Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids

The intravenous administration of the psychoactive constituent of marijuana, delta9-tetrahydrocannabinol (delta9-THC) (62.5-1000 microg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5-500 microg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n=4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.     

VTA dopamine neuron activity distinguishes alcohol-preferring (P) rats from Wistar rats

The mesolimbic dopamine (DA) system is innately deficient in rats selectively bred for high alcohol drinking behavior compared with rats selectively bred for low alcohol drinking and unselected rats. In alcohol-preferring (P) rats, compared with alcohol-nonpreferring (NP) rats, this is evidenced by fewer DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (ACB). Yet, despite this deficiency, DA release in the ACB is similar in P, NP, and Wistar rats. DA release is regulated by DA neuronal activity, and DA neurons fire tonically as well as in bursts. Burst firing has been shown to substantially enhance DA release compared with tonic firing. The present study was designed to test the hypothesis that the remaining VTA DA neurons in P rats have faster firing frequencies and/or burst fire more frequently than VTA DA neurons in Wistar rats. The spontaneous activity of VTA DA neurons was recorded in unanesthetized alcohol-naive P and Wistar rats. A conventional burst analysis on 500 consecutive action potentials revealed that P rats had a significantly (p < 0.05) greater percentage of action potentials in bursts when compared with Wistar rats (P: 50.9%, Wistar: 34.4%). Firing frequency and other burst parameters (burst interspike interval, burst length, interburst interval, and the number of action potentials per burst) did not distinguish the two groups of rats. The increased burst activity in P rats may represent a compensatory mechanism to maintain adequate basal levels of DA despite the deficiency in the mesolimbic DA system.     

Isolation and comparison of natural and recombinant human CENP-A autoantigen

Previous studies have shown that administration of gamma-hydroxybutyric acid (GHBA) or the GABA(B) receptor agonist baclofen are associated with a decrease in firing rate, a regularisation of firing pattern and a decrease in burst activity of midbrain dopamine (DA) neurons in the substantia nigra (SN). In the present study we compared the ability of the novel GABA(B) receptor antagonist SCH 50911 and the selective antagonist of GHBA binding sites, NCS-382, to antagonise the effects of baclofen or GHBA, respectively, on the neuronal activity of DA neurons in anaesthetised rats. SCH 50911 (75 mg/kg, i.v.) was found to antagonise the decrease in firing rate, the regularisation of firing rhythm and the decrease of burst activity in DA cells, induced by baclofen (1-32 mg/kg, i.v.) or GHBA (12.5-1600 mg/kg, i.v.). NCS-382 (100 mg/kg, i.v.) did not affect the baclofen-induced changes in neuronal activity. Neither was the drug able to influence the GHBA-induced alterations in firing rate or in burst activity, although NCS-382 to some extent antagonised the regularisation of the firing pattern observed following low doses of GHBA (< or =100 mg/kg). The results of the present study give further support for the notion that the GHBA-induced changes in neuronal activity of nigral dopamine neurons are mediated by stimulation of GABA(B) receptors.     

Insulin-induced hypoglycemia does not impair the surge of luteinizing hormone secretion in the proestrous rat

Dopamine (DA) neurons in the ventral tegmental area and substantia nigra pars compacta were induced to fire in bursts with application of N-methyl-D-aspartate (NMDA, 20 microM) and apamin (100 nM) while recording intracellularly in the rat brain slice. L-Arginine (300 microM), a substrate for nitric oxide (NO) production, increased both the number of spikes per burst and the magnitude of interburst hyperpolarizations. Nitric oxide synthase inhibitors N-nitro-L-arginine methyl ester (L-NAME, 100 microM), N-nitro-L-arginine, and 7-nitroindazole inhibited NMDA-induced burst firing by reducing the number of spikes per burst. Moreover, L-arginine (100 microM) reversed the inhibition of burst firing produced by L-NAME. These findings suggest that NO facilitates NMDA-induced burst firing in DA neurons.     

Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma

The electrophysiological properties of neurons of the medial septal nucleus and the nucleus of the diagnonal band of Broca (MS/DB) were studied using intracellular methods in urethane-anesthetized rats. Three types of rhythmically bursting neurons were identified in vivo on the basis of their action potential shapes and durations, afterhyperpolarizations (AHPs), membrane characteristics, firing rates and sensitivities to the action of muscarinic antagonist: (1) Cells with short-duration action potentials and no AHPs (2 of 34 rhythmic cells, 6%) had high firing rates and extremely reliable bursts with 6-16 spikes per theta cycle, which were highly resistant to scopolamine action. (2) Cells with short-duration action potentials and short-duration AHPs (8 of 34 rhythmic cells, 24%) also had high firing rates and reliable bursts with 4-13 spikes per theta cycle, phase-locked to the negative peak of the dentate theta wave. Hyperpolarizing current injection revealed a brief membrane time constant, time-dependent membrane rectification and a burst of firing at the break. Depolarizing current steps produced high-frequency repetitive trains of action potentials without spike frequency adaptation. The action potential and membrane and characteristics of this cell type are consistent with those described for GABAergic septal neurons. Many of these neurons retained their theta-bursting pattern in the presence of muscarinic antagonist. (3) Cells with long-duration action potentials and long-duration AHPs (24 of 34 rhythmic cells, 70%) had low firing rates, and usually only 1-3 spikes per theta cycle, locked mainly to the positive peak of the dentate theta rhythm. Hyperpolarizing current injection revealed a long membrane time constant and a break potential; a depolarizing pulse caused a train of action potentials with pronounced spike frequency adaptation. The action potential and membrane properties of this cell type are consistent with those reported for cholinergic septal neurons. The theta-related rhythmicity of this cell type was abolished by muscarinic antagonists. The phasic inhibition of "cholinergic" MS/DB neurons by "GABAergic" MS/DB neurons, followed by a rebound of their firing, is proposed as a mechanism contributing to recruitment of the whole MS/DB neuronal population into the synchronized rhythmic bursting pattern of activity that underlies the occurrence of the hippocampal theta rhythm.     

Spontaneous bursting activity of dopaminergic neurons in midbrain slices from immature rats: role of N-methyl-D-aspartate receptors

Dopamine neurons in midbrain coronal slices from adult rats (40-70 days old) discharged only in pacemaker-like mode. Irregular or bursting mode was never observed. In contrast, dopamine neurons in slices from immature rats (15-21 days old) exhibited not only pacemaker-like firing (53.4% of neurons), but also irregular and bursting patterns (28.3 and 18.3%, respectively). Glutamate and kainate increased the firing rate but failed to induce bursts in dopamine neurons from either adult or immature rats. N-Methyl-D-aspartate augmented the firing rate in all neurons from adult rats and produced a modest increase of bursts in only three out of 18 cells. In slices from immature rats, N-methyl-D-aspartate activated the discharge rate in all neurons and also induced bursts in 37 and 53% of pacemaker and irregular neurons, respectively, and increased the occurrence of spikes in bursts in 76% of spontaneously bursting neurons. The selective N-methyl-D-aspartate receptor antagonist (+/-)2-amino,5-phosphonopentanoic acid prevented N-methyl-D-aspartate-induced changes and also reduced spontaneous bursts, suggesting that bursting discharge is mediated by N-methyl-D-aspartate receptor activation. While pacemaker neurons from immature and from adult rats exhibited the same sensitivity to N-methyl-D-aspartate-induced stimulation of firing rate, spontaneously bursting neurons were more sensitive than pacemaker neurons from either immature or adult rats. The present study indicates that spontaneous bursting, dependent on N-methyl-D-aspartate receptor activation, is present, and may be induced, in dopamine neurons in slices from immature rats. Its absence from cells in slices from adult rats may reflect a reduced sensitivity of N-methyl-D-aspartate receptors on dopamine or the loss of the N-methyl-D-aspartate-activated burst generator.     

kappa-opioid regulation of neuronal activity in the rat supraoptic nucleus in vivo

We investigated the influence of endogenous kappa-opioids on the activity of supraoptic neurons in vivo. Administration of the kappa-antagonist nor-binaltorphimine (200 micrograms/kg, i.v.), increased the activity of phasic (vasopressin), but not continuously active (oxytocin), supraoptic neurons by increasing burst duration (by 69 +/- 24%) and decreasing the interburst interval (by 19 +/- 11%). Similarly, retrodialysis of nor-binaltorphimine onto the supraoptic nucleus increased the burst duration (119 +/- 57% increase) of vasopressin cells but did not alter the firing rate of oxytocin cells (4 +/- 8% decrease). Thus, an endogenous kappa-agonist modulates vasopressin cell activity by an action within the supraoptic nucleus. To eliminate kappa-agonist actions within the supraoptic nucleus, we infused the kappa-agonist U50,488H (2.5 micrograms/hr at 0.5 micrograms/hr) into one supraoptic nucleus over 5 d to locally downregulate kappa-receptor function. Such infusions reduced the spontaneous activity of vasopressin but not oxytocin cells and reduced the proportion of cells displaying spontaneous phasic activity from 26% in vehicle-infused nuclei to 3% in U50, 488H-infused nuclei; this treatment also prevented acute inhibition of both vasopressin and oxytocin cells by U50,488H (1000 micrograms/kg, i.v.), confirming functional kappa-receptor downregulation. In U50, 488H-infused supraoptic nuclei, vasopressin cell firing rate was increased by nor-binaltorphimine (100 and 200 micrograms/kg, i.v.) but not to beyond that found in vehicle-treated nuclei, indicating that these cells were not U50,488H-dependent. Thus, normally functioning kappa-opioid mechanisms on vasopressin cells are essential for the expression of phasic firing.     

The functional influence of burst and tonic firing mode on synaptic interactions in the thalamus

Thalamocortical and perigeniculate (PGN) neurons can generate action potentials either as Ca2+ spike-mediated high-frequency bursts or as tonic trains. Using dual intracellular recordings in vitro in monosynaptically connected pairs of PGN and dorsal lateral geniculate nucleus (LGNd) neurons, we found that the functional effect of synaptic transmission between these cell types was strongly influenced by the membrane potential and hence the firing mode of both the pre- and postsynaptic neurons. Activation of single action potentials or low-frequency spike trains in PGN or thalamocortical neurons resulted in the generation of PSPs that were 0.5-2.0 mV in amplitude. In contrast, the generation of Ca2+ spike-mediated bursts of action potentials in the presynaptic cell increased these PSPs to an average of 4.4 mV for the IPSP and 3.0 mV for the EPSP barrage, because of temporal summation and/or facilitation. If the postsynaptic neuron was at a resting membrane potential (e.g., -65 mV), these PSP barrages could result in the activation of a low-threshold Ca2+ spike and burst of action potentials. These results demonstrate that the burst firing mode of action potential generation is a particularly effective means by which perigeniculate and thalamocortical neurons may influence one another. We propose that the activation of burst discharges in these cell types is essential for the generation of some forms of synchronized rhythmic oscillations of sleep and of epileptic seizures.     

D-aspartate modulates melatonin synthesis in rat pinealocytes

The effect of protection of dopaminergic neurons by talipexole, a dopamine (DA) agonist, is investigated on a methamphetamine (MA)-induced parkinsonism model of mice (C57BL/6N). The reduction of tyrosine hydroxylase activity in the striatum 72 h after MA (5 mg/kg every 2 h, four times) treatment was attenuated by the administration of talipexole (0.25 mg/kg or 1.0 mg/kg) prior to the administration of MA. In an in vitro experiment, talipexole inhibited the adduction reaction of hydroxyl radicals to salicylate. Taken together, these data suggest that the protective effect of talipexole on DA neurons is, in part, caused by the hydroxyl radical-scavenging action of the drug.     

Phenotype of striatal cells expressing c-Fos following amphetamine treatment of rats with intrastriatal dopaminergic grafts

Activation of the nigrostriatal dopaminergic system by psychostimulants such as amphetamine increases c-Fos expression in the striatum, mostly in the striatonigral substance P-ergic pathway. This effect is greatly reduced in the neostriatum deprived of dopaminergic afferents. Dopaminergic grafts implanted into the denervated neostriatum restore the reactivity of the striatum to amphetamine. However, the number of striatal neurons expressing c-Fos is greatly increased in the graft-bearing striatum compared with the normal striatum. We examined whether this increase in the number of c-Fos-expressing neurons corresponds to the recruitment of a new neuron population, or whether it reflects an increase in the proportion of substance P-ergic neurons exhibiting activation of c-Fos. Adult rats received a unilateral 6-hydroxydopamine lesion of the ascending dopaminergic mesotelencephalic pathway, and a suspension of embryonic mesencephalic neurons was subsequently implanted into the denervated neostriatum. Three months after implantation, animals were injected with d-amphetamine (5 mg/kg) and killed 2 h later. In the first experiment, striatal sections were processed to visualize both c-Fos protein, by immunohistochemistry, and preproenkephalin A or substance P, by in situ hybridization. In the second experiment, c-Fos and neuropeptide Y were visualized on the same sections. In addition, some sections incubated with anti-c-Fos antibody were counterstained with toluidine blue in order to determine whether cholinergic neurons were expressing c-Fos following amphetamine treatment. The density of neurons expressing c-Fos following amphetamine treatment was three-fold higher in the graft-bearing striata than in the striata of control animals. Approximately 75% of the c-Fos expressing cells were substance P-ergic in control animals whereas 6% were enkephalinergic and only a few were neuropeptide Y-ergic or cholinergic. Similar proportions were found in the graft-bearing striatum, signifying that the pattern of activation of c-fos following amphetamine administration is not changed by the graft. Thus, the increased expression of c-Fos predominantly reflects a graft-induced increase in the proportion of neurons expressing c-Fos within the same population of neurons which normally expresses c-Fos in the striatum, i.e. the striatonigral substance P-ergic neurons; there is no recruitment of a new neuronal population. This increased activation of the striatonigral substance P-ergic pathway may underlie the abnormal behavioural reactions brought about by amphetamine-induced stimulation of the implanted dopaminergic neurons.     

Activity-dependent changes in the intrinsic properties of cultured neurons

Learning and memory arise through activity-dependent modifications of neural circuits. Although the activity dependence of synaptic efficacy has been studied extensively, less is known about how activity shapes the intrinsic electrical properties of neurons. Lobster stomatogastric ganglion neurons fire in bursts when receiving synaptic and modulatory input but fire tonically when pharmacologically isolated. Long-term isolation in culture changed their intrinsic activity from tonic firing to burst firing. Rhythmic stimulation reversed this transition through a mechanism that was mediated by a rise in intracellular calcium concentration. These data suggest that neurons regulate their conductances to maintain stable activity patterns and that the intrinsic properties of a neuron depend on its recent history of activation.     

Response properties of saccade-related burst neurons in the central mesencephalic reticular formation

We studied the activity of saccade-related burst neurons in the central mesencephalic reticular formation (cMRF) in awake behaving monkeys. In experiment 1, we examined the activity of single neurons while monkeys performed an average of 225 delayed saccade trials that evoked gaze shifts having horizontal and vertical amplitudes between 2 and 20 degrees . All neurons studied generated high-frequency bursts of activity during some of these saccades. For each neuron, the duration and frequency of these bursts of activity reached maximal values when the monkey made movements within a restricted range of horizontal and vertical amplitudes. The onset of the movement followed the onset of the burst by the longest intervals for movements within a restricted range of horizontal and vertical amplitudes. The range of movements for which this interval was longest varied from neuron to neuron. Across the population, these ranges included nearly all contraversive saccades with horizontal and vertical amplitudes between 2 and 20 degrees. In experiment 2, we used the following task to examine the low-frequency prelude of activity that cMRF neurons generate before bursting: the monkey was required to fixate a light-emitting diode (LED) while two eccentric visual stimuli were presented. After a delay, the color of the fixation LED was changed, identifying one of the two eccentric stimuli as the saccadic target. After a final unpredictable delay, the fixation LED was extinguished and the monkey was reinforced for redirecting gaze to the identified saccadic target. Some cMRF neurons fired at a low frequency during the interval after the fixation LED changed color but before it was extinguished. For many neurons, the firing rate during this interval was related to the metrics of the movement the monkey made at the end of the trial and, to a lesser degree, to the location of the eccentric stimulus to which a movement was not directed.     

Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons

In vivo extracellular single-unit recording techniques revealed that chronic cold stress significantly alters both the basal and the evoked electrophysiological activity of noradrenergic neurons in the locus coeruleus of the anaesthetized rat. Following 17-21 days of chronic cold exposure (5 degrees C), the single-unit activity of histologically-identified locus coeruleus neurons in chloral hydrate-anaesthetized rats was recorded and analysed in terms of their basal firing rate and pattern of spike activity, as well as their response to footshock stimulation. There was no significant difference in the incidence of spontaneously active cells/electrode track between cold-stressed rats and control rats. However, the basal spike activity of locus coeruleus cells recorded from cold-stressed rats differed significantly from that of control rats along two dimensions: i) they displayed significantly higher basal firing rates (mean = 1.88 Hz vs 1.20 Hz, respectively); and ii) they frequently exhibited spontaneous burst-firing activity that was not observed in control rats (observed in 15/17 cold-stressed rats vs 1/26 control rats). The evoked spike activity of locus coeruleus cells in cold-stressed rats also differed significantly from that of control rats along two dimensions: i) they were more likely to respond to footshock stimulation (mean = 90.3% vs 74.4%, respectively); and ii) these responses were more likely to consist of multispike bursts of action potentials (mean = 8 bursts/50 stimulations vs 1 burst/50 stimulations, respectively). These results indicate that alterations in the electrophysiological activity of noradrenergic locus coeruleus neurons may contribute to the phenomenon of stress-induced sensitization of norepinephrine release that is thought to underlie some of the neuropathological changes that accompany long-term stress.     

Antagonism of NMDA receptors but not AMPA/kainate receptors blocks bursting in dopaminergic neurons induced by electrical stimulation of the prefrontal cortex

Evidence suggests that the prefrontal cortex (PFC) plays an important role in the burst activity of midbrain dopaminergic (DA) neurons. In particular, electrical stimulation of the PFC elicits patterns of activity in DA neurons, closely time-locked to the stimulation, which resemble natural bursts. Given that natural bursts are produced by the activity of excitatory amino acid (EAA)-ergic afferents, if PFC-induced time-locked bursts are homologues of natural bursts, EAA antagonists should attenuate them. Hence, the NMDA (N-methyl-D-aspartate) antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) and the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid)/kainate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were applied by iontophoresis to DA neurons exhibiting time-locked bursts during PFC stimulation. CPP produced a significant reduction in time-locked bursting. In contrast, CNQX (at currents which antagonised AMPA responses) did not. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Since natural bursting and bursting induced by PFC stimulation are both blocked selectively by CPP, the present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.     

Conopressin affects excitability, firing, and action potential shape through stimulation of transient and persistent inward currents in mulluscan neurons

The molluscan vasopressin/oxytocin-related neuropeptide conopressin activates two persistent inward currents in neurons from the anterior lobe of the right cerebral ganglion of Lymnaea stagnalis that are involved in the control of male copulatory behavior. The low-voltage-activated (LVA) current is activated at a wide range of membrane potentials, its amplitude being only weakly voltage dependent. The high-voltage-activated (HVA) current is activated at potentials positive to -40 mV only and shows a steep voltage dependence. Occurrence of both currents varies from cell to cell, some expressing both and others only the HVA current. In most neurons that have the LVA current, a conopressin-independent persistent inward current (INSR) is found that resembles the HVA current in its voltage dependence. The functional importance of the LVA and HVA currents was studied under current-clamp conditions in isolated anterior lobe neurons. In cells exhibiting both current types, the effect of activation of the LVA current alone was investigated as follows: previously recorded LVA current profiles were injected into the neurons, and the effects were compared with responses induced by conopressin. Both treatments resulted in a strong depolarization and firing activity. No differences in firing frequency and burst duration were observed, indicating that activation of the LVA current is sufficient to evoke bursts. In cells exhibiting only the HVA current, the effect of conopressin on the response to a depolarizing stimulus was tested. Conopressin reversibly increased the number of action potentials generated by the stimulus, suggesting that the HVA current enhances excitability and counteracts accommodation. Conopressin enhanced action potential broadening during depolarizing stimuli in many neurons. Voltage-clamp experiments performed under ion-selective conditions revealed the presence of transient sodium and calcium currents. Using the action potential clamp technique, it was shown that both currents contribute to the action potential. The calcium current, which is activated mainly during the repolarizing phase of the action potential, is augmented by conopressin. Thus conopressin may directly modulate the shape of the action potential. In summary, conopressin may act simultaneously on multiple inward currents in anterior lobe neurons of Lymnaea to affect firing activity, excitability, and action potential shape.     

Tolerance to amphetamine hypophagia: A miscrostructural analysis of licking behavior in the rat.

The development of tolerance to amphetamine-induced hypophagia was assessed by recording changes in lick parameters in rats given chronic administration of the drug (2 mg/kg) and access to sweetened milk. Although licking and milk intake gradually recovered, the volume of milk ingested per lick remained suppressed. Amphetamine had no effect on the interlick interval or the force per lick. In contrast, the drug caused a sustained increase in the number of lick bursts (defined by pause criteria of 0.5-2.0 s) and a decrease in the number of licks per burst (but only at pause criteria of 0.5 and 1.0 s). These results suggest that tolerant rats frequently interrupt licking, resulting in less efficient capture of milk. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine-induced activation of locus coeruleus neurons--an analysis of peripheral versus central induction

Previous electrophysiological experiments have shown that the marked but short-lasting excitation of locus coeruleus (LC) neurons seen after systemic administration of low doses of nicotine is of a peripheral origin. In addition, nicotine induces a weak but more long-lasting activation of LC neurons which is preferentially observed following administration of high doses of the drug. In the present study this latter activation was pharmacologically analysed. Whereas low intravenous doses of nicotine caused a marked but short-lasting excitation of most LC cells recorded from, higher doses of nicotine were associated with a moderate but durable (> 20 min) activation. In contrast to the short-lasting activation of the LC, the long-lasting effect of the drug was not counteracted by chlorisondamine (0.3 mg/kg, i.v.; n = 5). On the other hand, administration of mecamylamine (4 mg/kg, i.v.; n = 5) rapidly and effectively decreased the elevated spontaneous firing rate of LC neurons (as observed following repeated nicotine injections) to the original baseline firing rate. Intravenous administration of tetramethylammonium (TMA, 50-800 mg/kg, i.v.), activated most LC neurons in a manner resembling that of nicotine at low doses, i.e. a marked but short-lasting excitation with no tachyphylaxis. However, in contrast to nicotine, TMA administered in higher doses did not affect the baseline firing rate of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endoscopic features of the columnar-lined esophagus

Electrophysiological characterization of neurons within the rat subiculum was carried out with intracellular recordings in an in vitro slice preparation. Subicular neurons responded to threshold pulses of depolarizing current delivered at a resting membrane potential (RMP) of 45.7+/-5.8 mV (mean+/-SD, n=85) with an initial burst of three to five fast action potentials that rode on a depolarizing envelope and was terminated by an afterhyperpolarization (burst AHP) (duration 113+/-35 ms; peak amplitude 2.7+/-0.6 mV, n=10). Tonic firing replaced the bursting mode at membrane potential less negative than -55 mV. Suprathreshold depolarizing pulses evoked at RMP both an initial burst and successive tonic firing. Intracellular staining with biocytin showed morphological features typical of pyramidal cells (n=8). The relationship between frequency of repetitive firing and injected current (f-I) revealed that the burst firing frequency (250-300 Hz) was only slightly influenced by the amount of injected current. By contrast, the f-I curve of the tonic firing phase depended upon current intensity: it displayed an initial segment that increased at first linearly and then turned into a plateau for both the early and the late inter-spike intervals. The frequency of the tonic firing declined only slightly with time, thus suggesting a lack of adaptation. During tonic firing, each single action potential was followed by a fast AHP and a depolarizing afterpotential. Termination of repetitive firing was followed by an AHP (spike-train AHP; duration 223+/-101 ms, peak amplitude 5.6+/-2.4 mV, n=17). Fast spike-train and burst AHPs were reduced by bath application of the Ca2+-channel blockers Co2+ (2 mM) and Cd2+ (1 mM) (n=8), thus suggesting the participation of Ca2+-dependent K+ conductances in these AHPs. Subicular bursting neurons generated persistent, subthreshold voltage oscillations at 5.3+/-1 Hz (n=20) during steady depolarization positive to -60 mV; at values positive to -55 mV, the oscillatory activity could trigger clusters of single action potentials with a periodicity of 0.9-2 Hz. Oscillations were not prevented by application of excitatory amino acid receptor and GABA(A) receptor antagonists (n=5), Ca2+-channel blockers (n=5), or Cs+ (3 mM; n=4), but were abolished by the Na+-channel blocker tetrodotoxin (1 microM; n=6). Our findings demonstrate that pyramidal-like subicular neurons generate both bursting and non-adapting tonic firing, depending upon their membrane potential. These neurons also display oscillatory activity in the range of theta frequency that depends on the activation of a voltage-gated Na+ conductance. These electrophysiological properties may play a role in the process of signals arising from the hippocampal formation before being funnelled towards other limbic structures.     

D1 and D2 dopamine receptor function in the striatum: coactivation of D1- and D2-dopamine receptors on separate populations of neurons results in potentiated immediate early gene response in D1-containing neurons

D1- and D2-dopamine receptor-mediated regulation of immediate early gene levels in identified populations of neurons in the striatum was examined with quantitative in situ hybridization histochemical techniques. Levels of messenger RNA (mRNA) encoding the immediate early genes zif268 and c-fos were examined in two experiments in rats with unilateral lesions of the nigrostriatal dopamine pathway. In a dose-response study, animals were treated with doses of 0.5, 1.0, and 1.5 mg/kg of the D1 agonist SKF-38393 either alone or in combination with the D2 agonist quinpirole (1 mg/kg). Levels of immediate early gene mRNAs 60 min following drug treatments showed a dose-related increase to the D1 agonist alone and a potentiation to combined D1 and D2 against treatment. In a second experiment, in animals receiving 1 mg/kg SKF-38393 either alone or in combination with 1 mg/kg quinpirole, the level of zif268 mRNA was measured with a double-labeling method in striatal neurons containing enkephalin mRNA, a marker of D2-containing neurons, and in neurons not containing enkephalin, putative D1-containing neurons. In the dopamine-depleted striatum, D1 agonist treatment alone did not affect enkephalin-positive neurons but significantly elevated zif268 mRNA levels in nearly all enkephalin-negative neurons. Combined D1 and D2 agonist treatment further increased zif268 mRNA levels in this population of enkephalin-negative neurons and decreased zif-268 mRNA levels in enkephalin-positive neurons. These data indicate that the synergistic response to combined D1- and D2-receptor stimulation is mediated by interneuronal interactions involving the activation of D1 and D2 receptors on separate populations of striatal neurons.     

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.