Phasic firing time locked to cocaine self-infusion and locomotion: dissociable firing patterns of single nucleus accumbens neurons in the rat

The activity of single nucleus accumbens (NAcc) neurons of rats was extracellularly recorded during intravenous cocaine self-administration sessions (0.7 mg/kg per infusion, fixed ratio 1). We reported previously that NAcc neurons showed a change, usually a decrease, in firing rate during the first 1 min after the cocaine-reinforced lever press. This postpress change was followed by a progressive reversal of that change, which began within the first 2 min after the press and was not complete until the last 1 min before the next lever press (termed the change + progressive reversal firing pattern). In the present study we documented a regular pattern of locomotion that occurred in parallel with the change + progressive reversal firing pattern. This observation suggested that discharges time locked to locomotion may determine the change + progressive reversal firing pattern. However, 55% of the neurons failed to show firing time locked to locomotion that could have contributed to the change + progressive reversal firing pattern. Moreover, for all neurons, the change + progressive reversal firing pattern was apparent even if the calculation of firing rate excluded all periods of locomotion. The present data showed that the change + progressive reversal firing pattern is not solely attributable to phasic changes in firing time locked to the execution of locomotion. The change + progressive reversal firing pattern closely mirrors changes in drug level and dopamine overflow observed by previous researchers and may thus be a component of the neurophysiological mechanism by which drug level regulates drug-taking behavior during an ongoing self-administration session.     

Patterns of excitatory and inhibitory synaptic transmission in the rat neostriatum as revealed by 4-AP

1. Synaptic potentials induced by 4-aminopyridine (4-AP) were recorded intracellularly from rat neostriatal neurons in an in vitro slice preparation. EC50 for this 4-AP action was approximately 120 microM. The threshold for activation of synaptic potentials was 5 microM. 2. 4-AP-induced synaptic potentials appeared stochastically. Most were blocked by 1 microM tetrodotoxin or 400 microM Cd2+. Therefore they reflect a release of neurotransmitters dependent on both Ca2+ entry to the terminals and action potential firing. 3. Bicuculline (BIC) (< or = 10 microM), a gamma-aminobuturic acid-A (GABAA) antagonist, blocked about half of the 4-AP-induced synaptic potentials. This suggests that intrinsic inhibitory connections within the neostriatum are activated by 4-AP administration. 4. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; < or = 10 microM) plus D-2-amino-5-phosphonovaleric acid (D-APV; < or = 100 microM) blocked most of the BIC-resistant 4-AP-induced synaptic potentials. This suggests that 4-AP induced release of glutamate (GLU) from extrinsic glutamatergic afferents. As most glutamatergic afferents are extrinsic, these afferents then would be able to fire spikes and release transmitter for several hours after they are cut from their somata. 5. If CNQX plus D-APV were administered before BIC, neostriatal neurons responded in different ways. In one half of the neurons, all induced synaptic potentials were blocked. This suggests that most GABAergic intrinsic connections between neostriatal neurons are activated indirectly by 4-AP. 4-AP would first activate extrinsic glutamatergic afferents and these in turn would activate GABAergic intrinsic neurons and connections. 6. In the remaining half of the recorded neurons, administration of CNQX plus D-APV blocked most, but not all of the 4-AP-induced synaptic potentials. The synaptic potentials that remained had a characteristic pattern: they were high amplitude, rhythmic, bursts of synaptic potentials. They were blocked by BIC (5 microM) but not by mecamylamine (> 10 microM). This suggests that these bursts of synaptic potentials were GABAergic and generated by intrinsic neurons. Therefore these neurons would not innervate all neostriatal neurons equally but just a subset of them. 7. Records from an identified aspiny neostriatal interneuron, obtained from the same preparation, are shown. This interneuron fired in bursts and its morphologically and physiologically similar to the recently described, fast spiking, parvalbumin immunoreactive, GABAergic, aspiny interneuron is functional in the slice preparation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene

Glutamatergic synaptic potentials induced by micromolar concentrations of the potassium conductance blocker 4-aminopyridine (4-AP) were recorded intracellularly from rat neostriatal neurons in the presence of 10 microM bicuculline (BIC). These synaptic potentials originate from neostriatal cortical and thalamic afferents and were completely blocked by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) plus 100 microM D-2-amino-5-phosphonovaleric acid (2-APV). Their inter-event time intervals could be fitted to exponential distributions, suggesting that they are induced randomly. Their amplitude distributions had most counts around 1 mV and fewer counts with values up to 5 mV. Since input resistance of the recorded neurons is about 40 M omega, the amplitudes agree to quantal size measurements in mammalian central neurons. The action of a D2 agonist, quinpirole, was studied on the frequency of these events. Mean amplitude of synaptic potentials was preserved in the presence of 2-10 microM quinpirole, but the frequency of 4-AP-induced glutamatergic synaptic potentials was reduced in 35% of cases. The effect was blocked by the D2 antagonist sulpiride (10 microM). Input resistance, membrane potential, or firing threshold did not change during quinpirole effect, suggesting a presynaptic site of action for quinpirole in some but not all glutamatergic afferents that make contact on a single cell. The present experiments show that dopaminergic presynaptic modulation of glutamatergic transmission in the neostriatum does not affect all stimulated afferents, suggesting that it is selective towards some of them. This may control the quality and quantity of afferent flow upon neostriatal neurons.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.     

CHRONOMERGE: an application for the merging and display of multiple time-stamped data streams

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.     

Coding of serial order by neostriatal neurons: a "natural action" approach to movement sequence

The neostriatum controls behavioral sequencing, or action syntax, as well as simpler aspects of movement. Yet the precise nature of the neostriatums role in sequencing remains unclear. Here we used a "natural action" approach that combined electrophysiological and neuroethological techniques. We identified neostriatal neurons that code the serial order of natural movement sequences of rats. During grooming behavior, rats emit complex but highly predictable species-specific sequences of movements, termed "syntactic chains." Neuronal activity of 41% of cells in the dorsolateral and ventromedial neostriatum coded the sequential pattern of syntactic chains. Only 14% coded simple motor properties of grooming movements. Neurons fired preferentially during syntactic chains compared with similar grooming movements made in different sequential order or to behavioral resting. Sequential coding differed between the dorsolateral and ventromedial neostriatum. Neurons in the dorsolateral site increased firing by 116% during syntactic chains, compared with only a 30% increase by neurons in the ventromedial site, and dorsolateral neurons showed strongest coding of grooming syntax by several additional criteria. These data demonstrate that neostriatal neurons code abstract properties of serial order for natural movement and support the hypothesis that the dorsolateral neostriatum plays a special role in implementing action syntax.     

Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat

A subpopulation of neurons in the globus pallidus projects to the neostriatum, which is the major recipient of afferent information to the basal ganglia. Given the moderate nature of this projection, we hypothesized that the pallidostriatal projection might exert indirect but powerful control over principal neuron activity by targeting interneurons, which comprise only a small percentage of neostriatal neurons. This was tested by the juxtacellular labeling and recording of pallidal neurons in combination with immunolabeling of postsynaptic neurons. In addition to innervating the subthalamic nucleus and output nuclei, 6 of 23 labeled pallidal neurons projected to the neostriatum. Both the firing characteristics and the extent of the axonal arborization in the neostriatum were variable. However, light and electron microscopic analysis of five pallidostriatal neurons revealed that each neuron selectively innervated neostriatal interneurons. A large proportion of the boutons of an individual axon (19-66%) made contact with parvalbumin-immunoreactive interneurons. An individual parvalbumin-immunoreactive neuron (n = 27) was apposed on average by 6.7 boutons (SD = 6.1) from a single pallidal axon (n = 2). Individual pallidostriatal boutons typically possessed more than one symmetrical synaptic specialization. In addition, 3-32% of boutons of axons from four of five pallidal neurons contacted nitric oxide synthase-immunoreactive neurons. Descending collaterals of pallidostriatal neurons were also found to make synaptic contact with dopaminergic and GABAergic neurons of the substantia nigra. These data imply that during periods of cortical activation, individual pallidal neurons may influence the activity of GABAergic interneurons of the neostriatum (which are involved in feed-forward inhibition and synchronization of principle neuron activity) while simultaneously patterning neuronal activity in basal ganglia downstream of the neostriatum.     

Rapid, corticosterone-induced disruption of medullary sensorimotor integration related to suppression of amplectic clasping in behaving roughskin newts (Taricha granulosa)

Endogenously secreted or injected corticosterone (CORT) rapidly suppresses courtship clasping in male roughskin newts (Taricha granulosa) by an action on a specific neuronal membrane receptor. Previous studies, using immobilized newts, showed that CORT administration rapidly depresses excitability of reticulospinal neurons and attenuates medullary neuronal responsiveness to clasp-triggering sensory stimuli. The present study used freely moving newts to examine clasping responses and concurrently record sensorimotor properties of 67 antidromically identified reticulospinal and other medullary reticular neurons before and after CORT injection. Before CORT, reticulospinal neurons fired in close association with onset and offset of clasps elicited by cloacal pressure. Reticulospinal neurons also showed firing correlates of nonclasping motor events, especially locomotion. Neuronal activity was typically reduced during clasping and elevated during locomotion. Medullary neurons that were not antidromically invaded (unidentified neurons) usually showed sensorimotor properties that resembled those of reticulospinal neurons. Intraperitoneal CORT (but not vehicle) reduced the probability and quality of hindlimb clasping in response to cloacal pressure, especially within 5-25 min of injection. Simultaneously, responses of reticulospinal and unidentified neurons to cloacal pressure and occurrence of clasping-related activity were attenuated or eliminated. CORT effects were relatively selective, altering clasping-related neuronal activity more strongly than activity associated with nonclasping motor events. The properties of CORT effects indicate that the hormone impairs clasping by depressing processing of clasp-triggering afferent activity and by disrupting the medullary control of clasping normally mediated by reticulospinal neurons. The rapid onset of these CORT effects implicates a neuronal membrane receptor rather than genomic action of the steroid.     

Cocaine-induced activation of striatal neurons during focused stereotypy in rats

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.     

Maximum discharge rates of respiratory neurons during opossum development

The observed low frequencies of action potentials observed in medullary respiratory neurons of immature opossums (Didelphis virginiana) could occur because these cells are incapable of achieving higher sustained firing rates. Nonsustainability of firing might also help explain why the inspired breath is brief (approximately 0.1 s) in the youngest opossums and rises very slowly during postnatal life. Firing frequencies of medullary respiratory neurons were examined in spontaneously breathing thiobarbiturate-anesthetized opossums before and after stimulation by the glutamate agonists, N-methyl-D-aspartate (NMDA; 20 mM) or kainic acid (KA; 0.5 mM). Drugs were applied using progressively larger pressure injections through a micropipette; animals were tested from the 5th postnatal wk to adulthood. With a sufficient injection volume, stimulation of cell firing would be followed by apparent suppression of action potentials. A maximum "sustained" firing frequency was obtained from the last injection where discharge remained elevated for at least 0.5 s. Inspiratory and expiratory neurons tested with either drug showed the lowest rates of firing in opossums at 5-9 wk of age compared with 10- to 14-wk-old animals and/or adults. Despite higher rates of discharge in 10- to 14-wk-old animals and/or adults, maximum sustained neuronal firing in the youngest animals was at a higher frequency than during spontaneous breathing and, at least in the cell population tested, does not represent a limitation that might affect breathing pattern.     

Neural firing in ventrolateral thalamic nucleus during conditioned vocal behavior in cats

The ventrolateral (VL) thalamus in mammals is a site well-situated to show vocalization-related neural activity if there is general or classical motor system involvement in vocal production. It receives input from both the basal ganglia and cerebellum, and forms reciprocal connections with motor cortical areas. The current study examined the activity in cat VL thalamus neurons during instrumentally conditioned vocalization. Units in our sample showed irregular spontaneous firing which could be modulated by slowly occurring fluctuations in intensity of vocalization task performance. Two main types of behavioral events were associated with changes in neural firing rate. The first of these was the ingestion of food reward. More than half of all recordings showed phasic bursting patterns during licking; a similar number had increases in firing preparatory to this phasic activity. The second behavioral event modulating unit responses was vocalization. Approximately 60% of recordings showed activity changes time-locked to vocalization. These responses were almost always excitatory, and often involved changes in firing that preceded vocalization onset. No spatial organization of differences in firing pattern between neurons could be distinguished. Our results suggest that VL thalamus may well be involved in mediating vocal behavior, although its functional role remains an object of speculation. Results are compared with previous studies of vocalization-related activity and of VL thalamus activity.     

Sensory responsiveness of "broad-spike" neurons in the laterodorsal tegmental nucleus, locus coeruleus and dorsal raphe of awake rats: implications for cholinergic and monoaminergic neuron-specific responses

Although cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei have been shown to have a pivotal role in neural mechanisms of paradoxical sleep, their function during wakefulness is less understood. To examine the latter, we have recorded from "broad-spike neurons", which were distinguished by their long spike duration, in the laterodorsal tegmental nucleus of undrugged, head-restrained rats, and examined their response properties to sensory stimuli such as light touch to the tail, air puff to the face, 2 kHz pure tone and flashes of light. Broad-spike neurons from the locus coeruleus and dorsal raphe nucleus were studied for comparison; these neurons have been demonstrated to be noradrenergic and serotonergic, respectively. The broad-spike neurons in the laterodorsal tegmental nucleus have also been suggested to be cholinergic. There were two kinds of responses: (1) a simple increase or decrease in firing, reflecting an elevated level of vigilance; and (2) a phasic response composed of a single spike or brief, high frequency burst, usually diminishing or disappearing upon repetition of the stimulus. When two or more types of stimuli were effective in a neuron, they evoked responses of the same quality. Most of the dorsal raphe neurons displayed only the simple increase of firing, whereas the locus coeruleus neurons gave a phasic response with rather weak attenuation upon repetition. Compared with these, the laterodorsal tegmental neurons were heterogeneous: about one-quarter showing only a simple change of firing (half increasing, half decreasing); and two-thirds displaying phasic responses. The latter response of many neurons attenuated strongly upon repetition. The laterodorsal tegmental neurons were classified into several groups according to their spontaneous firing behavior during sleep and wakefulness, but every neuron in a group did not show the same type of response. For example, some of the neurons which were most active during paradoxical sleep and essentially silent during wakefulness decreased or stopped firing upon sensory stimulation, while others in this group had strong phasic responses. These results suggest that putative cholinergic neurons in the laterodorsal tegmental nucleus have heterogenous properties not only with respect to their spontaneous activity during sleep and wakefulness but also with respect to their response to sensory stimulation. Some of these neurons may function to induce a global attentive state in response to a novel stimulus.     

Ascending afferent regulation of rat midbrain dopamine neurons

Standard, extracellular single-unit recording techniques were used to examine the electrophysiological and pharmacological responsiveness of midbrain dopamine (DA) neurons to selected, ascending afferent inputs. Sciatic nerve stimulation-induced inhibition of nigrostriatal DA (NSDA) neurons was blocked by both PCPA (5-HT synthesis inhibitor) and 5,7-DHT (5-HT neurotoxin), suggesting mediation by a serotonergic (5-HT) system. Direct stimulation of the dorsal raphe (which utilizes 5-HT as a neurotransmitter and inhibits slowly firing NSDA neurons) inhibited all mesoaccumbens DA (MADA) neurons tested. Paradoxically, DPAT, a 5-HT1A agonist which inhibits 5-HT cell firing, enhanced sciatic nerve stimulation-induced inhibition of NSDA neurons. MADA neurons were not inhibited by sciatic nerve stimulation and, therefore, could not be tested in this paradigm. In contrast to the dorsal raphe, electrical stimulation of the pedunculopontine tegmental nucleus preferentially excited slowly firing NSDA and MADA neurons. Thus, both excitatory and inhibitory ascending afferents influence the activity of midbrain DA neurons, and intact 5-HT systems are necessary for sciatic nerve stimulation to alter DA cell activity. However, the role that 5-HT plays in mediating peripheral sensory input remains unclear.     

Superior colliculus and active navigation: role of visual and non-visual cues in controlling cellular representations of space

To begin investigation of the contribution of the superior colliculus to unrestrained navigation, the nature of behavioral representation by individual neurons was identified as rats performed a spatial memory task. Similar to what has been observed for hippocampus, many superior collicular cells showed elevated firing as animals traversed particular locations on the maze, and also during directional movement. However, when compared to hippocampal place fields, superior collicular location fields were found to be more broad and did not exhibit mnemonic properties. Organism-centered spatial coding was illustrated by other neurons that discharged preferentially during right or left turns made by the animal on the maze, or after lateralized sensory presentation of somatosensory, visual, or auditory stimuli. Nonspatial movement-related neurons increased or decreased firing when animals engaged in specific behaviors on the maze regardless of location or direction of movement. Manipulations of the visual environment showed that many, but not all, spatial cells were dependent on visual information. The majority of movement-related cells, however, did not require visual information to establish or maintain the correlates. Several superior collicular cells fired in response to multiple maze behaviors; in some of these cases a dissociation of visual sensitivity to one component of the behavioral correlate, but not the other, could be achieved for a single cell. This suggests that multiple modalities influence the activity of single neurons in superior colliculus of behaving rats. Similarly, several sensory-related cells showed dramatic increases in firing rate during the presentation of multisensory stimuli compared to the unimodal stimuli. These data reveal for the first time how previous findings of sensory/motor representation by the superior colliculus of restrained/anesthetized animals might be manifested in freely behaving rats performing a navigational task. Furthermore, the findings of both visually dependent and visually independent spatial coding suggest that superior colliculus may be involved in sending visual information for establishing spatial representations in efferent structures and for directing spatially-guided movements.     

Ultrasonographic investigation of the pathogenesis of infusion thrombophlebitis

As shown on cultured striatal neurons recorded in whole-cell configuration, both acetylcholine (in the presence of atropine) and nicotine reduced voltage-dependent outward currents. Although, at early postnatal ages, outward currents in these cells are mainly carried by rapidly and slowly inactivating K+ channels, these inhibitions resulted from a selective and reversible effect on the slowly inactivating K+ conductance (IK+). This action was blocked by the nicotinic antagonist dihydro-beta-erythro?dine and reproduced by nicotinic agonists. When neurons were recorded under current-clamp conditions, nicotine increased reversibly their firing rate generated by step depolarizations. Therefore, in addition to its well documented muscarinic effects, acetylcholine also controls K+ currents in striatal neurons through mechanisms mediated by nicotinic receptors.     

Regulation of action-potential firing in spiny neurons of the rat neostriatum in vivo

Both silent and spontaneously firing spiny projection neurons have been described in the neostriatum, but the reason for their differences in firing activity are unknown. We compared properties of spontaneously firing and silent spiny neurons in urethan-anesthetized rats. Neurons were identified as spiny projection neurons after labeling by intracellular injection of biocytin. The threshold for action-potential firing was measured under three different conditions: 1) electrical stimulation of the contralateral cerebral cortex, 2) brief directly applied current pulses, and 3) spontaneous action-potentials occurring during spontaneous episodes of depolarization ( state). The average membrane potential and the amplitude of noiselike fluctuations of membrane potential in the state were determined by fitting a Gaussian curve to the membrane-potential distribution. All neurons in the sample exhibited spontaneous membrane potential shifts between a hyperpolarized state and a depolarized state, but not all fired action potentials while in the state. The difference between the spontaneously firing and the silent spiny neurons was in the average membrane potential in the state, which was significantly more depolarized in the spontaneously firing than in the silent spiny neurons. There were no significant differences in the threshold, the amplitude of the noiselike fluctuations of membrane potential in the state, or in the proportion of time that the membrane potential was in the state. In both spontaneously firing and silent neurons, the threshold for action potentials evoked by current pulses was significantly higher than for those evoked by cortical stimulation. Application of more intense current pulses that reproduced the excitatory postsynaptic potential rate of rise produced firing at correspondingly lower thresholds. Because the membrane potential in the state is mainly determined by the balance between the synaptic drive and the outward potassium conductances activated in the subthreshold range of membrane potentials, either or both of these factors may determine whether firing occurs in response to spontaneous afferent activity.     

Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.     

Reduction of cortical pyramidal neuron excitability by the action of phenytoin on persistent Na+ current

We examined the effect of the anticonvulsant phenytoin (PT) (20-200 microM) on the persistent Na+ current (INaP), INaP-dependent membrane potential responses and repetitive firing in layer 5 pyramidal neurons in a slice preparation of rat sensorimotor cortex. INaP measured directly with voltage-clamp was reduced in a concentration-dependent manner with an apparent EC50 value of 78 microM. Clear effects on current-evoked membrane potential responses were apparent at 50 microM PT: Subthreshold, depolarizing membrane potential rectification was reduced, rheobase current was increased and the relation between firing rate and injected current was shifted to the right, but action potential amplitude and duration were unaffected. We ascribed these effects of PT largely to the reduction of INaP. A slow decline of firing rate during the injected current pulse also became apparent at moderate PT concentrations. When PT concentration was raised to 150 to 200 microM, this slow adaption was enhanced markedly, and firing ceased during a sufficiently large current pulse. This enhanced slow adaptation and the cessation of firing were associated with a marked decline of spike amplitude and a rise in spike firing level during successive interspike intervals. We ascribe these effects largely to the action of PT on the transient Na+ current. We conclude that the reduction in cortical neuronal excitability by PT depends partly on its reduction of INaP, the effects of INaP blockade are apparent at PT concentrations lower than those required to abolish tonic firing and the cells need not be excessively depolarized for PT to decrease excitability by its effect on INaP.     

Correlates of change in depressive symptomatology among gay men with AIDS

The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, i.p.) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, i.p.). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2-4 days) and once, long (9-12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, i.p.) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions.     

Grooming in the rat as an aftereffect of lateral hypothalamic stimulation

Grooming occurred as an aftereffect of electrical stimulation at hypothalamic sites that elicited locomotion, drinking, or eating as stimulus-bound behaviors. Removal of food or water, which caused rats to switch from one stimulus-bound behavior to another, produced little or no change in the grooming aftereffect. Stimulation with pulse showed that the absolute refractory period for the neurons responsible for the occurrence of grooming is approximately 1 msec. This value is longer than those reported for drinking, eating, and locomotion. Finally, it was found that with some electrodes, low levels of stimulation elicited grooming directly, during the stimulation; at higher levels grooming occurred only as an aftereffect. It is concluded that grooming is activated through neurons separate from those that produce drinking, eating, or locomotion and that its occurrence as an aftereffect may be due to an interaction between short-lasting inhibitory and longer lasting excitatory effects of the stimulation.