A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson's disease patients.

BACKGROUND AND PURPOSE: Depressed mood is a common psychiatric problem associated with Parkinson's disease (PD), and studies have suggested a benefit of rasagiline treatment. METHODS: ACCORDO (see the ) was a 12-week, double-blind, placebo-controlled trial to evaluate the effects of rasagiline 1 mg/day on depressive symptoms and cognition in non-demented PD patients with depressive symptoms. The primary efficacy variable was the change from baseline to week 12 in depressive symptoms measured by the Beck Depression Inventory (BDI-IA) total score. Secondary outcomes included change from baseline to week 12 in cognitive function as assessed by a comprehensive neuropsychological battery; Parkinson's disease quality of life questionnaire (PDQ-39) scores; Apathy Scale scores; and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. RESULTS: One hundred and twenty-three patients were randomized. At week 12 there was no significant difference between groups for the reduction in total BDI-IA score (primary efficacy variable). However, analysis at week 4 did show a significant difference in favour of rasagiline (marginal means difference ± SE: rasagiline -5.46 ± 0.73 vs. placebo -3.22 ± 0.67; P = 0.026). There were no significant differences between groups on any cognitive test. Rasagiline significantly improved UPDRS Parts I (P = 0.03) and II (P = 0.003) scores versus placebo at week 12. Post hoc analyses showed the statistical superiority of rasagiline versus placebo in the UPDRS Part I depression item (P = 0.04) and PDQ-39 mobility (P = 0.007) and cognition domains (P = 0.026). CONCLUSIONS: Treatment with rasagiline did not have significant effects versus placebo on depressive symptoms or cognition in PD patients with moderate depressive symptoms. Although limited by lack of correction for multiple comparisons, post hoc analyses signalled some improvement in patient-rated cognitive and depression outcomes.

Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo. There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia.

Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed. METHODS: We performed in our stroke unit a single-centre randomized, double-blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n=25) at 2mA for 20min or sham TDCS (n=25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl-Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5days after stroke and after 3months. RESULTS: No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham. CONCLUSIONS: Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome.

Acute stroke treatment using the Penumbra endovascular mechanical thrombolysis device: a single-centre experience.

PURPOSE: Ischaemic stroke due to occlusion of large cerebral vessels has a poor prognosis. The clinical outcome is related to efficacy and timing of recanalisation of the occluded arteries. We report our experience with a thrombus aspiration device (Penumbra), and focus on pre- and postprocedural management. MATERIALS AND METHODS: We retrospectively reviewed 18 consecutive patients with acute ischaemic stroke due to the occlusion of large cerebral vessels who were treated with mechanical thrombolysis at our centre between September 2009 and July 2010. Preprocedural symptoms were quantified using the National Institutes of Health Stroke Scale (NIHSS). Mechanical thrombolysis was performed with the Penumbra system. Intravenous thrombolysis was done only if <3 h had elapsed since symptom onset. Associated vessel stenoses were treated with stenting. All patients underwent neurological examination and postprocedural magnetic resonance angiography (MRA) at 3 and 6 months. RESULTS: Mechanical thrombolysis using the Penumbra system was performed in all cases. A total of 83% of treated vessels had a value of 2/3 according to the Thrombolysis in Cerebral Infarction (TICI) scale. In seven patients (39%) intravenous thrombolysis was unsuccessful, and salvage mechanical thrombolysis followed. Three patients died after the procedure (16.7%). Five patients (27.8%) required a stenting procedure. All patients reported a significant improvement in symptoms (mean baseline NIHSS 19.6±5.6; mean postprocedural NIHSS, 7.8±5.5 p<0.0001) CONCLUSIONS: Our preliminary experience with the Penumbra mechanical thrombolysis system confirms previously reported results showing the efficacy and safety of the device in treating acute stroke caused by the occlusion of large intracranial vessels.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

BACKGROUND AND PURPOSE: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. METHODS: Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS)--Section III] and a battery of cognitive testing. RESULTS: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P < 0.05) and executive functions whilst the UPDRS revealed a modest (-21%) and variable treatment effect. CONCLUSIONS: Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD.

Deep brain stimulation of CM/PF of thalamus could be the new elective target for tremor in advanced Parkinson's Disease?

Aim of this study was to investigate whether Deep Brain Stimulation (DBS) of the Centre Median Nucleus/Parafascicular (CM/PF) Complex is useful in reducing extrapyramidal symptoms in advanced Parkinson's Disease (PD) patients. In particular, we compared the action of CM/PF and subthalamic nucleus (STN) DBS on resting hand tremor using EMG surface of ulnar and radial right-hand muscles. Our results show that C/M DBS is very effective in reducing tremor, indicating this complex as a new target in advanced PD patients.

CT Angiography ASPECTS Predicts Outcome Much Better Than Noncontrast CT in Patients with Stroke Treated Endovascularly.

BACKGROUND AND PURPOSE: Noncontrast CT ASPECTS has been investigated as a predictor of outcome in patients with acute ischemic stroke. Our purpose was to investigate whether CTA source images are a better predictor of clinical and radiologic outcomes than NCCT ASPECTS in candidates for endovascular stroke therapy. MATERIALS AND METHODS: CT scans of patients (n = 124) were independently evaluated by 2 readers for baseline NCCT and CTA source image ASPECTS and for follow-up ASPECTS. An mRS of ≤2 at 3 months was considered a favorable outcome. Receiver operating characteristic curve analysis was used to assess the ability of NCCT and CTA source image ASPECTS to identify patients with favorable outcomes. A stepwise multiple regression analysis was performed to find independent predictors of outcome. RESULTS: Baseline CTA source image ASPECTS correlated better than NCCT ASPECTS with follow-up ASPECTS (r = 0.76 versus r = 0.51; P for comparison of the 2 coefficients < .001). Receiver operating characteristic curve analysis showed that baseline CTA source image ASPECTS compared with NCCT ASPECTS can better identify patients with favorable outcome (CTA source image area under the curve = 0.83; 95% CI, 0.76-0.91; NCCT area under the curve = 0.67; 95% CI, 0.58-0.77; P < .001). Finally, the stepwise regression analysis showed that lower age, good recanalization, lower time to recanalization, and good baseline CTA source image ASPECTS, not NCCT ASPECTS, were independent predictors of favorable outcome. CONCLUSIONS: CTA source image ASPECTS predicts outcome better than NCCT ASPECTS; this finding suggests CTA rather than NCCT as a main step in the decision-making process for patients with acute ischemic stroke.

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Pathological Gambling in Parkinson's disease patients: Dopaminergic medication or personality traits fault?

Impulse control disorders (ICDs) are clinically relevant in Parkinson disease (PD) patients, with an established association with PD medication. Aim of our study was to study whether the increased frequency of pathological gambling (PG), reported in subgroups of PD patients, is related to specific personality tracts additional to dopaminergic medications. Thirty-seven PD patients with a personal history of PG where enrolled. Twenty one PD patients, matched for disease and dopaminergic therapy, never experiencing PG, were enrolled as controls. All subjects were tested with the Minnesota Multiphasic Inventory Personality scales (MMPI-2). Our data showed that PD group with PG exhibited significantly higher mean values of the three validity scales in comparison to the non-PG-PD group, demonstrating an higher tendency to lie. Content scales showed a significant increase of cynicism and bizarre ideation scales score in the PG-PD group, not exhibiting pathological values at the validity scales, (p: 0.02) in comparison to non-PG PD patients. According to our results, PG seems to be associated with precise personality tracts. Personality profiles of cluster A personality disturbances - Axys 2 according with DSM-5 TR (paranoid type) at MMPI-2 might be a warning index helpful in selecting dopaminergic treatment, to avoid subsequent ICDs appearance.

Sleep episodes and daytime somnolence as result of individual susceptibility to different dopaminergic drugs in a PD patient: a polysomnographic study.

The association between excessive daytime somnolence (EDS) and idiopathic Parkinson's disease (PD) is often reported but still debated. The possible role of antiparkinsonian therapy or primarily of PD on excessive diurnal sleepiness is controversial. We describe the case of a 61-year-old patient affected by PD who experienced sleep episodes (SE) occurring during pramipexole plus L-Dopa therapy. Polysomnographic sleep studies and subjective evaluations of daytime sleepiness (Epworth Sleepiness Scale) were carried out under administration of pramipexole plus L-Dopa, L-Dopa monotherapy and cabergoline plus L-Dopa. The polysomnography revealed two sleep events during pramipexole plus L-Dopa. Moreover, the polysomnographic data showed an increase of both diurnal and nocturnal sleep under pramipexole plus L-Dopa compared with cabergoline plus L-Dopa and L-Dopa as monotherapy. In addition, while Epworth Sleepiness Scale (ESS) Score showed a mild sleepiness under pramipexole (ESS score=11), ESS scores were normal under both L-Dopa and cabergoline plus L-Dopa. Sleep episodes also disappeared under both L-Dopa and cabergoline plus L-Dopa (2- and 12-month follow-up). We hypothesize that an individual susceptibility to specific antiparkinsonian drug may play a significant role in the genesis of sleepiness in our PD patient.

Visual alterations in de novo Parkinson's disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials.

There are increased latencies of pattern-reversal visual evoked potentials (VEPs) and electroretinograms (PERGs) in Parkinson's disease (PD) patients who have not received therapy. This study aimed to evaluate whether these delays are present in the early stage of PD and whether they are dopamine-sensitive. The results show that both PERG P50 and VEP P100 latencies are increased (p < 0.0001) in a group of patients with de novo PD (13 subjects; 13.3 +/- 5.6 months' mean disease duration) before therapy in comparison with an age-matched control group (eight subjects). A larger latency increase (9.9% at the 47% contrast level and 7.8% at the 96% contrast level) was present in PERG recordings than in VEPs (6.2% at the 47% contrast level and 3.9% at the 96% contrast level). Levodopa therapy produced recovery of both PERG and VEP latency increases at both contrast levels, but only the PERG recovery at 47% of contrast was statistically significant. Before therapy, five eyes from PD patients showed no reproducible PERG at the 47% contrast level although the simultaneously recorded VEP was present. Both potentials were recordable in the same eyes at the 96% contrast level. During therapy, four of those five eyes showed a clear PERG even at the 47% contrast level. We conclude that, using an adequate midspatial frequency, both VEPs and PERGs are delayed even in the early stage of PD, and that PERGs are more sensitive if low contrast (47%) is used. The larger alterations, as well as the larger recovery during levodopa therapy, seem to correlate the PERG response more than the VEP response to dopaminergic transmission.

Parkinson's disease and somatosensory evoked potentials: apomorphine-induced transient potentiation of frontal components.

We recorded somatosensory evoked potentials (SEPs) to median nerve stimulation from parietal and frontal districts in 32 patients with Parkinson's disease by evaluating latency/amplitude characteristics of the parietal P14-N20-P25 and of the frontal P20-N30-P40 wave complexes before and 10, 20, 30, and 60 minutes after subcutaneous administration of apomorphine chloride. The frontal complex N30-P40 was smaller than normal in 17 patients in baseline recordings. Following apomorphine, the parietal responses did not significantly vary in amplitude, but the frontal complex showed a remarkable amplitude potentiation in 22 of 32 patients (68.7%, p < 0.001), 19 of whom were also improving clinically. Amplitude potentiation was evident 10 minutes after apomorphine and faded away nearly in parallel with the end of its clinical efficacy. There were no SEP changes in three healthy controls after apomorphine.

Dopaminergic and noradrenergic responses in the hippocampal slice preparation. Evidence for different receptors.

The effects of iontophoretic applications of dopamine (DA) and noradrenaline (NA) on potentials evoked by the stimulation of the hippocampal slice preparations were investigated. Dopamine, ejected at the soma, produced an increase of the amplitude of the population spike of CA1 pyramidal cells; NA had an excitatory action on some responses, inhibitory on others. The field-excitatory postsynaptic potentials (EPSPs) were unaffected by ejection of DA and NA on the dendritic tree. Domperidone, a dopaminergic antagonist, blocked the increase of the population spike induced by DA, but was unable to antagonize noradrenergic responses. Timolol, a beta-adrenergic antagonist, blocked the excitatory action of NA, but did not modify either the effect of DA or the inhibition induced by NA. Phentolamine, an alpha-antagonist, antagonized only the inhibition induced by NA. These results indicate that DA and NA modulate the activity of hippocampal neurones by interacting on different receptors.

Morphine induces a spontaneous and evoked bursting activity in rat cortical neurons by adding a postsynaptic active mechanism to the synaptic input: an intracellular study in vivo.

The action of morphine on spontaneous and stimulus-evoked postsynaptic potentials was investigated in rat cortical neurons recorded intracellularly in vivo. Iontophoretically applied, morphine increased supra-threshold evoked depolarizing postsynaptic potentials inducing bursts of spikes, but only slightly increased weak (subthreshold) potentials. Spontaneous excitatory postsynaptic potentials were affected in a similar way, but their frequency did not change. Inhibitory postsynaptic potentials were only subsequently modified. Membrane hyperpolarization, induced by negative current injection, counteracts the morphine-induced burst generation. We suggest that the action of this alkaloid on threshold postsynaptic events involves a voltage-dependent mechanism, which may be triggered by synaptic currents.

Action of morphine on rat cortical neurons intracellularly recorded in vivo: evidence for an excitatory postsynaptic effect which is naloxone insensitive.

The action of morphine, applied either iontophoretically (40-200 nA balanced current) or systemically (5-10 mg/kg, intraperitoneally) to rat cortical neurons, was investigated in vivo, using intracellular electrodes. Morphine increased the apparent input resistance and increased the number of both spontaneous and evoked action potentials. Several cells, which normally generated single spikes, generated bursting potentials; neurons with bursting activity increased their activity. Naloxone, iontophoretically or systemically applied, did not reverse or prevent the morphine-induced excitation. The iontophoretic administration of cadmium suggested that the effects of morphine were due, at least in part, to a postsynaptic site of action. It is suggested that the increase of cellular excitability induced by morphine could contribute to its production of seizures in cortex.

Dopamine modulates CA1 hippocampal neurons by elevating the threshold for spike generation: an in vitro study.

Intracellular recordings were obtained from CA1 neurons of rat hippocampal slices preparation. Dopamine applied by perfusion (10(-5)-10(-7) M), microdrop (10(-4) M) and iontophoresis (+80, +200 nA balanced current) inhibited "spontaneous" and evoked action potentials. An increase in current injection restored the evoked action potentials which appeared unmodified. Membrane potential was not modified in 60% of the neurons; in the remaining ones, a slow depolarization was observed. Membrane resistance, measured at rest, was not modified by dopamine. Calcium-mediated events such as bursting activity and afterhyperpolarization, mainly in the late component, were also attenuated by the catecholamine. These effects were antagonized by domperidone, a dopaminergic antagonist. Calcium spikes, evoked in tetrodotoxin- and tetraethylammonium-poisoned slices, were reversibly inhibited by dopamine. Since an increase in the amplitude of a depolarizing pulse of injected current was able to evoke both sodium and calcium action potentials suppressed by dopamine without change in shape or duration, it is concluded that this catecholamine depresses cellular excitability by altering the interaction between membrane voltage and sodium and calcium entry and the subsequent increase in potassium conductance.

Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement.

Intracellular recordings were obtained from rat neostriatal slices. Bath-applied dopamine (1-10 microM) produced a reversible inhibition of the action potentials evoked by direct stimulation and a decrease in the amplitude of the intrastriatally evoked depolarizing postsynaptic potentials. No change in membrane potential was detected during the application of 1-10 microM dopamine. Dopamine application also produced a decrease in anomalous rectification in the depolarizing direction. This subthreshold inward rectification was abolished by tetrodotoxin, but not by calcium-free and cadmium (0.1-1 mM)-containing solutions. The dopamine-induced decrease in excitatory postsynaptic potential amplitude was evident at resting membrane potential or at more positive levels, but was absent at hyperpolarized values of the membrane potential. Addition of bicuculline (50-500 microM) to the medium did not affect the inhibitory action of dopamine. The inhibitory action of dopamine also persisted in calcium-free and cadmium-containing solutions. The adenosine 3',5'-cyclic monophosphate analogue, 8-bromo-adenosine 3',5'-cyclic monophosphate (0.1-1 mM), mimicked the effects produced by D1 receptor activation. Bath application of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (1-10 microM), a selective D1 dopaminergic agonist, mimicked the effects of micromolar concentrations of dopamine. The D2 dopaminergic agonists, 4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-3,4-g-quinoline (LY 171555) and bromocriptine (both at 10 nM-10 microM), had no effects on neostriatal cells. The inhibition induced by micromolar doses of dopamine or SKF 38393 was antagonized by bath applications of R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin++ +-7-ol (SCH 23390; 0.1-10 microM), a D1-selective antagonist, but not by sulpiride (10 nM-10 microM), a D2 antagonist. We conclude that the inhibitory effect of dopamine on rat striatal neurons is postsynaptically mediated by the activation of D1 dopaminergic receptors via the reduction of a voltage-dependent tetrodotoxin-sensitive inward conductance.

Action of neurotensin on spinal cord neurons in the rat.

Histochemical, biochemical and pharmacological data suggest that the tridecapeptide neurotensin (NT) may play a role as an intercellular messenger in the spinal cord of rats. In the present study the response of spinal cord neurons to NT was investigated employing conventional extra- and intracellular recording techniques in combination with iontophoresis or a microperfusion system which permits the control of the maximal concentration of NT reached near the neuron. Recordings were obtained from motoneurons, interneurons and from neurons in the dorsal horn receiving synaptic input from low and high threshold mechanoreceptors activated in their peripheral cutaneous receptive fields. The most commonly observed action of NT applied by either mode was an excitation after a dose-dependent delay. The response was dose-dependent, repeatable and reversible. The intracellular recordings revealed that these excitatory responses were due to a depolarizing action of NT associated with an increase in input resistance, not attributable to non-linearities in the current-voltage relationship. The present data are in agreement with most previous investigations reporting excitatory actions of NT on neurons in various neuronal structures in the peripheral and central nervous system. It seems unlikely that these excitatory effects are indirect actions mediated by an inhibition of other neurons in the vicinity.

Electrical stimulation of mesencephalic cell groups (A9-A10) produces monosynaptic excitatory potentials in rat frontal cortex.

Electrical stimulation of the ventral tegmental area and substantia nigra produces monosynaptic and polysynaptic excitatory postsynaptic potentials in rat frontal neurons that can be recorded intracellularly. The electrophysiological characteristics of the monosynaptic responses and the possibility that dopamine (DA) mediates these events are discussed.

Responses of intracellularly recorded cortical neurons to the iontophoretic application of dopamine.

Considering that a well-defined dopaminergic projection from the mesencephalic structures to the rat frontal cortex has been demonstrated, the purpose of this research was to study the action of iontophoretically applied dopamine (DA) on intracellularly recorded rat frontal neurons. The stimulation of the substantia nigra (SN) and the ventral tegmental area (VTA) evoked EPSP-IPSP sequences in these cells. About 50% of the tested neurons, widely distributed in all the frontal cortex, responded to DA application and no difference in the response to DA was observed between neurons with monosynaptic inputs and neurons with polysynaptic inputs. The catecholamine depolarized the cell membrane and decreased the firing rate, generally without significant changes in membrane resistance, as already observed in rat and cat striatal cells. In some neurons the decrease of the spikes preceded the membrane depolarization. Considering the complex effect of DA on the electrical properties of these neurons, these results seem to be indicative of a mechanism of action dependent on metabolic changes.