT activity of females, by itself, cannot explain the sex differences observed with MA, and our attention was then directed to the VMAT2. Administration of the VMAT2 blocker, reserpine, in vivo resulted in a significantly greater amount of striatal DA depletion within female mice and infusion of reserpine in vitro into striatal tissue produced significantly greater levels of extracellular DA in females. The data of these reserpine experiments suggest that females possess a more active/efficient VMAT2 function. Collectively, the data provide evidence for sex differences in both DAT and VMAT2 functioning, and we propose that the interaction of these two transporter systems contributes to the differences in response to MA between males and females.

Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens

Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K(+)-stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K(+) compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K(+)-stimulated DA levels in control rats, it did not decrease significantly either basal or K(+)-stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc.

Fluoxetine reduces l-DOPA-derived extracellular DA in the 6-hydroxydopamine-lesioned rat striatum

We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on l-3,4-dihydroxyphenylalanine (l-DOPA)-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following l-DOPA administration (50 mg/kg i.p.). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease (PD) by reducing efflux of exogenous l-DOPA-derived DA.

Amantadine increases l-DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats

We investigated the effect of amantadine on l-DOPA-derived extracellular dopamine (DA) levels and aromatic l-amino acid decarboxylase (AADC) activity in the striatum of rats with nigrostriatal dopaminergic denervation by 6-hydroxydopamine (6-OHDA). Pretreatment with 30 mg/kg amantadine increased the cumulative amount of extracellular DA in the striatum of 6-OHDA-lesioned rats treated with 10 mg/kg benserazide and 50 mg/kg l-DOPA to 250% of that without amantadine ( P<0.01). Under pretreatment with 10 mg/kg benserazide, AADC activity after 30 mg/kg amantadine administration was reduced to 43% of controls ( P<0.01). Amantadine-induced increase in l-DOPA-derived extracellular DA provides the basis for the clinical usefulness of amantadine in combination with l-DOPA. However, the effect of amantadine on l-DOPA-derived extracellular DA may not be caused by changes in AADC activity.

Validity of a quantitative technique to study striatal dopaminergic neurodegeneration by in vivo microdialysis

The development of a technique that allows the direct quantitative study of the damage produced by a toxin on a specific neurotransmitter system is very important. For that, we have used the microdialysis technique to validate a method to study the specific drug's toxicity on dopaminergic (DAergic) striatal terminals. We perfused different MPP + and 6-hydroxydopamine (6-OHDA) concentrations, with different toxicity for DAergic terminals, 24 h after the implantation of the microdialysis probe (day 1). One day later (day 2), MPP + was perfused through the microdialysis probe and DA extracellular output measured. We hypothesize that the amount of extracellular dopamine (DA) obtained on day 2 is directly proportional to the neurotoxic damage produced on day 1. To corroborate this hypothesis tyrosine hydroxylase (TH) immunohistochemistry was also carried out on day 2. There was a clear correlation index between the amount of DA measured after MPP + perfusion and the lack of TH immunoreactivity measured as the radius of the area showing decrease in TH immunoreactivity around the cannula. These results show the possibility to measure DAergic remaining terminals after a toxic drug exposure by in vivo MPP + perfusion. The possibility to extend this neurotoxic study to another neurotransmitter systems is suggested.

Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum.

We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on L-DOPA-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg, i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following L-DOPA administration (50 mg/kg, i.p.; p < 0.01). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its indirect 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease by reducing efflux of exogenous L-DOPA-derived DA.

Differential agonist profile of the enantiomers of 3‐PPP at striatal dopamine autoreceptors: Dependence on extracellular dopamine

The effects of the enantiomers of 3-hydroxyphenyl-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)- and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 microns, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 microM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)