Outcomes and Costs Following Mini-percutaneous Nephrolithotomy or Flexible Ureteroscopic Lithotripsy for 1-2-cm Renal Stones: Data From a Prospective, Randomized Clinical Trial.

PURPOSE: We evaluate the outcomes of ureteroscopy vs prone mini-percutaneous nephrolithotomy for 1-2-cm renal stones using a 2-group parallel randomized control trial. MATERIALS AND METHODS: Adult patients presenting with renal stones between 1 and 2 cm were randomized. Exclusion criteria included solitary kidney, multiple stones, and comorbidities precluding prone positioning. Block randomization was performed and was opened to the surgeon the morning of the procedure. Stone-free rate was evaluated by computed tomography 1-30 days postoperatively. Complications, re-treatment rates, and costs were evaluated. RESULTS: A total of 51 mini-percutaneous nephrolithotomy and 50 ureteroscopy patients were included. Baseline demographics were similar. Using a 2-mm cutoff, stone-free rate was higher in the mini-percutaneous nephrolithotomy group (76 vs 46%, P = .0023). The residual stone burden was significantly higher in the ureteroscopy group than the mini-percutaneous nephrolithotomy group (3.6 vs 1.4 mm, P = .0026). Fluoroscopy time was significantly higher in the mini-percutaneous nephrolithotomy group (273 vs 49 seconds, P < .0001). There were no differences in postoperative complications within 30 days, the necessity of a secondary procedure within 30 days, and pre- to postoperative creatinine change (P > .05). Surgical time did not vary significantly (P = .1788). Average length of stay was higher in the mini-percutaneous nephrolithotomy group (P < .0001). Both net revenue and direct costs were higher in mini-percutaneous nephrolithotomy procedures (P < .05), though they offset each other with a nonsignificant operating margin (P = .2541). CONCLUSIONS: In a prospective, randomized, controlled clinical trial using a 2-mm residual stone burden cutoff, mini-percutaneous nephrolithotomy was more likely to render patients stone-free than flexible ureteroscopy. Complications, surgical times, and operating margins did not vary between the approaches.

Photothermal nanoparticles for ablation of bacteria associated with kidney stones.

OBJECTIVE: To determine whether photothermal polymer nanoparticles (NPs) can interface with bacteria associated with kidney stones, generate heat when stimulated with near infrared (NIR) light, and aid in reducing bacterial burden. METHODS: Two types of kidney stones, artificial, and those removed during percutaneous nephrolithotomy (PCNL), were inoculated with Escherichia coli (E. coli) and then incubated with NPs composed of FITC-labeled Poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b']-dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe). Association of the PCPDTBSe NPs was evaluated using fluorescence microscopy. Infected stones were incubated with NPs and exposed to 800 nm light to generate temperature increases from 25.4 to 68.6 °C on the stones. Following photothermal treatment, the stones were homogenized and the bacteria was enumerated via colony counting assays to evaluate the bactericidal effect. The photothermal effect was also evaluated using scanning electron microscopy of the treated biofilms. RESULTS: Both kidney stone types sequestered E. coli. Control stones and stones treated with laser only had growth of numerous bacterial colonies, while stones exposed to NPs and laser grew significantly less, or none (p = 0.02). CONCLUSIONS: The polymer NPs interface with E. coli on artificial and patient-derived kidney stones, and they can impart a bactericidal effect, when stimulated with NIR to generate heat. This technique may possibly be extended to treating infected kidney stones in patients.

Can physicians detect hyperkalemia based on the electrocardiogram?

OBJECTIVE: Although there is no consensus on how to use an electrocardiogram (ECG) in patients with hyperkalemia, physicians often obtain it in the acute setting when diagnosing and treating hyperkalemia. The objective of this study is to evaluate if physicians are able to detect hyperkalemia based on the ECG. METHODS: The study was conducted at a large county hospital with a population of end stage renal disease (ESRD) patients who received hemodialysis (HD) solely on an emergent basis. Five hundred twenty eight ECGs from ESRD patients were evaluated. The prevalence of hyperkalemia was approximately 60% in this cohort, with at least half of them in the severe hyperkalemia range (K ≥ 6.5 mEq/L). RESULTS: The mean sensitivity and specificity of the emergency physicians detecting hyperkalemia were 0.19 (± 0.16) and 0.97(± 0.04) respectively. The mean positive predictive value of evaluators for detecting hyperkalemia was 0.92 (±0.13) and the mean negative predictive value was 0.46 (± 0.05). In severe hyperkalemia (K ≥ 6.5 mEq/L), the mean sensitivity improved to 0.29 (± 0.20), while specificity decreased to 0.95 (±0.07). CONCLUSION: An ECG is not a sensitive method of detecting hyperkalemia and should not be relied upon to rule it out. However, the ECG has a high specificity for detecting hyperkalemia and could be used as a rule in test.

The role of extracorporeal shock wave lithotripsy in the future of stone management.

PURPOSE OF REVIEW: The most relevant recent findings on the use of extracorporeal shock wave lithotripsy (ESWL) in adult population to provide an insight of its role in the current and future of stone treatment. Comparing ESWL with other modalities is not in the scope of this review. RECENT FINDINGS: We conducted a PubMed/Embase search and reviewed recent publications that include relevant information on the development of ESWL. Low-rate shock waves improve stone breakage, ramping energy modalities improve stone fragmentation and have lower incidence of hematoma and kidney injury. Transgluteal approach is suggested to improve stone-free rates for distal ureteral stones in a single session. Proper coupling is the most important technical aspect of the treatment and coupling improvement can be achieved by optical monitorization. Triple D score is a promising tool in proper patient selection, but external validation is needed. Predictive information arising from computed tomography scans has been refined by the variant coefficient of stone density and 3D texture analysis that might improve outcomes in the future. SUMMARY: Recent evidence suggests that modifying techniques and protocols, and better patient selection are the current trends for improving ESWL outcomes. EWSL will keep its role as the single noninvasive treatment in stone management with room for outcome improvement in the future.

Evaluation of Renal Function after Percutaneous Nephrolithotomy-Does the Number of Percutaneous Access Tracts Matter?

PURPOSE: Renal function following percutaneous nephrolithotomy has long been a concern to urologists, especially in the setting of multi-tract access. We determined whether the risk of renal injury after multi-tract percutaneous nephrolithotomy was greater than after a single access approach. MATERIALS AND METHODS: We retrospectively reviewed the records of 307 consecutive patients treated with percutaneous nephrolithotomy from 2011 to 2012 at Wake Forest Health. Perioperative (99m)Tc-mercaptoacetyltriglycine nuclear renogram parameters along with serum creatinine values were assessed within 1 year of the procedure. Patients were stratified by single access vs multi-access (2 or more). RESULTS: We identified 110 cases in which renography was done before and after percutaneous nephrolithotomy. A total of 74 patients (67.3%) underwent single access percutaneous nephrolithotomy while 36 (32.7%) underwent multi-access percutaneous nephrolithotomy. Serum creatinine did not significantly differ between the 2 cohorts postoperatively (p = 0.09). There was a significant 2.28% decrease in renal function based on mercaptoacetyltriglycine nuclear renogram results after percutaneous nephrolithotomy of the affected kidney in patients with multiple accesses (p <0.01). This relationship was not observed when patients were stratified by multiple comorbidities associated with nephrolithiasis. CONCLUSIONS: Multi-access percutaneous nephrolithotomy is associated with a small reduction in the function of the targeted kidney compared to a single access approach.

Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its Ca(2+) dependent modulation by CaMKII and calmodulin in striatonigral projections of the rat.

In striatonigral projections activation of dopamine D3 receptors (D3Rs) potentiates the stimulation of GABA release and cAMP production caused by activation of dopamine D1 receptors (D1Rs). Cytoplasmic [Ca(2+)] in the terminals controls this response by modulating CaMKII, an enzyme that depresses D3R action. To examine the effects of dopamine deprivation on D3R signaling we investigated their function in striatonigral terminals of hemiparkinsonian rats. Denervation switched the signaling cascade initiated by D3R activation. In the non-lesioned side activation of D3R potentiated the stimulatory effects of D1R activation on cAMP production and K(+)-depolarization induced [(3)H] GABA release. In contrast, in the denervated side the stimulatory effects of both D1R activation and forskolin administration were blocked by D3R activation. In non-lesioned slices, D3R responses were inhibited by the activation of CaMKII produced by K(+)-depolarization (via increased Ca(2+) entry). The CaMKII-induced inhibition was blocked by the selective inhibitor KN-62. In denervated tissues the response to D3R stimulation was not modified either by K(+) depolarization or by blocking CaMKII with KN-62. Immunoblotting studies showed that depolarization-induced CaMKII binding to the D3 receptor and CaMKII phosphorylation were suppressed in denervated tissues. We also determined calmodulin expression with PCR and immunoblot techniques. Both techniques showed that calmodulin expression was depressed in the lesioned side. In sum, our studies show that dopaminergic denervation switches the D3R signaling cascade and depresses CaMKII signaling through a process that appears to involve reduced calmodulin levels. Since calmodulin is a major cytoplasmic Ca(2+) buffer our findings suggest that abnormal Ca(2+) buffering may be an important component of the abnormalities observed during dopaminergic denervation.

Chronic pramipexole and rasagiline treatment enhances dendritic spine structural neuroplasticity in striatal and prefrontal cortex neurons of rats with bilateral intrastriatal 6-hydroxydopamine lesions.

Parkinson's disease manifests as neurological alterations within dendritic spines in the striatal and neocortical brain regions, where their functionality closely correlates with morphology. However, the impact of current pharmacotherapy on dendritic spine neuroplasticity, crucial for novel drug development in neurological and psychiatric disorders, remains unclear. This study investigated the effects of 6-OHDA intrastriatal bilateral lesions in male adult rats on behavior and dendritic spine neuroplasticity in striatal and cortical neurons. Furthermore, it evaluated the influence of chronic co-administration of pramipexole (PPX), a D3 receptor agonist, and rasagiline (Ras), a selective MAO-B inhibitor, on these alterations. Lesioned animals exhibited impaired balance behavior, with no improvement following PPX-Ras treatment. The 6-OHDA lesion decreased dendritic spine density in caudate putamen (CPU) spiny projection neurons (SPNs), a change unaffected by treatment, though PPX-Ras increased mushroom spines and reduced stubby spines in these neurons. In nucleus accumbens (NAcc) SPNs and prefrontal cortex layer 3 (PFC-3) pyramidal cells, dendritic spine density remained unaltered, but PPX-Ras decreased mushroom spines and increased bifurcated spines in the NAcc, while increasing mushroom spines and decreasing stubby spines in PFC-3 in lesioned rats. These findings emphasize the importance of dendritic spines as promising targets for innovative pharmacotherapies for Parkinson's disease.

Transfection of the BDNF Gene in the Surviving Dopamine Neurons in Conjunction with Continuous Administration of Pramipexole Restores Normal Motor Behavior in a Bilateral Rat Model of Parkinson's Disease.

In Parkinson's disease (PD), progressive degeneration of nigrostriatal innervation leads to atrophy and loss of dendritic spines of striatal medium spiny neurons (MSNs). The loss disrupts corticostriatal transmission, impairs motor behavior, and produces nonmotor symptoms. Nigral neurons express brain-derived neurotropic factor (BDNF) and dopamine D3 receptors, both protecting the dopamine neurons and the spines of MSNs. To restore motor and nonmotor symptoms to normality, we assessed a combined therapy in a bilateral rat Parkinson's model, with only 30% of surviving neurons. The preferential D3 agonist pramipexole (PPX) was infused for four ½ months via mini-osmotic pumps and one month after PPX initiation; the BDNF-gene was transfected into the surviving nigral cells using the nonviral transfection NTS-polyplex vector. Overexpression of the BDNF-gene associated with continuous PPX infusion restored motor coordination, balance, normal gait, and working memory. Recovery was also related to the restoration of the average number of dendritic spines of the striatal projection neurons and the number of TH-positive neurons of the substantia nigra and ventral tegmental area. These positive results could pave the way for further clinical research into this promising therapy.

Endoscopic Stone Composition Identification: Is Accuracy Improved by Stone Appearance During Laser Lithotripsy?

OBJECTIVE: To evaluate if videos during laser lithotripsy increase accuracy and confidence of stone identification by urologists compared to still pictures. METHODS: We obtained representative pictures and videos of 4 major stone types from 8 different patients during ureteroscopy with holmium laser lithotripsy. A REDCap survey was created and emailed to members of the Endourological Society. The survey included a picture followed by the corresponding video of each stone undergoing laser lithotripsy and additional clinical information. Each picture and video included multiple-choice questions about stone composition and response confidence level. Accuracy, confidence levels, and rates of rectification (change from incorrect to correct answer) or confounding (correct to incorrect) after watching videos were analyzed. RESULTS: One hundred eighty-seven urologists responded to the survey. The accuracy rate of stone identification with pictures was 43.8% vs 46.1% with videos (P = .27). Accuracy for individual stones was low and highly variable. Video only improved accuracy for 1 cystine stone. After viewing videos, participants were more likely to rectify vs confound their answers. Urologists were more likely to be confident with videos than pictures alone (65.4% vs 53.7%, respectively; P <.001); however, confident answers were not more likely to yield accurate predictions with videos vs still pictures. CONCLUSION: Stone identification by urologists is marginally improved with videos vs pictures alone. Overall, accuracy in stone identification is low irrespective of confidence level, picture, and lithotripsy video visualization. Urologists should be cautious in using endoscopic stone appearance to direct metabolic management.

Comparative outcomes and cost of ambulatory PCNL in select kidney stone patients.

Limited hospital resources and access to care during the COVID-19 pandemic led us to implement a quality-improvement study investigating the feasibility, safety, and costs of same-day discharge after PCNL. The outcomes of 53 consecutive first-look PCNL patients included in a same-day discharge protocol during COVID-19 were compared to 54 first-look PCNL patients admitted for overnight observation. Control group had a similar comorbidity profile. Demographics, operative details, 30 day outcomes and readmissions, complications, and cost were compared between the two groups. Same-day discharge and one-day admission post-PCNL patients did not have significantly different baseline characteristics. The study group were more likely to have mini-PCNL (81% vs 50%, p < 0.01). Operative characteristics including median pre-operative stone burden (1.4 vs 1.7 cm3, p = 0.47) and post-operative stone burden (0.14 vs 0.18 cm3, p = 0.061) were similar between the two groups. Clavien-Dindo complication rates were lower in the study group compared to controls (0 vs 7%, p = 0.045). Readmission rates (2 vs 4%, p = 0.569) and ED visits (4 vs 6%, p = 0.662) were similar between the two groups. Total cost ($6,648.92 vs $9,466.07, p < 0.01) was significantly lower and operating margin ($4,475.96 vs $1,742.16, p < 0.01) was significantly higher for the same-day discharge group. Percutaneous nephrolithotomy may be performed in select patients without an increase in short-term complications, ED visits, or readmissions. Patients undergoing mini-PCNL are particularly amenable to same-day discharge, however, standard PCNL patients should not be excluded from consideration. Avoiding overnight admission decreases total cost and increased hospital operating margin.

A PEDOT nano-composite for hyperthermia and elimination of urological bacteria.

Novel modalities for overcoming recurrent urinary tract infections associated with indwelling urinary catheters are needed, and rapidly induced hyperthermia is one potential solution. PEDOT nanotubes are a class of photothermal particles that can easily be incorporated into silicone to produce thin, uniform coating on medical grade silicone catheters; subsequent laser stimulation therein imparts temperature elevations that can eliminate bacteria and biofilms. PEDOT silicone coatings are stable following thermal sterilization and repeated heating and cooling cycles. Laser stimulation can induce temperature increases of up to 55 °C in 300 s, but only 45 s was needed for ablation of UTI inducing E. coli biofilms in vitro. This work also demonstrates that mild hyperthermia of 50 °C, applied for only 31 s in the presence of antibiotics could eliminate E. coli biofilm as effectively as high temperatures. This work culminates in the evaluation of the PEDOT NTs for photothermal elimination of E. coli in an in vivo model to demonstrate the safety and effectiveness of a photothermal nanocomposite (16 s treatment time) for rapid clearance of E. coli.

L-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata.

L-DOPA treatment induces abnormal involuntary movements (AIMs) in Parkinson's patients and experimental animals. We examined the relationship between the development of AIMs (dyskinesia) and changes in [(3)H]-GABA release and cAMP signaling in striatonigral terminals of rats with unilateral 6-OHDA lesions. Analysis of AIMs scores in hemiparkinsonian rats treated with L-DOPA for 20 days was fitted by the sum of two Gaussian distributions showing the presence of two populations: one with mild and the other with severe dyskinesia. cAMP signaling was evaluated in the two populations by determining changes in cAMP formation, Gα(olf) and adenylyl cyclase type V/VI levels. In animals that were not treated with L-DOPA, all the parameters were significantly increased in the denervated side. In the animals that had mild dyskinesia, L-DOPA treatment normalized these parameters. In contrast, in the animals in which l-DOPA treatment induced severe dyskinesia all the parameters, except for Gα(olf) levels, were significantly higher in the denervated side. Similarly, D1-stimulated [(3)H]-GABA release was not elevated in L-DOPA-treated animals with mild dyskinesia but was increased in animals with severe dyskinesia. Changes in Gα(olf) and adenylyl cyclase type V/VI levels in the striatum paralleled the response in the SNr. The linkage between the changes in [(3)H]-GABA release and cAMP activity was further evaluated with the selective adenylyl cyclase V/VI antagonist NKY80. This inhibitor blocked the increases of both [(3)H]-GABA release and cAMP production. These results indicate that increased expression of adenylyl cyclase V/VI is a major determinant of increased GABAergic transmission in the substantia nigra pars reticulata of animals in which L-DOPA induces severe dyskinesia.

Preoperative imaging in staghorn calculi, planning and decision making in management of staghorn calculi.

OBJECTIVE: Staghorn calculi present a particular and challenging entity of stone morphology. Treatment is associated with lower stone-free rates and higher complication rates compared to non-staghorn stones. In this review we looked for the most relevant data on preoperative imaging and access planning to help decision making for percutaneous surgery with this complex condition. METHODS: We conducted a PubMed search of publications in the past 2 decades that include relevant information on the planning for management of staghorn stones. Non-contrast computerized tomography (NCCT) is indeed the standard imaging tool for percutaneous nephrolithotomy (PCNL); additional tools such as three-dimensional computed tomography (CT) reconstruction of the staghorn calculus may help plan access in complex cases. Ultrasound guided percutaneous access may be considered for staghorn stones when planning upper pole access in kidney malposition or complex intrarenal anatomy or with complex body habitus. Wideband doppler ultrasound and real-time virtual sonography can assist. New technologies to improve kidney access such as Uro Dyna-CT or electromagnetic sensor have been reported, but have not shown utilization in staghorn cases. Staghorn morphometry-based prediction algorithms may predict the number of tract(s) and stage(s) for PCNL monotherapy. Lower pole access can be equally effective as upper pole when planning for staghorn and complex stones, with significantly less complications rate; Stone-Tract length-Obstruction-Number of involved calyces-Essence of stone density (STONE) nephrolithometry seems to be the best system to predict outcomes of PCNL in staghorn cases. There is a growing trend of endoscopic combined intrarenal surgery (ECIRS) in concordance with PCNL to treat larger stones. Conservative management of staghorn calculi is an undesired option, but can be an alternative for a carefully selected group of high-risk patients. CONCLUSION: Staghorn stones may lead to deterioration of renal function and life-threatening urosepsis. This entity should be managed aggressively with planning ahead for surgery using the different tools available as the cornerstone for a successful outcome.

Cannabinoid agonists stimulate [3H]GABA release in the globus pallidus of the rat when G(i) protein-receptor coupling is restricted: role of dopamine D2 receptors.

The motor effects of cannabinoids in the globus pallidus appear to be caused by increases in interstitial GABA. To elucidate the mechanism of this response, we investigated the effect of the selective cannabinoid type 1 receptor (CB1) cannabinoid agonist arachidonyl-2-chloroethylamide (ACEA) on [(3)H]GABA release in slices of the rat globus pallidus. ACEA had two effects: concentrations between 10(-8) and 10(-6) M stimulated release, whereas higher concentrations (IC(50) approximately 10(-6) M) inhibited it. Another cannabinoid agonist, WIN-55,212-2, also had bimodal effects on release. Studies of cAMP production indicate that under conditions of low G(i/o), availability the coupling of CB1 receptors with G(i/o) proteins can be changed into CB1:G(s/olf) coupling; therefore, we determined the effects of conditions that limit G(i/o) availability on [(3)H]GABA release. Blockers of G(i/o) protein interactions, pertussis toxin and N-ethylmaleimide, transformed the inhibitory effects of ACEA on GABA release into stimulation. It also has been suggested that stimulation of D2 receptors can reduce G(i/o) availability. Blocking D2 receptors with sulpiride [(S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamidersqb] or depleting dopamine with reserpine inhibited the ACEA-induced stimulation of release. Thus, the D2 dependence of stimulation is consistent with the proposal that D2 receptors reduce G(i/o) proteins available for binding to the CB1 receptor. In summary, CB1 receptor activation has dual effects on GABA release in the globus pallidus. Low concentrations stimulate release through a process that depends on activation of dopamine D2 receptors that may limit G(i/o) protein availability. Higher concentrations of cannabinoid inhibit GABA release through mechanisms that are independent of D2 receptor activation.

Presynaptic control of [3H]-glutamate release by dopamine receptor subtypes in the rat substantia nigra. Central role of D1 and D3 receptors.

Substantia nigra pars reticulata is the output station in basal ganglia; its GABAergic neurons control the activity of thalamo-cortical premotor nuclei, thus controlling motor behavior. D1-like and D2-like presynaptic dopamine receptors on subthalamo-nigral afferents by modulation of glutamate release change the firing rate of nigral neurons; however, their relative contribution to the control of glutamate release and their pharmacological properties have not been studied. This is important since the prevalence of the inhibition or stimulation of release determines the firing rate of nigral neurons, therefore motor activity. Here we used depolarization induced [3H]-glutamate release in slices of rat substantia nigra from reserpinized and non-reserpinized rats to explore the relative contribution of the D1-like and D2-like receptor subtypes to the control of glutamate release. We found a significant control of release by D1-like and D3R, and a modest effect of D2R. D4R exerted no effect. Dopamine showed more potency for D3R than for D1-like receptors; however, these latter enhanced release to a greater degree, as shown by the Emax. We also co-activated these to test their interaction; an antagonist interaction of D1-like with D2 and D3R, and an additive between D2 and D3R were found. Pharmacological receptor antagonist effects in release from reserpinized vs. non-reserpinized slices were similar, suggesting that endogenous dopamine stimulates receptors in the same way. These findings suggest differences in the control of glutamate release by different dopamine receptors in the substantia nigra, which could contribute to explaining the effect of dopamine and its agonists on motor behavior.

Blockade of Intranigral and Systemic D3 Receptors Stimulates Motor Activity in the Rat Promoting a Reciprocal Interaction among Glutamate, Dopamine, and GABA.

In vivo activation of dopamine D3 receptors (D3Rs) depresses motor activity. D3Rs are widely expressed in subthalamic, striatal, and dendritic dopaminergic inputs into the substantia nigra pars reticulata (SNr). In vitro studies showed that nigral D3Rs modulate their neurotransmitter release; thus, it could be that these changes in neurotransmitter levels modify the discharge of nigro-thalamic neurons and, therefore, motor behavior. To determine how the in vitro responses correspond to the in vivo responses, we examined the effect of intra-nigral and systemic blockade of D3Rs in the interstitial content of glutamate, dopamine, and GABA within the SNr using microdialysis coupled to motor activity determinations in freely moving rats. Intranigral unilateral blockade of D3R with GR 103,691 increased glutamate, dopamine, and GABA. Increments correlated with increased ambulatory distance, non-ambulatory activity, and induced contralateral turning. Concomitant blockade of D3R with D1R by perfusion of SCH 23390 reduced the increase of glutamate; prevented the increment of GABA, but not of dopamine; and abolished behavioral effects. Glutamate stimulates dopamine release by NMDA receptors, while blockade with kynurenic acid prevented the increase in dopamine and, in turn, of GABA and glutamate. Finally, systemic administration of D3R selective antagonist U 99194A increased glutamate, dopamine, and GABA in SNr and stimulated motor activity. Blockade of intra-nigral D1R with SCH 23390 prior to systemic U 99194A diminished increases in neurotransmitter levels and locomotor activity. These data highlight the pivotal role of presynaptic nigral D3 and D1R in the control of motor activity and help to explain part of the effects of the in vivo administration of D3R agents.