Cure with ledipasvir/sofosbuvir for chronic hepatitis C virus in an individual with gastric bypass.

WHAT IS KNOWN AND OBJECTIVE: The impact of gastric bypass surgery on the pharmacokinetics of various medications has been reported. Presently, no data exist for the treatment of chronic hepatitis C virus with ledipasvir/sofosbuvir (LDV/SOF) in an individual with a history of gastric bypass. CASE DESCRIPTION: We report the successful cure of an individual who was treated with LDV/SOF who had a history of gastric bypass. The patient tolerated LDV/SOF well while only experiencing a minor headache. WHAT IS NEW AND CONCLUSION: Ledipasvir/sofosbuvir treatment may still be effective in those with a history of gastric bypass surgery.

Curing the historically incurable: treatment success with ledipasvir/sofosbuvir for chronic hepatitis C virus in a heavily treatment-experienced individual.

WHAT IS KNOWN AND OBJECTIVE: Significant progression in the treatment of chronic hepatitis C virus has been made with the introduction of direct-acting antivirals (DAAs). However, limited data are available for the retreatment of individuals who have failed multiple prior DAAs. CASE DESCRIPTION: We report a single case of an individual who was unsuccessfully treated with five prior hepatitis C virus treatment regimens including simeprevir plus sofosbuvir who was successfully cured after treatment with ledipasvir/sofosbuvir. WHAT IS NEW AND CONCLUSION: Ledipasvir/sofosbuvir may be an option for treating patients who have failed multiple prior DAA regimens; however, further research is warranted.

How long to treat with antibiotics following amputation in patients with diabetic foot infections? Are the 2012 IDSA DFI guidelines reasonable?

WHAT IS KNOWN AND OBJECTIVE: To the best of our knowledge, there has been no published study designed to identify the most appropriate duration of antibiotic therapy in lower extremity skin and skin structure infections in diabetic patients [aka "diabetic foot infections" (DFI)] post-amputation. However, recent guidelines published by the Infectious Diseases Society of America (IDSA) provide recommendations for treatment duration in these patients. Therefore, our objective is to review the literature evaluating antibiotic treatment in DFI to determine if the IDSA guidelines are reasonable. COMMENT: Evidence for the use of antibiotics after amputation comes largely from perioperative surgical prophylaxis studies evaluating the rate of infection after amputation. Three such studies were identified; 2 found a 5-day course of antibiotics post-amputation resulted in a reduction of infection rate, while 1 found no additional benefit. Comparative antibiotic studies in DFI also offers evidence for treatment duration, of which, 10 studies were identified. Five included patients who received amputations; however, only 1 reported treatment outcomes in a subset of diabetics requiring amputation. In this study, the authors concluded that antibiotic treatment is likely necessary after amputation. WHAT IS NEW AND CONCLUSION: Given the general lack of data, we recommend that post-operative treatment duration be individualized, and, until further studies are done, it seems reasonable to adhere to the recommendation provided by the 2012 IDSA DFI guidelines for a 2-5 day course of antibiotic therapy post-operatively when no residual infected tissue remains.

Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump.

Dopamine-containing neurons of the mammalian midbrain are required for normal behavior and movements. In vivo they fire action potentials in bursts, but in vitro they discharge regularly spaced action potentials. Burst firing in vitro has now been shown to be robustly induced by the glutamate agonist N-methyl-D-aspartate (NMDA) although not by the non-NMDA agonists kainate or quisqualate. The hyperpolarization between bursts of action potentials results from electrogenic sodium ion extrusion by a ouabain-sensitive pump. This mechanism of burst generation in mammalian neurons may be important in the pathophysiology of schizophrenia and Parkinson's disease.

Apollo 12 lunar module impact: laboratory simulation and possible downrange ballistic effects.

Plastic pellets were fired into sand targets at a launch angle of 4 degrees and a velocity of 1.68 kilometers per second, the conditions of the Apollo 12 lunar module impact. Shallow elliptical or doublet craters were formed, similar to certain lunar craters. Analysis of the ejecta suggests (i) that lunar module debris skipped and, with some crater ejecta, reimpacted far downrange, but (ii) this ballistic rain does not account for the anomalous seismic signal.

5-HT inhibits synaptic transmission in rat subthalamic nucleus neurons in vitro.

The subthalamic nucleus (STN) plays a pivotal role in normal and abnormal motor function. We used patch pipettes to study effects of 5-HT on synaptic currents evoked in STN neurons by focal electrical stimulation of rat brain slices. 5-HT (10 microM) reduced glutamate-mediated excitatory postsynaptic currents (EPSCs) by 35+/-4%. However, a much higher concentration of 5-HT (100 microM) was required to inhibit GABA-mediated inhibitory postsynaptic currents (IPSCs) to a comparable extent. Concentration-response curves showed that the 5-HT inhibitory concentration 50% (IC50) for inhibition of IPSCs (20.2 microM) was more than fivefold greater than the IC50 for inhibition of EPSCs (3.4 microM). The 5-HT-induced reductions in EPSCs and IPSCs were accompanied by increases in paired-pulse ratios, indicating that 5-HT acts presynaptically to inhibit synaptic transmission. The 5-HT1B receptor antagonist NAS-181 significantly antagonized 5-HT-induced inhibitions of EPSCs and IPSCs. These studies show that 5-HT inhibits synaptic transmission in the STN by activating presynaptic 5-HT1B receptors.

GDNF acutely modulates excitability and A-type K(+) channels in midbrain dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) prevents lesion-induced death of midbrain dopaminergic neurons, but its function in normal brain remains uncertain. Here we show that GDNF acutely and reversibly potentiated the excitability of cultured midbrain neurons by inhibiting transient A-type K(+) channels. The effects of GDNF were limited to large, tyrosine hydroxylase (TH)-positive dopaminergic neurons, and were mediated by mitogen associated protein (MAP) kinase. Application of GDNF also elicited a MAP kinase-dependent enhancement of the excitability in dopaminergic neurons in midbrain slice. These results demonstrate an acute regulation of GDNF on ion channels and its underlying signaling mechanism, and reveal an unexpected role of GDNF in normal midbrain dopaminergic neurons.

Multiple conductances are modulated by 5-HT receptor subtypes in rat subthalamic nucleus neurons.

Firing patterns of subthalamic nucleus (STN) neurons influence normal and abnormal movements. The STN expresses multiple 5-HT receptor subtypes that may regulate neuronal excitability. We used whole-cell patch-clamp recordings to characterize 5-HT receptor-mediated effects on membrane currents in STN neurons in rat brain slices. In 80 STN neurons under voltage-clamp (-70 mV), 5-HT (30 microM) evoked inward currents in 64%, outward currents in 17%, and biphasic currents in 19%. 5-HT-induced outward current was caused by an increased K(+) conductance (1.4+/-0.2 nS) and was blocked by the 5-HT(1A) antagonist WAY 100135. The 5-HT-evoked inward current, which was blocked by antagonists at 5-HT(2C) and/or 5-HT(4) receptors, had two types of current-voltage (I-V) relations. Currents associated with the type 1 I-V relation showed negative slope conductance at potentials <-110 mV and were occluded by Ba(2+). In contrast, the type 2 I-V relation appeared linear and had positive slope conductance (0.64+/-0.11 nS). Type 2 inward currents were Ba(2+)-insensitive, and the reversal potential of -19 mV suggests a mixed cation conductance. In STN neurons in which 5-HT evoked inward currents, 5-HT potentiated burst firing induced by N-methyl-d-aspartate (NMDA). But in neurons in which 5-HT evoked outward current, 5-HT slowed NMDA-dependent burst firing. We conclude that 5-HT receptor subtypes can differentially regulate firing pattern by modulating multiple conductances in STN neurons.

Dopamine receptors set the pattern of activity generated in subthalamic neurons.

Information processing in the brain requires adequate background neuronal activity. As Parkinson's disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.

The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel.

The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SD11 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel. Inactivation of the PI3K/AKT signal transduction pathway either by its specific inhibitor LY294002 or by expression of dominant negative AKT inhibited p21 expression but had no inhibitory effect on the expression of the proapoptotic protein BAX by cisplatin and paclitaxel treatment. In addition, overexpression of wild-type or constitutively active AKT in A2780 cells sustained the regulation of p21 induction or increased the level of p21 expression, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplatin or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVCAR-5 cells, which lack functional p53. These data indicate that the PI3K/AKT signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response to drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, suggesting that the cell death induced by cisplatin or paclitaxel proceeds independently of cell protective effects of PI3K and AKT.

Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines.

We have examined a panel of 12 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy to determine whether a relationship is present between cisplatin sensitivity and: (a) cellular platinum accumulation; (b) glutathione levels; (c) platinum-DNA adduct formation; (d) platinum-DNA adduct removal; and (e) platinum-DNA damage tolerance. Multiple regression and correlation analysis revealed that of these resistance mechanisms, platinum-DNA damage tolerance correlates strongly with cisplatin sensitivity (r = 0.84, P = 0.001), whereas platinum accumulation (r = -0.11), cellular glutathione levels (r = 0.13), and platinum-DNA adduct removal (r = 0.44) correlate insignificantly. The correlation of platinum-DNA damage tolerance to cisplatin sensitivity (IC50s) is derived from the clustering of platinum-DNA adduct formation into three distinct groups spanning a 3-fold range, which is narrow relative to the corresponding 43-fold range in sensitivity. Adduct formation itself is not associated with cisplatin sensitivity (r = -0.38). Strong correlations were also observed between platinum-DNA damage tolerance and sensitivity to Adriamycin (r = 0.80, P = 0.002), paclitaxel (r = 0.87, P = 0.0002), etoposide (r = 0.78, P = 0.003), and mitomycin C (r = 0.73, P = 0.007). These results suggest that the failure of pathways that are involved in recognizing and processing platinum-DNA damage and other types of drug-induced damage that culminate in cell death may result in a broad resistance phenotype.

Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells.

We examined several aspects of platinum-DNA adduct formation and repair in cisplatin-sensitive and -resistant human ovarian cancer cell lines. The formation of cisplatin-interstrand crosslinks (ICLs) was measured in five DNA sequences by renaturing agarose gel electrophoresis. There were considerable differences (up to 4-fold) in ICL levels in these DNA sequences following a 4-h incubation with cisplatin; however, the pattern of ICL formation did not depend on whether the region was transcriptionally active or gene encoding. Incubation of purified DNA with cisplatin yielded an ICL pattern with considerably less variability between the regions examined. Cisplatin ICL and total DNA platination levels were significantly higher (up to 20- and 40-fold, respectively) in cisplatin-resistant cell lines as compared to the parental, cisplatin-sensitive cell line at equivalent levels of cisplatin cytotoxicity. Under cisplatin exposure conditions which yielded similar initial levels of sequence-specific ICLs, the cisplatin-resistant cells removed up to 2.5 times more ICLs by 12-h posttreatment than the parental cell line. Increased removal of the individual platinum-deoxyribonucleosides of platinum-DNA adducts was also observed in the highly resistant C200 cell line as determined by high performance liquid chromatography separation and quantitation by atomic absorption spectrometry. These results indicate that DNA repair contributes significantly to cisplatin resistance and that increased DNA-damage tolerance may also be a component of the resistance phenotype in this model system.

The chemopreventive agent oltipraz stimulates repair of damaged DNA.

Carcinogens may damage DNA either through the production of radicals that cause base modification in situ or through the formation of bulky adducts at relatively nucleophilic sites. Preclinical studies have demonstrated that administration of the dithiolethione oltipraz protects laboratory animals from the development of tumors following subsequent exposure to a variety of carcinogens. This may occur through a mechanism involving the induction of detoxicating gene expression. In some models, oltipraz treatment following carcinogen exposure may also confer protection. To investigate a possible mechanism for this observation, we studied the effects of oltipraz on base excision repair and platinum-DNA damage formation and removal. No effect of oltipraz was observed on base excision repair as determined by an in vitro assay measuring the repair of apurinic/apyrimidinic sites by untreated and oltipraz-treated HT-29 whole-cell extracts. Treatment of HT-29 cells with cisplatin in the absence or presence of 30 and 100 microM oltipraz decreased the accumulation of platinum in DNA. A dose-dependent reduction in DNA platination was also observed in purified DNA treated concurrently with cisplatin and increasing concentrations of oltipraz. When DNA was first platinated and subsequently incubated with oltipraz, no decrease in platinum content in DNA was found. Preincubation of HT-29 cells with oltipraz enhanced the rate of removal of total platinum-DNA adducts and interstrand cross-links. These data support a novel mechanism through which dithiolethiones may protect carcinogen-exposed animals from tumor formation and may expand their potential role in the clinic.

Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.

Evidence for altered regulation of gamma-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines.

We have shown previously that tumor cell resistance to cisplatin is associated with elevated intracellular levels of glutathione, which is accomplished at least in part by increased expression of the heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCS). To investigate the mechanism by which gamma-GCS expression is elevated, we have examined four related human ovarian cancer cell lines with increasing cisplatin resistance. Relative amounts of steady-state gamma-GCS mRNA in CP70, C30, and C200 were 4.8, 6.0, and 10.6, respectively, compared to the parental A2780 cell line, and a proportional increase in the transcriptional rate but not RNA stability was demonstrated. In contrast, no increase in mRNA for the gamma-GCS light subunit was found. To determine the mechanism of upregulation of this mRNA, we have cloned the promoter of the gene that encodes the heavy subunit of gamma-GCS. This region contains AP-1, NF-kappa B, XRE, AP-2, EpRE, CAAT, and TATA box elements upstream of the transcription initiation site and two MREs between this site and the start codon for the protein. Using gel mobility shift assays, we have found nuclear extract binding activity to the AP-1 response element to be closely associated with the level of gamma-GCS gene expression. A supershift assay showed that the AP-1 DNA-binding complexes are predominantly formed by dimers of JUN family members. Consistent with this finding, the expression of c-JUN was found to be elevated in the resistant cells. In contrast to AP-1 binding, AP-2 and NF-kappa B binding were inversely related to resistance. Furthermore, we have examined a partial revertant of the C200-resistant cells, which shows lower glutathione levels, and found decreased gamma-GCS expression associated with decreased AP-1 binding activity.

Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2.

AKT2 is a serine/threonine kinase implicated in human ovarian and pancreatic cancers. AKT2 is activated by a variety of growth factors and insulin via phosphatidylinositol 3-kinase (PI3K). However, its normal cellular role is not well understood. To gain insight into the function of AKT2, we performed yeast two-hybrid system to screen for interacting proteins. Using this technique, we identified a novel interactor, designated APPL, which contains a pleckstrin homology (PH) domain, a phosphotyrosine binding (PTB) domain and a leucine zipper, classes of motifs defined in signaling molecules as functional interaction domains with specific targets. The PH domain of APPL shows similarity to those found in GTPase-activating proteins such as oligophrenin-1 and Graf, whereas its PTB domain exhibits homology with CED-6, an adaptor protein that promotes engulfment of apoptotic cells, and IB1, a transactivator of the GLUT2 gene. APPL is highly expressed in skeletal muscle, heart, ovary and pancreas, tissues in which AKT2 mRNA is abundant. APPL interacts with the inactive form of AKT2; moreover, APPL binds to the PI3K catalytic subunit, p110alpha. These data suggest that APPL is an adaptor that may tether inactive AKT2 to p110alpha in the cytoplasm and thereby may expedite recruitment of AKT2 and p110alpha to the cell membrane upon mitogenic stimulation. Furthermore, the APPL gene was mapped to human chromosome 3p14.3-p21.1, where deletions and other rearrangements have often been reported in a variety of tumor types. The identification of APPL may facilitate further analysis of the physiological and oncogenic activities of AKT2.

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel.

In a clinical trial of paclitaxel (Taxol) and carboplatin in combination, the severity of thrombocytopenia was less than would be expected with an equivalent dose of carboplatin alone. To determine whether a pharmacokinetic interaction was responsible for this observation, the effect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of two treatment groups that determined the order of drug treatments. The treatments were carboplatin as a 30-min infusion alone or immediately following 175 mg/m2 Taxol administered as a 3-h i.v. infusion. The treatments were separated by 1 week. The carboplatin dose was chosen to produce a target area under the concentration-time curve (AUC) of 3.75 mg-min/ml according to a previously published formula (A. H. Calvert et al., J. Clin Oncol., 7: 1748-1756, 1989). The mean administered dose of carboplatin was 338 mg. Serial blood samples were collected over 24 h and analyzed for total and free platinum, and, in some patients, Taxol. The pharmacokinetics of carboplatin (i.e., total clearance and volume of distribution at steady state), was not significantly affected by pretreatment with Taxol. Total clearances of carboplatin were 67.2 +/- 28.8 ml/min and 64.6 +/- 27.9 ml/min in the absence and presence of Taxol, respectively (P = 0.56). The AUC of free carboplatin (3.45 mg-min/ml) obtained in the absence of Taxol was not significantly different from that measured in the presence of Taxol (3.27 mg-min/ml). The AUC of carboplatin in both the absence and presence of Taxol agreed with the projected target AUC of 3.75 mg-min/ml. In conclusion, the application of an individualized dosing strategy is valid for the calculation of the carboplatin dose in this combination. The pharmacokinetics of carboplatin is not altered by pretreatment with Taxol at a standard dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.

The biology of ovarian cancer.

The biology of ovarian cancer broadly defined covers essentially all aspects of the disease from how it arises to how it responds to chemotherapy, often becomes refractory to treatment, and ultimately kills the patient. In this article, we take the liberty of discussing many of these issues to some degree in context of the "natural/clinical" history/biology of the disease. We focus on concepts of how the disease develops, efforts to identify histologic changes that may precede the development of overt ovarian cancer, efforts to define how the growth and function of the normal ovarian surface epithelium are regulated to gain insights into how aberrant function of these pathways may contribute to the initiation of the disease, molecular biological studies on clinical ovarian cancer specimens, efforts to experimentally induce the malignant transformation of ovarian surface epithelial cells, and efforts to understand why ovarian cancer is often initially responsive to chemotherapy but ultimately becomes refractory.

Effects of dopamine on spontaneous and evoked activity of caudate neurons.

This study examined the effects of dopamine (DA), pressure ejected from multi-barrelled micropipettes, on the spontaneous and evoked activity of caudate neurons, recorded extracellularly in rats anesthetized with urethane. Neurons were categorized according to their discharge latencies in response to supramaximal cortical stimulation: neurons which fired with latencies less than 13 msec were classified "short-latency-discharge neurons", while neurons with latencies greater than or equal to 13 msec were classified "long-latency-discharge neurons". This procedure also allowed the detection of neurons with low levels of spontaneous activity. The predominant effect of DA on both neuronal types was inhibition of spontaneous activity. However, DA exerted a modulatory effect in that spontaneous activity was inhibited at "doses" which did not affect activity evoked by cortical stimulation. Although DA-induced excitation was infrequent, it was significantly more prevalent among long-latency neurons than among short-latency-discharge neurons. Long-latency-discharge neurons were also significantly more spontaneously active than were short-latency neurons. In rats depleted of endogenous DA by treatment with reserpine, caudate neurons had significantly increased rates of spontaneous and evoked activity, shorter duration of stimulus-evoked inhibition, and longer latency for evoked discharges than in control rats. These results suggest that DA exerts modulatory effects on caudate neuronal activity. Furthermore, these results suggest that short- and long-latency-discharge neuronal groups may consist of pharmacologically, as well as physiologically, distinct neuronal types.