[Interferon α therapy in patients with chronic hepatitis C infection: biopsychosocial consequences]. / Interferon α bei Patienten mit chronischer Hepatitis C : Biopsychosoziale Auswirkungen.

BACKGROUND: Interferon α (IFN-alpha) is widely used in the treatment of viral infections, including hepatitis C. Unfortunately depression is a common side effect of IFN-alpha therapy. The presence of depressive symptoms is important because they have an adverse effect on the course of the illness and reduce the quality of life and the treatment adherence. The current prospective study examines the effects of IFN-alpha on the development of depressive disorders, on cognitive functioning and on quality of life. METHOD: A total of 25 patients with chronic hepatitis C infection were investigated. All patients were treated in the Department of Gastroenterology and Hepatology, University of Medicine of Graz, Austria. Psychometric observer rating and self-rating scales were administered 1 month and 3 months after the beginning of the antiviral treatment to evaluate depressive symptoms [Beck Depression Inventory (BDI); Hamilton Depression Scale]. The data on life satisfaction before therapy and health-related quality of life were obtained from the Fragebogen zur Lebenszufriedenheit (FLZ) and the SF-36 (Health Status Questionnaire). Cognitive function was based on the SKT (Syndrom Kurztest). All patients completed the Social Support Questionnaire (SSS), a multidimensional self-report measure of social support. RESULTS: Three months after the initial IFN-alpha administration in the whole sample significant impairments in health-related quality of life were found in the health-related domains "physical functioning", "role physical", "role emotional", "social functioning" and "vitality". The whole sample showed cognitive impairments. No changes in social support were recorded. Three months after the first INF-alpha administration, 48% (n=12) of the sample suffered from moderate clinical depression. In comparison to patients without pathological affective findings, patients with INF-alpha-induced clinical depression showed decreased life satisfaction before the initial antiviral therapy. Impairments in health-related quality of life (SF-36) were found in the sample with clinical depression in the health-related domains "general health", "social functioning", "role emotional", "vitality" and "mental health". CONCLUSION: Hepatitis C is associated with an increased prevalence of psychiatric disorders, particularly depression. INF-alpha patients having low levels of life satisfaction in the domains "self-concept" (skills, appearance, self-confidence, vitality …), "employment" and "physical health and constitution" seem to face a major risk of depression.

[The relationship between emotional distress, cognitive performance and health - related quality of life in patients with hepatitis C prior to antiviral treatment]. / Der Zusammenhang zwischen emotionalen Befindlichkeitsstörungen, kognitiver Leistungsfähigkeit und gesundheitsbezogener Lebensqualität bei mit dem Hepatitis-C-Virus infizierten Patienten vor einer antiviralen Therapie.

Recent epidemiologic studies suggest that more than 175 million individuals are infected with hepatitis C virus (HCV) worldwide. In the past few years, outcome studies in chronic HCV patients are no longer focusing solely on traditional end points such as mortality rates but on psychosocial well-being such as health-related quality of life (HRQoL), emotional states, and neuropsychological functioning. The purpose of our exploratory study was to assess cross sectionally the frequency of depression, posttraumatic stress symptoms, cognitive deficits, and impairments in HRQoL in chronic HCV patients prior to antiviral treatment, and to investigate how cognitive impairments and emotional distress were related to quality of life. We recruited 34 chronic HCV patients who had presented for initial assessment of the need for antiviral therapy. Psychometric observer-rating and self-rating scales were administered to evaluate posttraumatic stress symptoms (PTSS-10), depressive symptoms (BDI), HRQoL (SF-36 Health Status Questionnaire), and cognitive functioning (SKT). 32.4 % (n = 11) of the sample suffered from clinical depression, and 8.8 % (n = 3) had a posttraumatic stress syndrome. 8.8 % (n = 3) of the sample showed cognitive impairments. Significant impairments in HRQoL were found in the health-related domains vitality, role-emotional, and role-physical. The severity of emotional distress as measured on the BDI and PTSS-10 was associated with decrements in HRQoL. However, lower cognitive function scores on the SKT were not associated with lower HRQoL SF-36 values. Chronic HCV patients seem to face a major risk of depression, posttraumatic stress symptoms, and cognitive dysfunction, and the presence of emotional distress is associated with impairments in quality of life. We therefore underscore the need for early and comprehensive bio-psycho-social diagnosis and therapy of chronic HCV patients in order to treat emotional distress and enhance patients; quality of life at an early stage before initiating antiviral therapy, as well as to expand the pool of patients eligible to receive antiviral therapy.

[Sexual dysfunction in remittent depressive women]. / Sexualleben remittierter depressiver Patientinnen.

BACKGROUND: Very little is known about the incidence of sexual problems in remittent depressive women, which are independent of prescribed medication. The current study examined the sexual life of such remittent patients and the effects of sexual dysfunction on the quality of life. METHOD: A total of 39 female patients who had no sexual side effects caused by antidepressive medication and 39 healthy subjects were investigated. All patients were treated in the Department of Psychiatry, University of Medicine of Graz, Austria. The data on sexual problems and quality of life were obtained from the short questionnaire for sexual problems (KFSP-F) and the questionnaire on quality of life (FLZ). RESULTS: Even after remission, reduced libido and impaired sexual fantasies appeared to be the core sexual problems. Remittent depressive women with sexual dysfunction had a decreased quality of life. CONCLUSION: Impaired sexual function is a common feature in depressive disorders. In some cases sexual problems even persist after remission and the observed sexual dysfunctions negatively affect quality of life. A detailed patient history is important to detect sexual problems.

[The effects of stalking on psychiatrists, psychotherapists and psychologists. Prevalence of stalking and its emotional impact]. / Auswirkung von Stalking auf Psychiater, Psychotherapeuten und Psychologen. Häufigkeit von Stalking und dessen emotionale Folgen.

Stalking in the psychiatric context describes a pathological behaviour which is characterized by repeated persecution, harassment, or menacing of or assault on a person. Because of the association between stalking and mental disorders, psychiatrists, psychologists and psychotherapists belong to particularly exposed professions. If they fall victim to stalking during their career, disruptive impacts up to posttraumatic stress disorder (PTSD) can be the consequence. A total of 117 psychiatrists, psychologists or psychotherapists in Graz participated in an anonymous interview. To register possible experiences with stalking defined behaviour, a modified version of the questionnaire of Kamleiter was used. The prevalence and severity of posttraumatic stress symptoms were determined using the Impact of Event Scale of Horowitz. The study showed an incidence of stalking of 38.5%. The rate of female stalkers (60%) was extraordinary high. Most victims (68.9%) experienced non-violent threats. Most of the offenders (41.9%) were diagnosed as suffering from schizophrenia, schizotype and delusional disorders (F2) followed by disorders of adult personality and behaviour (F6) (30.2%). Some 44.4% of the victims developed symptoms of PTSD, which were usually only slight. The analyses suggest that stalking, in the psychiatric field of activity, is a common and serious phenomenon, and that strategies for the prevention and protection of potentially affected professions have to be developed.

Different neurorescue profiles of selegiline and p-fluoro-selegiline in gerbils.

The neuroprotective/neuronal rescue effects of selegiline are not exactly understood, and show great variability in clinical trials. In this study, the dose-dependence of neuronal rescue potency of selegiline and its analogue para-fluoro-selegiline (PFS) was investigated in gerbils. The compounds were tested in a transient global cerebral ischemia model. Selegiline expressed a bell-shaped, dose-response curve with high intrinsic activity (with greatest effect at 0.001 mg/kg), as opposed to PFS which shows a saturation profile. These findings indicate possible therapeutic differences between PFS and selegiline in the treatment of neurodegenerative disorders. Inhibition of progression of the disease (neuroprotective effect) and improvements of symptoms (MAO-B inhibition) may occur at the same dose level using PFS, while these doses are separated in case of selegiline.

Synaptic origin and stimulus dependency of neuronal oscillatory activity in the primary visual cortex of the cat.

1. We have studied the oscillatory activity of single neurons (91 recorded extracellularly and 76 intracellularly) in the primary visual cortex of cats and kittens to characterize its origins and its stimulus dependency. A new method for the detection of oscillations was developed in order to maximize the range of detectable frequencies in both types of recordings. Three types of activity were examined: spontaneous background activity, responses to intracellular current steps and visual responses. 2. During spontaneous activity, persistent oscillatory activity was very rare in both types of recordings. However, when intracellular records were made using KCl-filled micropipettes, spontaneous activity appeared rhythmic and contained repeated depolarizing events at a variety of frequencies, suggestive of tonic periodic inhibitory input normally masked at resting potential. 3. Patterns of firing activity in response to intracellular current steps allowed us to classify neurons as regular spiking, intrinsically bursting, and fast-spiking types, as described in vitro. In the case of rhythmically firing cells, the spike frequency increased with the amount of injected current. Subthreshold current-induced oscillations were rarely observed (2 out of 76 cells). 4. Visual stimulation elicited oscillations in one-third of the neurons (55 out of 167), predominantly in the 7-20 Hz frequency range in 93% of the cases. Rhythmicity was observed in both simple and complex cells, and appeared to be more prominent at 5 and 6 weeks of age. 5. Intracellular recordings in bridge mode and voltage clamp revealed that visually evoked oscillations were driven by synaptic activity and did not depend primarily on the intrinsic properties of recorded neurons. Hyperpolarizing the membrane led to an increase in the size of the rhythmic depolarizing events without a change in frequency. In voltage-clamped cells, current responses showed large oscillations at the same frequency as in bridge mode, independently of the actual value of the holding potential. 6. In fourteen intracellularly recorded neurons, oscillations consisted of excitatory events that could be superimposed on a depolarizing or a hyperpolarizing slow wave. In two other neurons, visual responses consisted of excitatory and inhibitory events, alternating with a constant phase shift. 7. Drifting bars were much more efficient in evoking oscillatory responses than flashed bars. Except in three cells, the frequency of the oscillation did not depend on the physical characteristics of the stimulus that were tested (contrast, orientation, direction, ocularity and position in the receptive field). No significant correlation was found between the intensity of the visual response and the strength of the rhythmic component. 8. Although it cannot be excluded that the dominant frequency of oscillations might be related to the type of anaesthetics used, no correlation was found between local EEG and the oscillatory activity elicited by visual stimulation. 9. We conclude that the oscillations observed in the present work are generated by synaptic activity. It is likely that they represent an important mode of transmission in sensory processing, resulting from periodic packets of synchronized activity propagated across recurrent circuits. Their relevance to perceptual binding is further discussed.

Electrophysiological characterization of different types of neurons recorded in vivo in the motor cortex of the cat. I. Patterns of firing activity and synaptic responses.

1. Patterns of firing activity and characteristics of antidromic and synaptic responses to stimulation of the pyramidal tract at peduncular level [peduncular pyramidal tract (PP)] and the ventrolateral thalamic nucleus (VL) were studied in neurons of area 4 gamma of the motor cortex of awake, chronic cats using intracellular microelectrode techniques. The results offer a new functional classification of neocortical neurons based on electrophysiological properties of the 640 recorded cells. 2. Four classes of neurons were distinguished: (class i) inactivating bursting (ib) neurons (n = 60) including fast antidromic response PP (fPP) (n = 0), slow antidromic response PP (sPP) (n = 11), and no antidromic response PP cells (nPP) (n = 49); (class ii) noninactivating bursting (nib) neurons (n = 79), including fPP (n = 23), sPP (n = 0), and nPP cells (n = 56); (class iii) fast-spiking (fsp) neurons (n = 56), including fPP (n = 0), sPP (n = 0), and nPP cells (n = 56); and (class iv) regular-spiking (rsp) neurons (n = 445), including fPP (n = 96), sPP (n = 38), and nPP cells (n = 311). (Neurons in each classification were further separated by their antidromic responses to PP stimulation: fast PP (fPP) slow PP (sPP), or nPP cells, the latter not responding antidromically to electrical stimulation of the peduncle.) 3. Recurrent monosynaptic excitatory postsynaptic potentials (EPSPs) followed antidromic spikes elicited by PP stimulation in most (96%) fPP but much fewer (24%) sPP cells. In fPP cells, it was possible to separate the PP EPSPs into two monosynaptic EPSP components that were generated by other fPP and sPP cells, respectively. VL stimulation evoked monosynaptic EPSPs in 100% of fPP cells (vs. 63% of sPP cells) and antidromic action potentials in 16% of fPP cells (vs. 12% of sPP cells). 4. Firing activity consisted of single spike discharges in most PP cells; however, noninactivating bursting was observed in 19% of fPP cells, and inactivating bursting was observed in 23% of sPP cells (see below). In 18% of ib and 11% of nib/nPP neurons, VL stimulation elicited antidromic action potentials. Other bursting neurons proved to be PP cells with characteristic differences in axonal conduction velocity (see above). All PP cells among the nib cells were fPP, and all PP cells among the ib cells were sPP cells. All fsp neurons were found to be nPP cells, and none could be activated antidromically by VL stimulation. Thus the fsp pattern of discharge distinguished a unique class of nPP cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrophysiological characterization of different types of neurons recorded in vivo in the motor cortex of the cat. II. Membrane parameters, action potentials, current-induced voltage responses and electrotonic structures.

1. Electrical properties of four functional classes [inactivating bursting (ib), noninactivating bursting (nib), fast spiking (fsp), and regular spiking (rsp)] of neurons in the motor cortex of conscious cats were studied with the use of intracellular voltage recording and single-electrode voltage-clamp (SEVC) techniques. Evaluations were made of action potentials and afterpotentials, current-voltage (I-V) relationships, and passive cable properties. Values of membrane potential (Vm), input resistance (RN), membrane time constant (T0), and firing threshold (T50) were also measured. The data were used to extend the electrophysiological classifications of neurons described in the companion paper. 2. Average values of Vm (from -63 to -66 mV), action-potential amplitudes (from 72 to 77 mV), and firing threshold (-54 mV) were not statistically different in different types of neurons. However, the magnitude of intracellularly injected depolarizing current required to induce spike discharge at 50% probability varied significantly (from 0.6 to 1.1 nA) among cell types. The mean RN and T0 measured at Vm varied between 8.3 and 19.8 M omega, and 7.2 and 15.1 ms, respectively, in the cell classes. 3. Action potentials were overshooting. Their mean duration at half amplitude varied from 0.25 to 0.73 ms among different cell types. Three types of action-potential configurations were distinguished. Type I action potentials found in nib and rsp neurons were relatively fast and had a depolarizing afterpotential (DAP) as well as fast and slow after hyperpolarizations (fAHPs, sAHPs). Type II action potentials found in ib and rsp cells had relatively slow rise and decay phases, DAPs, and sAHPs. Their fAHPs were small or absent. Type III action potentials were found exclusively in fsp cells, had very short durations, prominent fAHPs, but no sAHPs. 4. Steady-state I-V relationships were determined by measuring voltage responses to 0.2- to 1.0-nA hyperpolarizing, rectangular current pulses at different membrane potentials. Both RN and T0 exhibited nonlinear behavior over wide ranges of membrane potential; however, between -65 and -75 mV, the I-V relationships varied little, and they appeared constant in most cells. The steady-state values of RN increased with decreasing, and decreased with increasing the membrane potential in all but fsp cells. The I-V relationships were virtually linear in fsp neurons. 5. Transient I-V relationships were studied by measuring voltage responses to depolarizing and hyperpolarizing, rectangular current pulses of increasing amplitude from a preset membrane potential of -70 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Early X-irradiation of rats. 5. Influence of irradiation on the development of extracellular field potentials evoked by antidromic stimulation.

Rat pups were treated by low, fragmented and repeated doses of X-rays, from late prenatal days until the end of the third postnatal week. Extracellular field potentials, evoked by antidromic stimulation of the lateral olfactory tract were recorded in different layers of the olfactory bulb at 1, 2, 3 and 6 weeks of age, from control (non-irradiated) and experimental rats. Development of the field potentials was analysed in both groups of animals. In controls, the amplitude of responses was gradually increasing along with age while the latency of peaks decreased; inhibitory waves were tuned even after the third postnatal week. When compared to controls at similar ages, irradiated rats had smaller peak amplitude of responses and the shortening of the response latency was delayed. In addition, a new, late-appearing excitatory wave component was observed in the granule cell layer by the sixth week. The effect of irradiation on field potentials of the olfactory bulb is discussed in light of the marked reduction of the inhibition in the local neuronal assembly, which is also indicated by the depressed development of its structural and neurochemical correlates.

Effects of intracellularly applied aminopyridine on firing activities and synaptic responses of electrophysiologically identified cell types in the motor cortex of cats.

Effects of 3-aminopyridine (3-Ap) applied intracellularly into electrophysiologically identified cortical neurons in the cat motor cortex were studied. Actions on the membrane and firing activity properties, excitatory and inhibitory postsynaptic responses were investigated. Intracellular microelectrode techniques and single electrode voltage clamp methods were used in experiments on anesthetized and chronic nonanesthetized cats. In addition to changes in neuronal excitability and firing activity properties the evoked postsynaptic responses were significantly altered. Augmentation of EPSPs was accompanied by increases of the total duration and amplitude of the second slow component of IPSPs without influencing the early fast IPSP component. It is concluded that most actions of 3-Ap reported here are derived from direct effects of 3-Ap on the postsynaptic membrane.

Synaptic origin of rhythmic visually evoked activity in kitten area 17 neurones.

Rhythmic patterns in neuronal activity in response to moving stimuli were observed in 28% of cells recorded extracellularly or intracellularly in area 17 of 4-16 week old anaesthetized and paralysed kittens. In both recording modes, oscillation frequencies ranged between 7 and 71 Hz, and were confined for 88% of cells in the 7-20 Hz band of the spectrum. A comparative study of firing autocorrelograms) and subthreshold activity (autocorrelation functions) indicates that the regularity of discharge stemmed from visually evoked oscillations of membrane potential at the same frequency. These oscillations are shown to result from extrinsic excitatory activity, since their amplitude, but not their frequency, depends on the resting membrane potential. The dependency on stimulus configuration supports the hypothesis that oscillations in neuronal output are dictated by periodic activity in afferent circuits selectively recruited by different attributes of the visual input which are not exclusively processed at the cortical level.

Properties of associative long-lasting potentiation induced by cellular conditioning in the motor cortex of conscious cats.

Mechanisms of long-lasting potentiation of synaptic responses induced in the thalamocortical and recurrent collateral pathways of the pyramidal tract were studied in intracellular recordings from the motor cortex of unanesthetized, chronically implanted cats. The observations provide the first description of long-lasting potentiation in the unanesthetized neocortex in vivo. Monosynaptic excitatory postsynaptic potentials of 2-5 mV in amplitude were evoked as test responses by stimulation of the pyramidal tract and thalamic ventrolateral nucleus at 0.1-0.5 Hz frequency. Pressure microinjections of drugs and ions were also performed during intracellular recordings. In the first series of experiments, test synaptic responses were paired with intracellular current injection-induced action potentials at an interstimulus interval set between 0-200 ms and 0.1-0.5 Hz frequency. Pairings (30-100 x) induced long-lasting potentiation of the test responses in 58% of cells. The increased synaptic responses typically initiated action potentials and their potentiation usually lasted over the period of recordings. Increases in amplitude of synaptic responses were not correlated with statistically significant changes in electrical membrane properties (resting potential, input resistance, time constant, spike threshold) or parameters of action potentials and their afterpotentials. The failure to induce increases in synaptic efficacy by unpaired stimuli (pseudoconditioning) demonstrated the associative property of the long-lasting potentiation. In a second series of experiments, differential cell conditioning was employed. This paradigm induced long-lasting potentiation of the explicitly paired synaptic response without noticeable modification of unpaired or pseudorandomly paired synaptic responses tested conjointly in the same neuron. These observations demonstrated the input-specificity of long-lasting potentiation. In a third series of experiments, subthreshold depolarizing current pulses were summated with synaptic responses to induce firing in the recorded neuron during pairing. Long-lasting potentiation occurred in 55% of the summated synaptic inputs. Pseudoconditioning did not induce synaptic potentiation in these cells. In a fourth series of experiments, conditioning was employed in neurons in which firing activity was suppressed by an intracellularly injected lidocaine derivative. Long-lasting potentiation was induced in 50% of the attempts when synaptic responses were paired with current-induced depolarizations greater than 30 mV. These results suggest that postsynaptic induction of long-lasting synaptic potentiation can be successful in the absence of postsynaptic sodium spikes in neurons of the motor cortex in vivo. In a fifth series of experiments, homosynaptic high-frequency tetanization (80-200 Hz for 5-15 s) was applied to the thalamocortical and recurrent pyramidal afferents.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of protein kinase C inhibitor H-7 on membrane properties and synaptic responses of neocortical neurons of awake cats.

Electrophysiological effects of intracellularly pressure-injected H-7, an inhibitor of protein kinase C, were investigated in neocortical neurons of awake cats. H-7 reduced spontaneous and depolarizing current-induced firing activity and increased the latency and apparent threshold of action potentials elicited by depolarizing currents. Slow afterhyperpolarizations following action potentials and depolarizing pulses increased after injection of H-7, without detectable changes in the time course of the fast components of the action potentials. H-7 induced increases in IPSPs evoked by stimulation of the ventrolateral thalamus (VL) or the pyramidal tract (PT). Besides slight increases in the amplitude of IPSPs measured at peak, H-7 induced pronounced increases in the amplitude measured 50-100 ms after stimulation and in the total duration of IPSPs. EPSPs evoked by VL or PT stimulation did not show measurable alterations after injection of H-7. The effects occurred 2-15 min after injection of H-7 and lasted at least 90 min without essential changes in the baseline values of resting membrane potential or input resistance. The results suggest that in addition to playing a role in regulating membrane excitability, protein kinase C influences the inhibitory synaptic mechanisms of neocortical neurons.

Properties of depolarizing plateau potentials in aminopyridine-induced ictal seizure foci of cat motor cortex.

The mechanisms of generation of self-sustained depolarizing plateau potentials (DPs) were studied in intracellular recordings in aminopyridine-induced ictal seizure foci in the motor cortex of the cat. In some experiments single-electrode voltage clamp techniques were used and intracellular pressure injection of aminopyridine (Ap), phorbol esters (PhEs) and tetraethylammonium (TEA) was carried out. After several ictal episodes, DPs with bursts of action potentials or with spike inactivation developed gradually in the clonic and interictal phases, without synchronism with surface ictal seizure potentials. In many cases DPs were followed by hyperpolarizing afterpotentials and neuronal inhibition. In bursting neurons DPs originated from the augmented depolarizing envelope of bursts of action potentials. In non-bursting neurons DPs were initiated from summated depolarizing afterpotentials and slow spikes with high threshold, resembling Ca-spikes. In a few neurons DPs were triggered by enlarged excitatory postsynaptic potentials. It was possible to evoke DPs by injections of depolarizing current pulses into single neurons of the Ap-focus, or by intracellular injection of AP, PhEs or TEA. We conclude that DPs are not causal cellular bases of the ictal paroxysmal discharges, rather they occur as consequences of abnormal neuronal activity. It is suggested that DPs are intrinsic regenerative membrane events induced by a transient dominance of voltage-dependent inward currents (carried primarily by calcium ions although sodium ions may contribute) by simultaneous decreases in concurrent outward potassium currents.

An aminopyridine-sensitive, early outward current recorded in vivo in neurons of the precruciate cortex of cats using single-electrode voltage-clamp techniques.

Studies were performed in cortical neurons to determine if voltage- and time-dependent membrane currents could be recognized and characterized in the dynamic, in vivo state. Intracellular measurements made in neurons of the precruciate cortex of awake cats with single-electrode voltage-clamp (SEVC) techniques disclosed an early outward current to depolarizing command steps in 124 of 137 cells studied. The voltage-dependent properties of the early outward current closely resembled those of A-currents studied in vitro in vertebrate and invertebrate neurons. The current was activated rapidly at onset latencies of less than two ms, fell to flat plateau levels within 60-120 ms during sustained depolarization, and was reduced or eliminated in 22 of 23 cells following intracellular administration of 3- or 4-aminopyridine. The magnitude of outward current in response to depolarizing commands was increased by preceding steady hyperpolarization and reduced by preceding steady depolarization. (The steady potentials were of 9.8 s duration and +/- 40 mV apart from the holding potentials.) Since return to the holding potentials occurred 80 ms before the onset of the command steps, the changes in membrane properties that were induced lasted beyond cessation of the steady polarizing stimuli themselves. Spiking did not prevent recognition of the early outward current as judged from its appearance before and after intracellular application of QX-314 to reduce spike activity. Apart from fast inward currents associated with spike potentials, the early outward current was the most conspicuous and characteristic membrane current noted in these recordings. An additional current component that was noted but not characterized in these studies was a slow, depolarization-induced inward current that could be reduced by intracellular injection of QX-314.

Intracellular injection of apamin reduces a slow potassium current mediating afterhyperpolarizations and IPSPs in neocortical neurons of cats.

Electrophysiologic effects of intracellularly injected apamin, a Ca2+-dependent K+ channel blocker, were investigated in neurons of the motor cortex of awake cats. Single-electrode voltage clamp techniques were used to measure changes in membrane currents including those that were synaptically activated. All changes occurred within 2-4 min after pressure injection of apamin with partial recovery observed within 8-15 min. Apamin selectively abolished an outward current that mediated a slow afterhyperpolarization (AHP) following intracellular depolarizing current pulses and action potentials without influencing the time course of the action potentials or an associated fast AHP component. In addition apamin increased the number and frequency of spike discharges evoked by the depolarizing current pulses and produced a small increase in the rate of background firing activity. The baseline resting potential and input resistance were essentially unchanged by apamin. Apamin also diminished a late, slowly decaying component of inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) elicited by stimulation of the ventrolateral thalamus or the pyramidal tract. The apamin-induced changes were concomitant with a decrease of the decay time constant of both IPSPs and IPSCs and a positive shift in their reversal potential. The results suggest that the late, slowly decaying component of these inhibitory postsynaptic responses is generated by an apamin-sensitive Ca2+-dependent K+ conductance which is also responsible for the slow AHP.

Activation of protein kinase C induces long-term changes of postsynaptic currents in neocortical neurons.

Intracellularly injected phorbol 12,13-dibutyrate (PdiB), a phorbol ester that activates protein kinase C (PKC), altered the postsynaptic responses of neurons of the motor cortex of cats. PdiB increased the amplitudes and durations of EPSPs and decreased the amplitudes and durations of IPSPs elicited by stimulation of the ventrolateral (VL) thalamus or the pyramidal tract (PT). The changes lasted for 50 min or longer. Corresponding changes in peak excitatory and inhibitory postsynaptic currents (EPSCs, IPSCs) were measured directly with the single electrode voltage clamp technique. Quantitative analysis of EPSCs in response to VL thalamic stimulation and IPSCs in response to PT stimulation made in a subgroup of fast PT cells suggested that PdiB acted within the injected neuron rather than presynaptically to alter the synaptic currents. No consistent changes in resting membrane parameters that would account for these modifications were found. Control injections of a phorbol ester that did not activate PKC failed to induce changes in synaptic responses or resting membrane properties. These observations suggest that activation of PKC, in vivo, can induce long-lasting changes in synaptic responses of neocortical neurons by direct modification of postsynaptic ion channel conductivities.

Effect of inhibitory amino acid antagonists on IPSPs induced in lumbar motoneurons upon stimulation of the nucleus reticularis gigantocellularis during active sleep.

The present study was performed to generate data implicating glycine or gamma-aminobutyric acid as neurotransmitter candidates mediating the IPSPs which are recorded in lumbar motoneurons following electrical stimulation of the nucleus reticularis gigantocellularis (NRGc) during the atonia of active sleep. Accordingly, intracellular records were obtained from lumbar motoneurons in unanesthetized, normally respiring cats during naturally occurring states of active sleep, while inhibitory amino acid antagonists were microiontophoretically released next to the recorded cell. Electrical stimuli, applied to the NRGc during active sleep under drug-free conditions, evoked inhibitory postsynaptic potentials (IPSPs) in all of the lumbar motoneurons which were examined. These NRGc-induced IPSPs exhibited an average latency-to-onset of 26.6 +/- 1.3 ms, a latency-to-peak of 42.5 +/- 1.3 ms, an average amplitude of 3.9 +/- 0.4 mV and a duration of 34.4 +/- 2.1 ms. Strychnine, when applied microiontophoretically, abolished or markedly suppressed these NRGc-induced IPSPs. In contrast, the microiontophoretic application of picrotoxin or bicuculline methiodide failed to block these IPSPs. To the extent that strychnine may be considered to be a specific antagonist of glycine, the present results suggest that glycine (or a structurally related amino acid) participates in the generation of NRGc-induced IPSPs during the atonia of active sleep.

Intracellular injection of phorbol ester increases the excitability of neurons of the motor cortex of awake cats.

The electrophysiological effects of two intracellularly injected phorbol esters (PhEs) which activate protein kinase C, phorbol 12,13-dibutyrate and phorbol 12-myristate 13-acetate, were investigated in neurons of the motor cortex of awake cats. The major finding was that intracellularly injected PhEs increased the excitability of the neurons. This was indicated by (1) an increase in spontaneous firing and depolarizing current-induced spike activity, accompanied by a decrease in the latency and threshold of current-induced spike discharges, (2) a reduction in slow afterhyperpolarizations following action potentials and depolarizing pulses, and (3) the development of bursting activity. Neither increases in input resistance nor depolarization of the resting potential sufficient to account for these excitability changes were found. Increases in the amplitudes of action potentials and their fast afterhyperpolarizations were also observed. All changes occurred within 2-8 min after injection and lasted for 50 min or longer. Control injections of 4 alpha-phorbol 12,13-didecanoate, which does not activate protein kinase C, failed to induce changes in neuronal excitability or in any of the above parameters. We conclude that the excitability of neurons of the motor cortex of the awake cats can be increased by phorbol esters that translocate and activate protein kinase C.