Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. (65/551)

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.  (+info)

New oral agents for erectile dysfunction: what is changing in our practice? (66/551)

Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i. e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.  (+info)

Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats. (67/551)

In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.  (+info)

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. (68/551)

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.  (+info)

Increased burst firing in substantia nigra pars reticulata neurons and enhanced response to selective D2 agonist in hemiparkinsonian rats after repeated administration of apomorphine. (69/551)

Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, intraperitoneal, i.p.) twice daily for 6 days enhanced the rotation induced by apomorphine from 341 turns/hour at the beginning to 755 turns/hr at the end. At the same time, the response to selective D2 agonist quinpirole (0.26 mg/kg, i.p.) was also enhanced from 203 to 555 turns/hr. Extracellular single unit recording revealed no significant difference in the basal firing rates of substantia nigra pars reticulata (SNr) neurons between the ipsilateral and contralateral side of the 6-OHDA lesion regardless of the repeated administrations of apomorphine. In SNr of the lesion side, the units with burst firing pattern were found more frequently after repeated administrations of apomorphine and the suppressive effect of quinpirole on the firing rate was enhanced. These findings suggest that the increased percentage of the burst units is the important electrophysiological change in the development of enhanced response to selective D2 agonist.  (+info)

Agonist-independent and -dependent oligomerization of dopamine D(2) receptors by fusion to fluorescent proteins. (70/551)

Oligomerization of the short (D(2S)) and long (D(2L)) isoforms of the dopamine D(2) receptor was explored in transfected Cos-7 cells by their C-terminal fusion to either an enhanced cyan or enhanced yellow fluorescent protein (ECFP or EYFP) and the fluorescent fusion protein interaction was monitored by a fluorescence resonance energy transfer (FRET) assay. The pharmacological properties of the fluorescent fusion proteins, as measured by both displacement of [(3)H]nemonapride binding and agonist-mediated stimulation of [(35)S]GTPgammaS binding upon co-expression with a G(alphao)Cys(351)Ile protein, were not different from the respective wild-type D(2S) and D(2L) receptors. Co-expression of D2S:ECFP+D2S:EYFP in a 1:1 ratio and D2L:ECFP+D2L:EYFP in a 27:1 ratio resulted, respectively, in an increase of 26% and 16% in the EYFP-specific fluorescent signal. These data are consistent with a close proximity of both D(2S) and D(2L) receptor pairs of fluorescent fusion proteins in the absence of ligand. The agonist-independent D(2S) receptor oligomerization could be attenuated by co-expression with either a wild-type, non-fluorescent D(2S) or D(2L) receptor subtype, but not with a distinct beta(2)-adrenoceptor. Incubation with the agonist (-)-norpropylapomorphine dose-dependently (EC(50): 0.23+/-0.06 nM) increased the FRET signal for the co-expression of D2S:ECFP and D2S:EYFP, in support of agonist-dependent D(2S) receptor oligomerization. In conclusion, our data strongly suggest the occurrence of dopamine D(2) receptor oligomers in intact Cos-7 cells.  (+info)

Effects of apomorphine, ergocornine and piribedil on audiogenic seizures in DBA/2 mice. (71/551)

Audiogenic seizures in DBA/2 mice have been studied after administration of drugs believed to act as dopamine agonists. Apomorphine at 0.4 mg/kg delays all phases of the response, the tonic phase is absent after 2.0 mg/kg; the clonic phase is abolished by 10 mg/kg. Ergocornine (0.5-8.0 mg/kg) produces effects on the latency and occurrence of seizure stages similar to those of apomorphine. Piribedil, ET 495 (4-100 mg/kg) is less potent; even after 100 mg/kg clonic and tonic phases occurred in 50% of the mice.  (+info)

Conditioning taste aversions to locoweed (Oxytropis sericea) in horses. (72/551)

Locoweed (Oxytropis sericea) is a serious poisoning problem for horses grazing on infested rangelands in the western United States. Our objectives were to determine 1) whether lithium chloride or apomorphine would condition aversions to palatable foods, and at what doses, and 2) whether horses could be averted to fresh locoweed in a pen and grazing situation. Apomorphine was not an acceptable aversive agent because at the dose required to condition an aversion (> or = 0.17 mg/kg BW), apomorphine induced unacceptable behavioral effects. Lithium chloride given via stomach tube at 190 mg/kg BW conditioned strong and persistent aversions to palatable feeds with minor signs of distress. Pen and grazing tests were conducted in Colorado to determine if horses could be averted to fresh locoweed. Pen tests indicated that most horses (5/6) were completely averted from locoweed. Treated horses ate 34 g of fresh locoweed compared to 135 g for controls (P < 0.01) during three pen tests when offered 150 g per test. One horse (T) in the treatment group ate locoweed each time it was offered in the pen, but ate no locoweed while grazing. In the grazing trial, control horses averaged 8.6% of bites of locoweed (P < 0.01) during the grazing portion of the study, whereas treated horses averaged <0.5%. One treated horse (S) accounted for all consumption; he consumed 15% of his bites as locoweed in a grazing bout on d 2 of the field study. Thereafter, he was dosed a second time with lithium chloride and ate no locoweed in the subsequent 5 d. Three of six horses required two pairings of lithium chloride with fresh locoweed to condition a complete aversion. The results of this study indicate that horses can be averted from locoweed using lithium chloride as an aversive agent, and this may provide a management tool to reduce the risk of intoxication for horses grazing locoweed-infested rangeland.  (+info)