Repeated conditionally automated driving on the road: How do drivers leave the loop over time?

The goal of this on the road driving study was to investigate how drivers adapt their behavior when driving with conditional vehicle automation (SAE L3) on different occasions. Specifically, we focused on changes in how fast drivers took over control from automation and how their gaze off the road changed over time. On each of three consecutive days, 21 participants drove for 50 min, in a conditionally automated vehicle (Wizard of Oz methodology), on a typical German commuting highway. Over these rides the take-over behavior and gaze behavior were analyzed. The data show that drivers' reactions to non-critical, system initiated, take-overs took about 5.62 s and did not change within individual rides, but on average became 0.72 s faster over the three rides. After these self-paced take-over requests a final urgent take-over request was issued at the end of the third ride. In this scenario participants took over rapidly with an average of 5.28 s. This urgent take-over time was not found to be different from the self-paced take-over requests in the same ride. Regarding gaze behavior, participants' overall longest glance off the road and the percentage of time looked off the road increased within each ride, but stayed stable over the three rides. Taken together, our results suggest that drivers regularly leave the loop by gazing off the road, but multiple exposures to take-over situations in automated driving allow drivers to come back into loop faster.

Keeping the driver in the loop through semi-automated or manual lane changes in conditionally automated driving.

In the current study we investigated if drivers of conditionally automated vehicles can be kept in the loop through lane change maneuvers. More specifically, we examined whether involving drivers in lane-changes during a conditionally automated ride can influence critical take-over behavior and keep drivers' gaze on the road. In a repeated measures driving simulator study (n = 85), drivers drove the same route three times, each trial containing four lane changes that were all either (1) automated, (2) semi-automated or (3) manual. Each ride ended with a critical take-over situation that could be solved by braking and/or steering. Critical take-over reactions were analyzed with a linear mixed model and parametric accelerated failure time survival analysis. As expected, semi-automated and manual lane changes throughout the ride led to 13.5% and 17.0% faster maximum deceleration compared to automated lane changes. Additionally, semi-automated and manual lane changes improved the quality of the take-over by significantly decreasing standard deviation of the steering wheel angle. Unexpectedly, drivers in the semi-automated condition were slowest to start the braking maneuver. This may have been caused by the drivers' confusion as to how the semi-automated system would react. Additionally, the percentage gaze off-the-road was significantly decreased by the semi-automated (6.0%) and manual (6.6%) lane changes. Taken together, the results suggest that semi-automated and manual transitions may be an alarm-free instrument which developers could use to help maintain drivers' perception-action loop and improve automated driving safety.

Development of an Age Band on the ManuVis for 3-Year-Old Children with Visual Impairments.

AIM: To compare fine motor performance of 3-year-old children with visual impairment with peers having normal vision, to provide reference scores for 3-year-old children with visual impairment on the ManuVis, and to assess inter-rater reliability. METHOD: 26 children with visual impairment (mean age: 3 years 7 months (SD 3 months); 17 boys) and 28 children with normal vision (mean age: 3 years 7 months (SD 4 months); 14 boys) participated in the study. The ManuVis age band for 3-year-old children comprised two one-handed tasks, two two-handed tasks, and a pre-writing task. RESULTS: Children with visual impairment needed more time on all tasks (p < .01) and performed the pre-writing task less accurately than children with normal vision (p < .001). Children aged 42-47 months performed significantly faster on two tasks and had better total scores than children aged 36-41 months (p < .05). Inter-rater reliability was excellent (Intra-class Correlation Coefficient = 0.96-0.99). CONCLUSIONS: The ManuVis age band for 3-year-old children is appropriate to assess fine motor skills, and is sensitive to differences between children with visual impairment and normal vision and between half-year age groups. Reference scores are provided for 3-year-old children with visual impairment to identify delayed fine motor development.

A trade-off study revealing nested timescales of constraint.

This study investigates human performance in a cyclic Fitts task at three different scales of observation, either in the presence (difficult condition) or in the absence (easy condition) of a speed-accuracy trade-off. At the fastest scale, the harmonicity of the back and forth movements, which reflects the dissipation of mechanical energy, was measured within the timeframe of single trials. At an intermediate scale, speed and accuracy measures were determined over a trial. The slowest scale pertains to the temporal structure of movement variability, which evolves over multiple trials. In the difficult condition, reliable correlations across each of the measures corroborated a coupling of nested scales of performance. Participants who predominantly emphasized the speed-side of the trade-off (despite the instruction to be both fast and accurate) produced more harmonic movements and clearer 1/f scaling in the produced movement time series, but were less accurate and produced more random variability in the produced movement amplitudes (vice versa for more accurate participants). This implied that speed-accuracy trade-off was accompanied by a trade-off between temporal and spatial streams of 1/f scaling, as confirmed by entropy measures. In the easy condition, however, no trade-offs nor couplings among scales of performance were observed. Together, these results suggest that 1/f scaling is more than just a byproduct of cognition. These findings rather support the claim that interaction-dominant dynamics constitute a coordinative basis for goal-directed behavior.

An interaction-dominant perspective on reading fluency and dyslexia.

The background noise of response times is often overlooked in scientific inquiries of cognitive performances. However, it is becoming widely acknowledged in psychology, medicine, physiology, physics, and beyond that temporal patterns of variability constitute a rich source of information. Here, we introduce two complexity measures (1/f scaling and recurrence quantification analysis) that employ background noise as metrics of reading fluency. These measures gauge the extent of interdependence across, rather than within, cognitive components. In this study, we investigated dyslexic and non-dyslexic word-naming performance in beginning readers and observed that these complexity metrics differentiate reliably between dyslexic and average response times and correlate strongly with the severity of the reading impairment. The direction of change in the introduced metrics suggests that developmental dyslexia resides from dynamical instabilities in the coordination among the many components necessary to read, which could explain why dyslexic readers score below average on so many distinct tasks and modalities.

Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation.

BACKGROUND: Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood. METHODS: We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice. RESULTS: Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice. CONCLUSION: This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development.

Does sample rate introduce an artifact in spectral analysis of continuous processes?

Spectral analysis is a widely used method to estimate 1/f(α) noise in behavioral and physiological data series. The aim of this paper is to achieve a more solid appreciation for the effects of periodic sampling on the outcomes of spectral analysis. It is shown that spectral analysis is biased by the choice of sample rate because denser sampling comes with lower amplitude fluctuations at the highest frequencies. Here we introduce an analytical strategy that compensates for this effect by focusing on a fixed amount, rather than a fixed percentage of the lowest frequencies in a power spectrum. Using this strategy, estimates of the degree of 1/f(α) noise become robust against sample rate conversion and more sensitive overall. Altogether, the present contribution may shed new light on known discrepancies in the psychological literature on 1/f(α) noise, and may provide a means to achieve a more solid framework for 1/f(α) noise in continuous processes.

Improvement of fine motor skills in children with visual impairment: an explorative study.

In this study we analysed the potential spin-off of magnifier training on the fine-motor skills of visually impaired children. The fine-motor skills of 4- and 5-year-old visually impaired children were assessed using the manual skills test for children (6-12 years) with a visual impairment (ManuVis) and movement assessment for children (Movement ABC), before and after receiving a 12-sessions training within a 6-weeks period. The training was designed to practice the use of a stand magnifier, as part of a larger research project on low-vision aids. In this study, fifteen children trained with a magnifier; seven without. Sixteen children had nystagmus. In this group head orientation (ocular torticollis) was monitored. Results showed an age-related progress in children's fine-motor skills after the training, irrespective of magnifier condition: performance speed of the ManuVis items went from 333.4s to 273.6s on average. Accuracy in the writing tasks also increased. Finally, for the children with nystagmus, an increase of ocular torticollis was found. These results suggest a careful reconsideration of which intervention is most effective for enhancing perceptuomotor performance in visually impaired children: specific 'fine-motor' training or 'non-specific' visual-attention training with a magnifier.

Low vision aids for visually impaired children: a perception-action perspective.

It is a widely accepted belief in clinical practice that children with a visual impairment can profit from the use of a low vision aid (LVA). However, we found a considerable gap in our scientific understanding of LVA use, particularly in young children. This is the reason for the analysis presented in this paper. A selected overview of LVA use in adults is given, from which valuable insights are taken. Additionally, an action perspective for analysing LVA use is discussed as well as the results of tool-use studies in children. Mainly based on these three ingredients, we developed a conceptual framework for LVA use. The framework consists of three interacting relations between LVA, child and task. Performance of a particular child on a specific task with a certain LVA is constrained by the following three reciprocal and dynamic relations: the Child-to-Task relation (related to goal-information), the Child-to-LVA relation (related to control-information), and the LVA-to-Task relation (related to topology information).

The effects of benzodiazepines on human opioid receptor binding and function.

UNLABELLED: We performed in vitro studies to investigate the potential interaction of benzodiazepines with cloned human opioid receptor subtypes. Midazolam, chlordiazepoxide, and diazepam directly displaced [(3)H]-diprenorphine binding from kappa and delta receptors, but not mu receptors, whereas flumazenil was inactive. These benzodiazepines also stimulated (35)S-GTPgammaS binding in membranes containing human kappa receptors, and the effect of midazolam was prevented by a selective kappa antagonist. Midazolam was also weakly active at delta-receptor activation, whereas all three were inactive at mu receptors. The results suggest that the analgesic efficacy reported for intrathecal benzodiazepines may be attributed, in part, to direct interaction with kappa-opioid receptors. IMPLICATIONS: Several human and animal studies have shown analgesic effects of benzodiazepines after spinal injection. Our results show that large concentrations of midazolam, chlordiazepoxide, and diazepam displace the binding of [(3)H]-diprenorphine-an opiate radioligand from kappa receptors. In an in vitro functional assay, midazolam is a weak agonist at the delta-opioid receptor, whereas all three benzodiazepines are kappa-opioid agonists. These findings may partially explain the mechanism of benzodiazepine-induced spinal analgesia.

Preclinical neurochemical and electrophysiological profile of 1192U90, a potential antipsychotic.

11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.

The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.

The putative dopamine D3 receptor agonist 7-OH-DPAT: lack of mesolimbic selectivity.

7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), an agonist with relative selectivity for the dopamine D3 receptor, was examined in several electrophysiological assays to determine whether it exhibits preferential effects in the mesolimbic versus nigrostriatal dopamine systems. Extracellular single unit activities of substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine neurons, and caudate-putamen and nucleus accumbens neurons, were recorded in male rats anesthetized with chloral hydrate. Intravenous (+/-)-7-OH-DPAT potently and completely inhibited the firing of both A9 and A10 dopamine neurons (ED50's: 3.5 +/- 0.7 micrograms/kg and 3.9 +/- 0.9 micrograms/kg, respectively). The active enantiomer, (+)-7-OH-DPAT, was 2 to 3 times more potent than the racemic drug (ED50's: 1.2 +/- 0.3 micrograms/kg and 1.7 +/- 0.4 micrograms/kg for A9 and A10 cells, respectively). There were no significant differences in potency for either form in inhibiting A9 and A10 dopamine neurons. In other studies, iontophoretically applied (+)-7-OH-DPAT caused current-dependent inhibitions of spontaneously active or glutamate-driven caudate-putamen and nucleus accumbens neurons (I50 values, 6.5 and 7.9 nA, respectively). Again, no difference in potency between cell populations was noted. Finally, in cell-attached patch-clamp recordings from freshly dissociated rat caudate-putamen neurons, an 85 pS K+ channel known to be activated by dopamine and the "D2-like" agonist quinpirole was also observed with (+/-)-7-OH-DPAT (0.2-1 microM) applied in the patch pipette.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism.

Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists.

Previous studies [Meller et al. (1990) Mol. Pharmacol., 37:231-237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5-HT1A receptor activation, i.e., the inhibition of dorsal raphe cell firing. Intravenous dose-response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg, s.c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 micrograms/kg, 8-OH-DPAT; 30.0 micrograms/kg, ipsapirone; 17.5 micrograms/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose-response curves were shifted to the right (ED50's: 10.1 micrograms/kg, 6.7-fold shift, 8-OH-DPAT; 139.9 micrograms/kg, 4.7-fold shift, ipsapirone; 53.8 micrograms/kg, 3.1-fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8-OH-DPAT > ipsapirone > BMY 7378), a large (> 50%) receptor reserve was estimated for all three drugs in this electrophysiological system.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of substantia nigra dopamine cell firing by R(-)-N-n-propylnorapomorphine: electrophysiological and autoradiographic studies after regional inactivation of dopamine receptors by microinjection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

The irreversible receptor inactivator, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), was injected into rat striatum or substantia nigra to study potential contributions of dopamine receptors in each area to the inhibition of substantia nigra (A9) dopamine cell firing by i.v. R(-)-N-n-propylnorapomorphine (NPA), a dopamine agonist. Extracellular, single unit recording studies showed that the numbers of active dopamine cells, basal firing rates and responses to i.v. R(-)-NPA were unchanged a day after striatal EEDQ injections, despite significant losses of striatal D1 and D2 receptors (confirmed by autoradiography). These results indicate that striatal receptors do not control the basal activity of A9 neurons, nor do they mediate inhibitions of firing by R(-)-NPA. Microinjections of EEDQ into substantia nigra, however, inactivated 75-78% of nigral D1 and D2 receptors and reduced the number of active dopamine cells and slightly increased firing rates. Moreover, dose-response curves to R(-)-NPA were shifted 10-fold to the right and the maximum inhibitory response was depressed. Furchgott analysis of the dose-response curves yielded a steep occupancy-response curve with maximum (> 95%) inhibition of firing at only 24% receptor occupation (i.e., 76% reserve). Thus, the substantial (approximately 70%) receptor reserve previously shown to exist for inhibition of dopamine cell firing by i.v. R(-)-NPA20,21 appears to be intrinsic to the nigra. To assess contributions of nigral D1 and D2 receptors to this response, selective inactivation of each receptor subtype was achieved (confirmed autoradiographically) by treating rats with SCH 23390 (4 mg/kg) or S(-)eticlopride (2 mg/kg), respectively, 30 min before intranigral EEDQ. Selective D2, but not D1, receptor inactivation produced rightward shifts and depressed the maximum of the R(-)-NPA dose-response curve in a manner like that observed after non-selective inactivation of nigral dopamine receptors. Unexpectedly, pretreatment with SCH 23390 (to protect D1 receptors) also produced a modest rightward shift in the R(-)-NPA dose-response curve, suggesting a slight role for D1 receptors in this response. These results indicate that inhibition of A9 dopamine cell firing by i.v. R(-)-NPA is mediated by dopamine receptors located in substantia nigra, but not striatum and confirm the predominant role of nigral D2 receptors.

Autoradiography of dopamine D2 receptors using [3H]YM-09151-2.

Rat brain dopamine D2 receptors were labeled autoradiographically using the potent and selective benzamide, [3H]YM-09151-2. Saturation binding data, quantified from autoradiograms, showed specific binding of [3H]YM-09151-2 to striatal D2 receptors with a KD of 82 pM and Bmax of 0.696 pmol/mg protein. Binding equilibrium occurred within 3 h, and a dissociation constant of 15 pM was obtained in kinetic studies. Antagonist competition curves were monophasic and displayed an order of potency expected for D2 receptors: (+)-butaclamol greater than (-)-sulpiride greater than SCH 23390 greater than mianserin. Competition by dopamine resulted in a shallow, biphasic displacement curve. The distribution of [3H]YM-09151-2 binding sites matched the known pattern for D2 receptors, with dense labeling in striatum, olfactory tubercles and nucleus accumbens, and moderate levels in substantia nigra pars compacta and mamillary nuclei. Much lower levels of non-specific binding were observed than are typically obtained when using [3H]spiperone as the ligand. The coincident high affinity and selectivity of [3H]YM-09151-2 for D2 sites should make this compound a preferred choice for tritium-based D2 autoradiography.

Irreversible receptor inactivation reveals differences in dopamine receptor reserve between A9 and A10 dopamine systems: an electrophysiological analysis.

Partial receptor inactivation was used as a tool to examine whether differences in receptor reserve exist between the dopamine receptor populations which mediate responses of substantia nigra (A9) and ventral tegmental area (A10) dopamine neurons to dopamine agonist drugs. The irreversible receptor inactivator, N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ), was administered to rats intraperitoneally at a dose of 6 mg/kg (in an ethanol-water vehicle). Approximately 24 h after EEDQ treatments, extracellular, single-unit recording experiments were carried out. In the first series of experiments, dose-response curves were constructed for the inhibition of A9 and A10 dopamine cell firing by intravenous administration of the potent dopamine agonist, R-(-)-N-n-propylnorapomorphine (NPA). For the A9 dopamine cell group, EEDQ pretreatments caused a 3-fold rightward shift in the NPA dose-response curve (ED50S, 0.3 vs 0.8 micrograms/kg for vehicle- and EEDQ-treated rats, respectively), but there was no change in the maximum attainable response (greater than 95% inhibition of cell firing). For A10 neurons, the same EEDQ treatments produced a greater rightward shift in the dose-response curve to NPA (ED50s, 0.6 vs 5.4 micrograms/kg for vehicle- and EEDQ-treated rats), and also depressed the maximum response by about 25% relative to the control (vehicle) curve. The dose-response curves from each region were subjected to Furchgott analysis to determine relative receptor occupancy-response relationships for NPA. For the A9 system, a steep, hyperbolic occupancy-response plot revealed that a 50% inhibitory response required only 4% receptor occupancy, while complete (greater than 95%) inhibition of cell firing required about 30% occupancy. This suggests about a 70% receptor reserve for this agonist in inhibiting A9 dopamine cell firing. The occupancy-response curve for A10 cells was less steep with 50% and maximal (greater than 95%) responses occurring when 11 and 70% of receptors were occupied by the agonist, indicating only about a 30% reserve for A10 cell responses to NPA. While the level of 'spare' receptors differed substantially between the two areas, calculated pseudo-KA values were similar (7.7 micrograms/kg for A9 cells and 5.5 micrograms/kg for A10 cells), suggesting no regional differences in receptor affinity. To explore where the differences in receptor reserve might reside, a second series of studies evaluated the effects of iontophoretically applied dopamine and NPA on both cell groups in vehicle- and EEDQ-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)