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PubMed1975

Pancreatic islet cells: effects of monosaccharides, glycolytic intermediates and metabolic inhibitors on membrane potential and electrical activity.

1. The effects of monosaccharides, glycolytic intermediates, metabolic inhibitors and anxia, have been studied on the membrane electrical activity of mouse pancreatic islet cells in vitro using a single intracellular micro-electrode for both voltage recording and current injection. 2. In addition to D-glucose (28mM), D-mannose (16-6mM), and L-leucin (10mM), the substances D-glyceraldehyde (11mM), and acetoacetate (20 mM), induced action potentials in islet cells but other glucos analogues and metabolic intermediates including L-glucose dod not. 3. Mannoheptulose 20 mM), but not D-galactose or 2-deoxy-D-glucose, antagonized the electrical activity induced in islet cells by D-glucose, 28mM. Prior treatment of the cells with mannoheptulose caused them to hyperpolarize and completely prevented the appearance of electrical activity on subsequent exposure to D-glucose. 4. Electrical activity induced by D0glucose 28mM, was progressively inhibited by phloridzin, 10mM, if the cells were exposed to D-glucose and inhibitor simultaneously, and abolished on pretreatment with inhibitor for 30-60 min. Phloridzin also caused depolarization of the islet cells which was independent of extracellular glucose. 5. Anoxia completely blocked the electrical activity induced by glucose but not that evoked by D-glyceraldehyde, L-leucine, tolbutamide or glibenclamide. 6. Iodoacetic acid, 5 mM, rapidly blocked glucose-induced electrical activity whilst that elicited by tolbutamide was relatively resistant to inhibition. 7. The nature and possible location of the glucoreceptor in pancreatic islet cells is discussed in relation to the origin and functional significance of glucose-induced electrical activity and insulin secretion.

Acetoacetates↗
PubMed1999

Electrolytic generation of oxygen partially explains electrical enhancement of tobramycin efficacy against Pseudomonas aeruginosa biofilm.

The role of electrolysis products, including protons, hydroxyl ions, reactive oxygen intermediates, oxygen, hydrogen, and heat, in mediating electrical enhancement of killing of Pseudomonas aeruginosa biofilms by tobramycin (the bioelectric effect) was investigated. The log reduction in biofilm viable cell numbers compared to the numbers for the untreated positive control effected by antibiotic increased from 2.88 in the absence of electric current to 5.58 in the presence of electric current. No enhancement of antibiotic efficacy was observed when the buffer composition was changed to simulate the reduced pH that prevails during electrolysis. Neither did stabilization of the pH during electrical treatment by increasing the buffer strength eliminate the bioelectric effect. The temperature increase measured in our experiments, less than 0.2 degree C, was far too small to account for the greatly enhanced antibiotic efficacy. The addition of sodium thiosulfate, an agent capable of rapidly neutralizing reactive oxygen intermediates, did not abolish electrical enhancement of killing. The bioelectric effect persisted when all of the ionic constituents of the medium except the two phosphate buffer components were omitted. This renders the possibility of electrochemical generation of an inhibitory ion, such as nitrite from nitrate, an unlikely explanation for electrical enhancement. The one plausible explanation for the bioelectric effect revealed by this study was the increased delivery of oxygen to the biofilm due to electrolysis. When gaseous oxygen was bubbled into the treatment chamber during exposure to tobramycin (without electric current), a 1.8-log enhancement of killing resulted. The enhancement of antibiotic killing by oxygen was not due simply to physical disturbances caused by sparging the gas because similar delivery of gaseous hydrogen caused no enhancement whatsoever.

Anti-Bacterial Agents↗
PubMed1999

Utilization of electrically reduced neutral red by Actinobacillus succinogenes: physiological function of neutral red in membrane-driven fumarate reduction and energy conservation.

Neutral red (NR) functioned as an electronophore or electron channel enabling either cells or membranes purified from Actinobacillus succinogenes to drive electron transfer and proton translocation by coupling fumarate reduction to succinate production. Electrically reduced NR, unlike methyl or benzyl viologen, bound to cell membranes, was not toxic, and chemically reduced NAD. The cell membrane of A. succinogenes contained high levels of benzyl viologen-linked hydrogenase (12.2 U), fumarate reductase (13.1 U), and diaphorase (109.7 U) activities. Fumarate reductase (24.5 U) displayed the highest activity with NR as the electron carrier, whereas hydrogenase (1.1 U) and diaphorase (0.8 U) did not. Proton translocation by whole cells was dependent on either electrically reduced NR or H2 as the electron donor and on the fumarate concentration. During the growth of Actinobacillus on glucose plus electrically reduced NR in an electrochemical bioreactor system versus on glucose alone, electrically reduced NR enhanced glucose consumption, growth, and succinate production by about 20% while it decreased acetate production by about 50%. The rate of fumarate reduction to succinate by purified membranes was twofold higher with electrically reduced NR than with hydrogen as the electron donor. The addition of 2-(n-heptyl)-4-hydroxyquinoline N-oxide to whole cells or purified membranes inhibited succinate production from H2 plus fumarate but not from electrically reduced NR plus fumarate. Thus, NR appears to replace the function of menaquinone in the fumarate reductase complex, and it enables A. succinogenes to utilize electricity as a significant source of metabolic reducing power.

Actinobacillus↗
PubMed1988

Electrical correlate of circumferential contractions in human colonic circular muscle.

The role of myogenic electrical activity in the coordination of circumferential contraction of the human colon circular muscle was investigated. Five suction electrodes were placed (5-7 mm apart) on isolated rings of human colon and simultaneously electrical and motor activities were measured. In normal Krebs solution, the slow waves were not synchronised in most preparations studied. The electrical activities at the different recording sites were different with respect to slow wave frequency and amplitude, and amount of spiking activity. This resulted in irregular contractile activity. Cholinergic stimulation resulted in the development of a specific pattern of electrical activity: periodic slow wave activity with superimposed spiking activity which was synchronised over the length of the segment studied. This synchronised electrical activity resulted in regular phasic contractions at the frequency of the bursts of electrical activity (approximately 1/min). The response to carbachol was mediated by muscarinic receptors since it was blocked by atropine. The periodic activity in the continuous presence of carbachol was not the result of periodic input of neural activity as it occurred in the presence of TTX. Intrinsic properties of the muscle cells were responsible for the carbachol induced pattern of activity. The present study presents evidence that the electrical correlate of circumferential contractions is different in man compared with the most commonly studied animal models. It is a specific, stimulus induced pattern of myogenic activity. Its characteristics closely resemble those of a particular pattern of in vivo recorded activity referred to as the 'long spike bursts'.

Action Potentials↗
PubMed2004

Electrical synapses in the mammalian brain.

Many neurons in the mammalian central nervous system communicate through electrical synapses, defined here as gap junction-mediated connections. Electrical synapses are reciprocal pathways for ionic current and small organic molecules. They are often strong enough to mediate close synchronization of subthreshold and spiking activity among clusters of neurons. The most thoroughly studied electrical synapses occur between excitatory projection neurons of the inferior olivary nucleus and between inhibitory interneurons of the neocortex, hippocampus, and thalamus. All these synapses require the gap junction protein connexin36 (Cx36) for robust electrical coupling. Cx36 appears to interconnect neurons exclusively, and it is expressed widely along the mammalian neuraxis, implying that there are undiscovered electrical synapses throughout the central nervous system. Some central neurons may be electrically coupled by other connexin types or by pannexins, a newly described family of gap junction proteins. Electrical synapses are a ubiquitous yet underappreciated feature of neural circuits in the mammalian brain.

Action Potentials↗
PubMed1984

"Functional polarity" of the spinal cord caused by its longitudinal electric dipole moment.

Specific reactions of the vertebrates that occur through lengthwise application of direct-current (DC) electric fields in the spinal cord and are dependent on the direction of the current (e.g., electric narcosis and electric excitation) can be explained by the existence of a longitudinal dipole moment in the spinal cord. The relationship between "functional polarity of the spinal cord" and its longitudinal dipole moment was established in two different experimental series. 1) Reactions of functional polarity were quantitatively tested on Amphioxus (lancelet) and on numerous Teleostei. On this point the findings of other researchers were confirmed and complemented. 2) Fresh, almost-live spinal cord preparations (cow) were quantitatively tested using pyroelectric (PE) methods. A longitudinal electric dipole moment was demonstrated along the entire length of the white matter. Moreover fresh spinal cord preparations showed a polar orientation on sudden temperature change in a high-voltage DC field. The PE behavior showed a pronounced electric field dependence. Because the white matter is largely composed of longitudinally arranged nerve fibers, individual axons may also have a longitudinal electric dipole moment. Consequently one might expect the following: polar orientation of the growing neurite by an applied DC field, an electric dipole field inside and outside the axon, and a transport of charge carriers along the lines of flux of this dipole field. Moreover PE and piezoelectric (PZE) properties of the neuron should be provable.

Animals↗
PubMed2003

Modeling interactions between electrical activity and second-messenger cascades in Aplysia neuron R15.

The biophysical properties of neuron R15 in Aplysia endow it with the ability to express multiple modes of oscillatory electrical activity, such as beating and bursting. Previous modeling studies examined the ways in which membrane conductances contribute to the electrical activity of R15 and the ways in which extrinsic modulatory inputs alter the membrane conductances by biochemical cascades and influence the electrical activity. The goals of the present study were to examine the ways in which electrical activity influences the biochemical cascades and what dynamical properties emerge from the ongoing interactions between electrical activity and these cascades. The model proposed by Butera et al. in 1995 was extended to include equations for the binding of Ca(2+) to calmodulin (CaM) and the actions of Ca(2+)/CaM on both adenylyl cyclase and phosphodiesterase. Simulations indicated that levels of cAMP oscillated during bursting and that these oscillations were approximately antiphasic to the oscillations of Ca(2+). In the presence of cAMP oscillations, brief perturbations could switch the electrical activity between bursting and beating (bistability). Compared with a constant-cAMP model, oscillations of cAMP substantially expanded the range of bistability. Moreover, the integrated electrical/biochemical model simulated some early experimental results such as activity-dependent inactivation of the anomalous rectifier. The results of the present study suggest that the endogenous activity of R15 depends, in part, on interactions between electrical activity and biochemical cascades.

Adenylyl Cyclases↗
PubMed1996

Electrical properties of neocortical neurons in slices from children with intractable epilepsy.

1. The intrinsic electrical properties of human neocortical neurons were studied with current-clamp and single-electrode voltage-clamp techniques in slices obtained from children, aged 3 mo to 15 yr, undergoing surgical treatment of intractable epilepsy. Neocortical samples were classified as most or least abnormal based on clinical data. Recorded neurons were labeled with biocytin for correlation of electrical properties with morphological characteristics and laminar position. All recorded neurons were divided into three cell types--fast-spiking, low-threshold spiking (LTS) and non-LTS cells--on the basis of their electrical characteristics. 2. Fast-spiking cells generated brief, rapidly repolarizing action potentials. Most of these cells showed only weak spike-frequency adaptation. Fast-spiking cells labeled with biocytin were aspiny or sparsely spiny nonpyramidal neurons located in cortical layers 2-4. 3. LTS cells generated Ca(2+)-dependent low-threshold potentials and were the most numerous of the three cell types. Their Na(+)-dependent action potentials were broader than those of fast-spiking cells and showed marked spike-frequency adaptation. The size of low-threshold Ca2+ potentials and currents varied across cells, but they never supported more than two or, occasionally, three fast action potentials. LTS cells were pyramidal neurons located throughout cortical layers 2-6. Unlike the bursting neocortical cells described in lower mammals, LTS neurons in neocortex from children failed to generate bursts of inactivating Na+ action potentials. 4. Non-LTS cells also had relatively broad Na(+)-dependent action potentials and showed spike-frequency adaptation, but they did not generate detectable low-threshold potentials or currents. Non-LTS cells were also pyramidal neurons located throughout layers 2-6. 5. The electrical properties of cells from different age groups (< or = 1, 2-8, and 9-15 yr) and from most-abnormal and least-abnormal tissue samples were compared. A statistically significant trend toward a lower input resistance, a faster membrane time constant, and a decreased spike duration was observed with increasing age. There were no significant differences between the electrical properties of cells from the most-abnormal tissue and cells from the least-abnormal tissue. 6. These data indicate that the intrinsic electrical properties of neocortical neurons from children vary according to cell morphology and change with increasing age, as has been observed in rodent and feline neocortical neurons. No obvious evidence of epileptogenicity was detected in the intrinsic electrical properties of any of the neurons studied.

Action Potentials↗
PubMed1999

Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Animals↗
PubMed2006

Integrin activation in the heart: a link between electrical and contractile dysfunction?

Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated alpha(5) integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca(2+) transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca(2+) is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.

Animals↗
PubMed2002

Electric field enhanced plasmid delivery to liver hepatocellular carcinomas.

Electric field enhanced molecular delivery for cancer research and treatment is a new technology that has demonstrated its effectiveness in clinical trials using bleomycin or cisplatin (Heller, R., Gilbert, R., Jaroszeski, M. J. Clinical applications of electrochemotherapy, Advanced Drug Delivery Reviews 35,119-129, 1999), as chemotherapeutic agents. The technology is being investigated in research applications for applicability as a method to enhance gene expression in a target tumor. Success is predicated on an appropriate effective electric field mediated delivery protocol that triggers significant appropriate gene expression duration and levels. An electric field mediated delivery protocol includes a set of conditions associated with the electric field, the electroporation signature, as well as parameters associated with the plasmid and the electric field applicator. Manipulation of the electrical parameters within the electroporation signature generates different gene expression levels in liver hepatocellular carcinomas. Statistically significant gene expression levels were obtained that differed by an order of magnitude when two different electric field strength and duration conditions were employed.

Animals↗
PubMed2006

Electric-current-assisted application of self-etch adhesives to dentin.

The use of electric current during the application of etch-and-rinse adhesive systems has been recently claimed to increase bonding of etch-and-rinse adhesives by enhancing substrate impregnation. The null hypothesis tested in this study was that electrically assisted application has no effect on bond strength of self-etching bonding systems. Three self-etch adhesives (Protect-Bond, Xeno III, and Prompt L-Pop) were applied with the aid of an electric signal-generating device (ElectroBond) and tested vs. controls prepared with the same disposable sponges but without electric current. Specimens bonded under the influence of electric current exhibited increased microtensile bond strength compared with the controls (p<0.05). High-resolution SEM analysis showed that bonding under the influence of electricity reduced interfacial nanoleakage. It is speculated that resin infiltration may be improved by the attraction of polar monomers by an electric current or by modification of the dentin surface charges, resulting in better water substitution or evaporation.

Ammonia↗
PubMed2006

Continuous assessment of electrical epileptic activity in acute stroke.

OBJECTIVE: To determine the incidence and risk factors of electrical seizures and other electrical epileptic activity using continuous EEG (cEEG) in patients with acute stroke. METHODS: One hundred consecutive patients with acute stroke admitted to our stroke unit underwent cEEG using 10 electrodes. In addition to electrical seizures, repetitive focal sharp waves (RSHWs), repetitive focal spikes (RSPs), and periodic lateralized epileptic discharges (PLEDs) were recorded. RESULTS: In the 100 patients, cEEG was recorded for a mean duration of 17 hours 34 minutes (range 1 hour 12 minutes to 37 hours 10 minutes). Epileptic activity occurred in 17 patients and consisted of RSHWs in seven, RSPs in seven, and PLEDs in three. Electrical seizures occurred in two patients. On univariate Cox regression analysis, predictors for electrical epileptic activity were stroke severity (high score on the National Institutes of Health Stroke Scale) (hazard ratio [HR] 1.12; p = 0.002), cortical involvement (HR 5.71; p = 0.021), and thrombolysis (HR 3.27; p = 0.040). Age, sex, stroke type, use of EEG-modifying medication, and cardiovascular risk factors were not predictors of electrical epileptic activity. On multivariate analysis, stroke severity was the only independent predictor (HR 1.09; p = 0.016). CONCLUSION: In patients with acute stroke, electrical epileptic activity occurs more frequently than previously suspected.

Adult↗
PubMed2005

Golgi polarization in a strong electric field.

Directional cell migration requires proper cell polarization. The redistribution of the Golgi apparatus is an important event in the polarization and migration of many types of cells, as a polarized Golgi supplies membrane components for leading edge protrusion. Direct current electric fields induce directional cell migration in a wide variety of cells. Here we show that electric fields of 300 mV/mm induce robust Golgi polarization and directional cell migration in CHO cells. Asymmetric Src and PI 3-kinase signalling as well as actin polymerization are essential for electric field-induced Golgi polarization and directional cell migration. The Golgi polarizes at the same time as cells change morphology and migrate directionally in response to an electric field. Golgi polarization in turn significantly reinforces and maintains optimal electrotaxis. It is not known whether electrical signals, when contradicting other directional cues, are still able to polarize cells and direct cell migration. Most strikingly, Golgi polarization and cell migration simply follow the direction of an applied electric field and ignore all other cues generated by wounding a monolayer of CHO cells. Thus, an electric field of 300 mV/mm is the predominant cue to polarize the Golgi and direct cell migration mediated by PI 3-kinase and Src signalling.

Actins↗
PubMed2004

Voltage-dependent enhancement of electrical coupling by a subthreshold sodium current.

Voltage-dependent changes in electrical coupling are often attributed to a direct effect on the properties of gap junction channels. Identifiable auditory afferents terminate as mixed (electrical and chemical) synapses on the distal portion of the lateral dendrite of the goldfish Mauthner cells, a pair of large reticulospinal neurons involved in the organization of sensory-evoked escape responses. At these afferents, the amplitude of the coupling potential produced by the retrograde spread of signals from the postsynaptic Mauthner cell is dramatically enhanced by depolarization of the presynaptic terminal. We demonstrate here that this voltage-dependent enhancement of electrical coupling does not represent a property of the junctions themselves but the activation of a subthreshold sodium current present at presynaptic terminals that acts to amplify the synaptic response. We also provide evidence that this amplification operates under physiological conditions, enhancing synaptic communication from the Mauthner cells to the auditory afferents where electrical and geometrical properties of the coupled cells are unfavorable for retrograde transmission. Retrograde electrical communication at these afferents may play an important functional role by promoting cooperativity between afferents and enhancing transmitter release. Thus, the efficacy of an electrical synapse can be dynamically modulated in a voltage-dependent manner by properties of the nonjunctional membrane. Finally, asymmetric amplification of electrical coupling by intrinsic membrane properties, as at the synapses between auditory afferents and the Mauthner cell, may ensure efficient communication between neuronal processes of dissimilar size and shape, promoting neuronal synchronization.

Animals↗
PubMed2006

Electrically-assisted nucleic acids delivery to tissues in vivo: where do we stand?

Electropulsation (electroporation) is a physical method for delivery of various molecules into the cells in vitro and in vivo. It is an expanding field due to its applicability in cancer therapy, where combined application of electric pulses and chemotherapeutic drugs is used for treatment of cutaneous and subcutaneous nodules of different malignancies. Another application of electropulsation in vivo is electrogene therapy, where after injection of naked plasmid DNA and delivery of electric pulses directly to the tissue the expression of gene of interest can be obtained. However, the transfection efficiency of this methodology in vivo is still lower than with viral vectors. Nevertheless, due to the lack of immunogenicity of the method, easiness of the preparation of large quantities of endotoxin free plasmid DNA, control and reproducibility of the method and the development of electropulsators approved for the clinical use, electrically-assisted nucleic-acid delivery holds a great potential for the clinical application. This aim of this minireview is to critically discuss the main limitations and obstacles associated with electrogene therapy and the failures and problems as well as the successes. Topics on electric field distribution in the tissue, electrode geometries, construction of plasmid, modulation of extracellular space, tissue damage, pro-inflammatory and immune response as well as blood flow modification associated with application of electric pulses and injection of naked DNA are presented with possible directions how to overcome these limitations. Furthermore, for successful electrogene therapy in clinical setting it is of utmost importance to elucidate the mechanisms of DNA transfer into the cells of tissues in vivo. This will enable appropriate selection of electric pulse parameters and plasmid DNA constructs for each particular intended use. In the long run, this review should encourage other scientists to consider electrically assisted gene delivery for gene therapy as it matures.

Age Factors↗
PubMedDate not supplied

In vitro electro-mechanical activity of the human colon. Simultaneous recording of the electrical patterns of the two muscle layers.

Electrical and mechanical activity on longitudinal and circular layers of the human sigmoid colon were simultaneously studied. Recordings were obtained from two electrode sites spaced 3 cm apart in a piece of colon which had been resected surgically and perfused in an organ bath. Spontaneous electrical activity of the colon showed slow waves and spikes. Slow waves were present for only 24.5% and 12% of the recording time on the longitudinal and circular layers, respectively, and they appeared as localized activity which was irregular in amplitude and varying in frequency. Electrical coupling between the two muscle layers was rarely seen and slow waves were not associated with pressure changes. Spiking activity were recorded as short and long spike bursts on both muscle layers. Short spike bursts were localized activity superimposed on slow waves. The associated mechanical activity, which consisted of single weak pressure changes or prolonged contractions with summation, was determined by slow wave frequency. Long spike bursts were seen at irregular intervals and were either propagated or not propagated activity associated with electrical oscillations ranging from 24 to 46 cpm. Mechanical activity consisted of sustained tonic contractions propagated or not propagated in the same way as the electrical pattern. Coordinated electrical activity of the two muscle layers seldom occurred when spontaneous activity was being recorded. Electrical activity on both muscle layers was very sensitive to stretching and could be initiated or modulated by pharmacological agents. In particular, our findings showed that stimulation induced coordinated spiking activity on the two muscle layers and caused mechanical activity, propagated orally or aborally, which consisted of long lasting, high amplitude contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1979

Behavioral effects of self-administered cocaine: responding maintained alternately by cocaine and electric shock in squirrel monkeys.

Squirrel monkeys responded under a fixed-interval schedule of intravenous cocaine injection that alternated with a fixed-interval schedule of either presentation of electric shock or termination of a stimulus associated with electric shock. As the dose of cocaine was increased from 10 to 1000 microgram/kg/injection, responding maintained by cocaine injection or alternately by electric shock first increased and then decreased. The lowest doses of cocaine that reliably maintained self-administration often increased responding maintained by electric shock; the highest doses of cocaine that continued to maintain self-administration often decreased responding maintained by electric shock. When saline was substituted for cocaine, responding that had previously been maintained by cocaine injection occurred irregularly and at very low rates, whereas rates and patterns of responding maintained by electric shock were characteristic of fixed-interval schedules. When the fixed-interval schedule of cocaine injection was replaced by intravenous injections that occurred without regard to antecedent responding, the effects of cocaine on responding maintained by electric shock were found to be independent of the way in which cocaine was administered.

Animals↗