Halothane enhances acetylcholine release by decreasing dopaminergic activity in rat striatal slices

The present study investigated the effect of halothane on acetylcholine (ACh) and dopamine (DA) release from the rat striatum. Halothane decreased DA release in a concentration-dependent manner, while increased ACh release. In our previous investigation, a volatile anesthetic, halothane, inhibited DA release from the rat striatal slices in a concentration-dependent manner. Although the release of ACh from cholinergic interneurons is tonically modulated by DA in the striatum, the effect of halothane on the relationship between the release of ACh and DA has not been discussed. Using double-labeled techniques, we investigated the effect of halothane on ACh and DA release simultaneously. The slices were incubated with [14C]-choline and [3H]-DA and superfused with modified Krebs solution containing 1 microM of hemicholinium-3. We applied electrical field stimulation (2 Hz, 240 shocks), and the amount of the release of radioactivity evoked by stimulation was calculated by subtraction of the basal radioactive outflow from the total outflow at the beginning of the respective stimulation periods. The effects of drugs on the release were expressed as the ratio of stimulation-evoked fractional releases (FR), measured in the presence and absence (FRS2/FRS1) of the drug. Halothane decreased DA release in a concentration-dependent manner (FRS2/FRS1=0.767+/-0.021, 0.715+/-0.026, 0.671+/-0.014 and 0.639+/-0.033 at the concentration of 0, 0.5, 2 and 4%, respectively), while ACh release showed a biphasic change in the presence of different concentrations of halothane. The release of ACh was significantly increased at the concentration of 2%, but not at 0.5 or 4%. Halothane failed to increase the release of ACh in striatal slices after lesion by 6-OH-dopamine. The application of amphetamine reduced the release of ACh and abolished the effect of halothane. These results indicate that the effect of halothane on ACh release is indirect: it increases the release by attenuating the inhibitory effect of DA released from the nigro-striatal pathway. The nonsynaptic interaction between DA and ACh release is involved in the effect of halothane on ACh release.     

Biochemical effects of quipazine on rat striatal dopaminergic system

At high doses quipazine, a serotonergic agonist, induces a dose-dependent reduction of homovanillic acid (HVA) and of dihydroxyphenylacetic acid (DOPAC) levels in rat striatum, and reduces the conversion of tyrosine into dopamine. These effects are not mediated by a serotonergic-dopaminergic interaction as they are not antagonized by pretreatment with the serotonin antagonist methergoline. Neither are they caused by direct action on dopamine receptors as the drug does not antagonize the increase in HVA induced by haloperidol. 3-methoxytyramine (3MT), a DA metabolite which is the expression of DA present in the synaptic cleft, is high after quipazine treatment, but this is not because of monoamine oxidase inhibition. The increase in 3MT is already evident shortly after quipazine administration, while the effect on HVA and DOPAC levels appears later. The different effects of quipazine on DA metabolites and the temporal sequence of their appearance suggest that the lowered levels of acidic metabolites are an index of reduced DA turnover secondary to the increase in DA at the receptor sites caused by quipazine.     

Parity decreases methamphetamine-induced striatal dopaminergic perturbation

The role of parity upon methamphetamine-induced neurotoxicity of the striatal dopaminergic system was assessed. Female CD-1 mice either remained nulliparous or underwent one or three complete pregnancies and were designated as the 0, 1 or 3 pregnancy groups. The mice were then treated with a neurotoxic regimen of methamphetamine (MA - 40 mg/kg) or its saline vehicle (control) and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured at 7-days post-MA. Basal levels of striatal DA, DOPAC and the DOPAC/DA ratio were similar among the saline (control) 0, 1 and 3 pregnancy groups. In response to MA, striatal DA and DOPAC were significantly decreased in the 0 and 1 pregnancy as compared with the control group. Mice with 3 pregnancies showed DA and DOPAC levels that did not differ from controls and were significantly greater than the 0 pregnancy group. The DOPAC/DA ratios of the 0 pregnancy group were significantly greater than all other groups (control, 1 and 3 pregnancy) which failed to differ among each other. These results demonstrate that parity decreases MA-induced striatal dopaminergic neurotoxicity, and the degree of this neuroprotection is related to the number of pregnancies experienced.     

Alpha-MSH injected into the substantia nigra or intraventricularly alters behavior and the striatal dopaminergic activity

Rats were injected with 1 μg of alpha-melanocyte stimulating hormone (α-MSH) into the third ventricle and locally in the ventral tegmental area and in different regions of the substantia nigra. The modifications produced on grooming behavior and locomotion as well as on the dopamine content of the nucleus accumbens and the caudate putamen, were studied. Both intraventricular peptide administration and microinjections into the ventral tegmental area induced excessive grooming and a significant increase of the locomotor activity. The dopamine content of the nucleus accumbens and caudate putamen was markedly reduced. Injections of the peptide into the substantia nigra pars compacta failed to induce excessive grooming but did provoke a slight increase in locomotor activity and a smaller change in caudate dopamine content than that observed by injections in the ventral tegmental area or in the third ventricle. Dopamine levels in the nucleus accumbens were not changed. Finally, the injections of α-MSH into the lateral substantia nigra did not produce either biochemical or behavioral changes.The results suggests that α-MSH can modify, directly or indirectly, the striatal dopaminergic activity and that the behavioral alterations observed such as excessive grooming, could be mediated by the activation of the dopamine cells from the ventral tegmental area, that in turn may provoke a significative release of dopamine at the caudate putamen nucleus as well as in nucleus accumbens.     

Pyrethroids and the striatal dopaminergic system in vivo

1. Type I (permethrin and allethrin) or type II (cypermethrin and fenvalerate) pyrethroids caused 23-37% increases in the striatal content of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). 2. Toxicity symptoms and increases in DOPAC were associated with higher brain concentrations for type I (2.6-5.8 micrograms/gm) than type II pyrethroids (0.4-0.6 micrograms/gm). 3. No specific difference in the interaction between type I and II pyrethroids and the striatal dopaminergic system were recognized.     

Pharmacologic evidence for direct dopaminergic regulation of striatal acetylcholine release

This study was done to provide pharmacologic evidence for the location of those striatal dopamine D-1 and D-2 receptors that participate in the regulation of local acetylcholine (ACh) release. Striatal tissue slices from adult male Sprague-Dawley rats were preloaded with [3H]choline and superfused in separate experiments with buffer containing either: a D-2-specific agonist (LY141865 or LY171555), a D-2 specific antagonist (L-sulpiride), a D-1 specific agonist (SKF38393), or a D-1 antagonist (SCH23390), in the presence or absence of tetrodotoxin (TTX), used to block interneuronal activity. With either D-2 agonist there was a dose-dependent decrease in K+-stimulated [3H]ACh release, maximally at 5 X 10(-7)-10(-6) M [agonist] and to the same extent with each drug. Both SKF38393 and SCH23390 increased [3H]ACh release at tested concentrations of these agents. Results were unchanged when any of the drugs used was superfused in the presence of TTX, 5 X 10(-7) M. These data are consistent with the hypothesis that populations of striatal D-1 and D-2 receptors exist on local cholinergic neurons, where they regulate ACh release. Alternative interpretations are discussed.     

Neuropeptide-dopamine interactions. IV. Effect of thyrotropin-releasing hormone on striatal dopaminergic neurons

Many biologic effects of TRH seem to be mediated via a dopaminergic mechanism. The present study examined the effects of chronic TRH administration on the properties of nigrostriatal dopaminergic neurons. Ten days, continuous subcutaneous TRH administration via an osmotic minipump led to a significant rise in striatal level of 3,4-dihydroxyphenylacetic acid, but not of homovanillic acid or dopamine. These treatments also did not elicit any significant changes in the maximal binding capacity (Bmax) or affinity (KD) of either D1- or D2-dopamine receptor. By contrast, TRH administration led to a significant increase in both Bmax and KD of striatal mazindol binding. This effect of TRH, however, was not observed in in vitro studies. In conclusion, these data suggest that in vivo administration of TRH may modulate dopaminergic activities by altering, directly or indirectly, dopamine release and reuptake.     

Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers

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A possible mechanism of participation of dopaminergic cells and striatal cholinergic interneurons in the conditioned selection of motor activity

A possible mechanism of participation of cholinergic striatal interneurons and dopaminergic cells in conditioned selection of a certain types of motor activity is proposed. This selection is triggered by simultaneous increase in the activity of dopaminergic cells and a pause in the activity of cholinergic interneurons in response to a conditioned stimulus. This pause is promoted by activation of striatal inhibitory interneurons and action of dopamine at D2 receptors on cholinergic cells. Opposite changes in dopamine and acetylcholine concentration synergistically modulate the efficacy of corticostriatal inputs, modulation rules for the "strong" and "weak" corticostriatal inputs are opposite. Subsequent reorganization of neuronal firing in the loop cortex--basal ganglia--thalamus--cortex results in amplification of activity of the group of cortical neurons that strongly activate striatal cells, and simultaneous suppression of activity of another group of cortical neurons that weakly activate striatal cells. These changes can underlie a conditioned selection of motor activity performed with involvement of the motor cortex. As follows from the proposed model, if the time delay between conditioned and unconditioned stimuli does not exceed the latency of responses of dopaminergic and cholinergic cells (about 100 ms), conditioned selection of motor activity and learning is problematic.     

High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is thought to be superior to stimulation of the internal pallidum (GPi) in alleviating symptoms of Parkinson's disease (PD). However, preliminary controlled studies comparing the effectiveness of both targets have not found significant differences in the improvement of parkinsonian symptoms, but have shown that STN stimulation allows a dramatic decrease in dopaminergic medication. We have previously shown that STN-HFS increases striatal extracellular dopamine (DA) metabolites, but not DA, in both naive and 6-hydroxydopamine (6-OHDA)-lesioned rats, whereas stimulation of the entopeduncular nucleus (EP), the rodent equivalent of the internal pallidum, does not affect DA or metabolite levels. Intriguingly, STN-HFS increases striatal DA release after inhibition of DA reuptake or metabolism, suggesting that this observation may have been obscured in non-drug treated animals by rapid and effective DA reuptake. Since STN-HFS further enhances DA metabolism after DA reuptake inhibition or depletion it has been proposed that STN-HFS increases both, striatal DA release and metabolism, independently. Therefore, the present study assesses the impact of EP-HFS on striatal DA release and metabolism in normal rats after inhibition of DA reuptake or metabolism, using microdialysis. In summary, our data demonstrate that, contrary to STN stimulation, EP-HFS has no effect on striatal DA release and metabolism. Thus, the present study provides a partial explanation for the reported clinical differences, and experimental evidence for differential mechanisms of action between HFS of the internal pallidum and the STN, that are most likely related to differences in functional anatomy.     

Effects of dopaminergic drugs and acute medial forebrain bundle lesions on striatal acetylcholine levels.

Placement of radio frequency lesions in the medial forebrain bundle resulted in a 50% depletion of striatal acetylcholine levels but did not change hippocampal levels. A similar result was obtained with the administration of chlorpromazine, haloperidol and pimozide. When these drugs were administered simultaneously with placement of lesions, there was the same 50% depletion of striatal acetylcholine. Apomorphine reversed the depletion due to lesions. These results suggest that the action of antipsychotic drugs on the cholinergic system in the striatum is primarily due to their action at dopamine receptors rather than a direct action on cholinergic receptors which would be due to their anticholinergic activity.     

Role of estrogens in development of prostate cancer

Estrogens have previously been extensively used in prostate cancer treatment. Serious side effects, primarily in cardiovascular system have, however, limited their use. The therapeutic effect of estrogen in preventing prostate cancer growth was mainly obtained indirectly by feedback inhibition of the hypothalamic release of LRH leading to lowered serum androgen levels and castration like effects. Prostate tissue is also most probably a target for direct regulation by estrogens. Prostate contains estrogen receptor alpha (ERalpha) and beta (ERbeta), which are localized characteristically in stroma and epithelium, respectively. The physiological function of these receptors is not known but there is evidence of the role of estrogens in prostatic carcinogenesis. Developing prostate seems particularly sensitive to increased level of endogenous and/or exogenous estrogens. Perinatal or neonatal exposure of rats and mice to estrogens leads to "imprinting" of prostate associated with increased proliferation, inflammation and dysplastic epithelial changes later in life. Prolonged treatment of adult rodents with estrogens along with androgens also leads to epithelial metaplasia, PIN-like lesions and even adenocarcinoma of prostate speaking for the role of estrogen in prostate cancer development. Recent results concerning antiestrogen inhibition of prostate cancer development beyond PIN-type lesions in transgenic mouse models further suggests a role for estrogens in prostate cancer progression. These results also suggest that direct inhibition of estrogen action at the level of prostate tissue may provide an important novel principle of development of prostate cancer therapies.     

Role of estrogens in adipocyte development and function

Estrogen has historically been viewed as a major regulator of adipose tissue in adult females, but recent work has indicated that estrogen's role in adipose biology may be broader than initially appreciated and has also provided important insights into the mechanism of estrogen effects on adipose tissue. Estrogen has direct effects on adipocytes to inhibit lipogenesis and may also have direct effects on other cellular constituents of adipose tissue, as well as metabolic effects on other target organs that can regulate adipose tissue. Estrogen has central effects on food consumption and energy expenditure that contribute to its overall inhibitory effects on adipose deposition. Estrogen also plays an important role in regulating adipose deposition in males and recently has been shown to be an important factor in the determination of adipocyte number, indicating that it regulates key developmental events in adipogenesis. Although critical questions still remain in our understanding of the overall role of estrogen in adipose tissue, it is clear that estrogen plays a more important role in adipose tissue than originally realized and that it is a major regulator of adipose tissue in both sexes during development and adulthood.     

Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystonia

Background

DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding ε-sarcoglycan (ε-SG); the mouse homolog of this gene is Sgce. Paternally-inherited Sgce heterozygous knockout (Sgce KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of Sgce KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.

Methodology/Principal Findings

The protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in Sgce KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in Sgce KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in Sgce KO mice without altering DAT and D1R. Sgce KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates.

Conclusion/Significance

The results suggest ε-SG may have a role in the regulation of D2R expression. The loss of ε-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in Sgce KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients.