Dopamine Cell Firing Rate Research Articles

Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques.

The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.

Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity

Event Abstract Back to Event Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity Sjoerd Murris1*, John Arsenault1, 2 and Wim Vanduffel1, 2, 3 1 Department of Neurosciences, KU Leuven, Belgium 2 Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, United States 3 Harvard Medical School, United States The Ventral Tegmental Area (VTA) and neighbouring Substantia Nigra are integral structures at the heart of the dopamine system, underlying adaptive behaviour. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity, possibly supporting diverse cognitive functionss1. Artificial perturbations of the VTA through electrical and optogenetic stimulation methods generate different and sometimes even contrasting behavioural outcomes depending on stimulation parameters such as frequency, amplitude and pulse width2–4. Here we investigate the brain-wide functional effects of electrical stimulation frequency (10, 20, 50 and 100 Hz) of the VTA of two rhesus macaques implanted with chronic electrodes5. We stimulated both animals while measuring brain-wide fMRI signal changes during a passive fixation task or under anaesthesia. In the awake state, activity in many cortical and subcortical structures followed an inverted u-shape as a function of stimulation frequency, with highest evoked activity when stimulating at 20 and 50 Hz and less activity at 10 and 100 Hz. In addition, we tested whether the state of the animals had an effect on stimulation-induced network activity by performing the same experiment under ketamine-induced anaesthesia. Under anaesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10Hz stimulation, but became negative and decreased linearly as a function of higher stimulation frequencies. In conclusion, brain wide network effects induced by electrical stimulation of the VTA are to a large degree frequency and state-dependent. The remarkably different stimulation-induced amplitudes and patterns of fMRI activity may explain varying and even opposing behavioural effects observed using Deep Brain Stimulation in patients. In addition, they call for a careful design and interpretation of electrical microstimulation procedures in fundamental research. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Acknowledgements This work received funding from KU Leuven C14/17/109; Hercules II funds; Fonds Wetenschappelijk Onderzoek-Vlaanderen G0D5817N, G090714N and Odysseus G0007.12; and the European Union's Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 785907 (Human Brain Project SGA2).

Effects of amphetamine on subcellular distribution of dopamine and DOPAC

Amphetamine effects on distribution of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and amphetamine in vesicular, cytosolic, and extracellular compartments associated with a striatal varicosity were estimated through use of a computer simulation model. In addition, contribution to overall effects of amphetamine by each of five actions--transport by dopamine transporter (DAT), transport by vesicular monoamine transporter, stimulation of reverse transport, inhibition of monoamine oxidase (MAO), and slowing of dopamine cell firing rate--were evaluated. Amphetamine enters a varicosity almost entirely by DAT and accumulates to very high levels within the varicosity. Both reverse transport by DAT and passive diffusion contribute to continual amphetamine egress across the plasma membrane. Amphetamine enters storage vesicles by both transport and diffusion. The transport portion competes with dopamine storage, resulting in redistribution of approximately half of dopamine from vesicles to cytosol. The high concentration of amphetamine in the cytosol inhibits MAO, protecting cytosolic dopamine. A very small fraction of cytosolic dopamine is moved to extracellular compartment via reverse transport by DAT. The amount of dopamine moved by reverse transport is limited because of competition by very high cytosolic levels of amphetamine. In the presence of amphetamine, rate of dopamine transfer to extracellular compartment is less than control; however, high levels of extracellular dopamine are maintained because amphetamine occupies the DAT, thus limiting dopamine reuptake. Simulation output from a model using exchange-diffusion mechanism of reverse transport does not match all published data that were simulated, suggesting that inward transport of a substrate is not required to initiate reverse transport.

Pharmacological Modulation of the Gating Properties of Small Conductance Ca2+-Activated K+ Channels Alters the Firing Pattern of Dopamine Neurons In Vivo

Dopamine (DA) neurons are autonomous pacemakers that occasionally fire bursts of action potentials, discharge patterns thought to reflect tonic and phasic DA signaling, respectively. Pacemaker activity depends on the concerted and cyclic interplay between intrinsic ion channels with small conductance Ca(2+)-activated K(+) (SK) channels playing an important role. Bursting activity is synaptically initiated but neither the transmitters nor the specific ion conductances involved have been definitively identified. Physiological and pharmacological regulation of SK channel Ca(2+) sensitivity has recently been demonstrated and could represent a powerful means of modulating the expression of tonic/phasic signaling in DA neurons in vivo. To test this premise, we characterized the effects of intravenous administration of the novel positive and negative SK channel modulators NS309 and NS8593, respectively, on the spontaneous activity of substantia nigra pars compacta DA neurons in anesthetized C57BL/6 mice. NS309, dose-dependently decreased DA cell firing rate, increased the proportion of regular firing cells, and eventually stopped spontaneous firing. By contrast, systemic administration of the negative SK channel modulator NS8593 increased firing rate and shifted the pattern toward increased irregularity/bursting; an effect similar to local application of the pore blocking peptide apamin. The altered firing patterns resulting from inhibiting SK currents persisted independently of changes in firing rates induced by administration of DA autoreceptor agonists/antagonists. We conclude that pharmacological modulation of SK channel Ca(2+)-sensitivity represents a powerful mechanism for switching DA neuron firing activity between tonic and phasic signaling modalities in vivo.

Probabilistic reversal learning is impaired in Parkinson's disease

In many everyday settings, the relationship between our choices and their potentially rewarding outcomes is probabilistic and dynamic. In addition, the difficulty of the choices can vary widely. Although a large body of theoretical and empirical evidence suggests that dopamine mediates rewarded learning, the influence of dopamine in probabilistic and dynamic rewarded learning remains unclear. We adapted a probabilistic rewarded learning task originally used to study firing rates of dopamine cells in primate substantia nigra pars compacta [Morris G, Nevet A, Arkadir D, Vaadia E, Bergman H (2006) Midbrain dopamine neurons encode decisions for future action. Nat Neurosci 9:1057–1063] for use as a reversal learning task with humans. We sought to investigate how the dopamine depletion in Parkinson's disease (PD) affects probabilistic reward learning and adaptation to a reversal in reward contingencies. Over the course of 256 trials subjects learned to choose the more favorable from among pairs of images with small or large differences in reward probabilities. During a subsequent otherwise identical reversal phase, the reward probability contingencies for the stimuli were reversed. Seventeen PD patients of mild to moderate severity were studied off of their dopaminergic medications and compared to 15 age-matched controls. Compared to controls, PD patients had distinct pre- and post-reversal deficiencies depending upon the difficulty of the choices they had to learn. The patients also exhibited compromised adaptability to the reversal. A computational model of the subjects' trial-by-trial choices demonstrated that the adaptability was sensitive to the gain with which patients weighted pre-reversal feedback. Collectively, the results implicate the nigral dopaminergic system in learning to make choices in environments with probabilistic and dynamic reward contingencies.

Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior.

Withdrawal from non-contingent exposure to psychostimulants increases the activity of midbrain dopamine cells and impairs the function of impulse-regulating dopamine autoreceptors. It is unclear whether these neuroadaptations play an important role in withdrawal-associated drug seeking. We determined whether cocaine self-administration modifies the impulse activity of midbrain dopamine neurons and dopamine autoreceptor function, and whether experimentally induced reduction in dopamine cell activity (by autoreceptor activation) could influence drug-seeking behavior. Animals were trained to self-administer saline or cocaine (500 micro g/kg per infusion) for 7 days. At different withdrawal periods, we used single-unit extracellular recordings to measure impulse activity of dopamine cells and administered the D2/D3 dopamine receptor agonist quinpirole to determine autoreceptor sensitivity. In a separate set of experiments, we determined the effects of autoreceptor-selective doses of quinpirole on drug-seeking behavior (non-reinforced responding in the absence of cocaine) during an extinction/reinstatement task. Cocaine self-administration induced a short-lived increase in the mean firing rate and bursting activity of midbrain dopamine cells. This effect was greatest at early withdrawal and was paralleled by decreased ability of quinpirole to inhibit dopamine cell firing rate and drug-seeking behavior. Changes in dopamine cell activity dissipated over time; at late withdrawal, when both impulse activity and autoreceptor sensitivity returned to control values, quinpirole dramatically decreased drug-seeking behavior. These results show that inhibiting dopamine cell impulse activity, by activation of dopamine autoreceptors, reduces drug-seeking behavior. This suggests that the impulse activity of midbrain dopamine cells could be an important factor contributing to relapse.

Effects of forebrain microinjection of cholecystokinin on dopamine cell firing rate

In anesthetized rats, midbrain dopamine (DA) neuronal firing rate was differentially sensitive to focal brain microinjection of cholecystokinin peptides (CCK-4 and CCK-8) and N-methyl-D-aspartate (NMDA) into nucleus accumbens, amygdala and prefrontal cortex. Whereas changes in DA neuronal firing rate were frequently observed in response to intra-amygdalar microinjection of CCK peptides, NMDA was most effective in eliciting changes in DA neuronal activity following intra-accumbal microinjection. Thus, stimulation of amygdalar CCK receptors and accumbal excitatory amino acid receptors may participate in the afferent regulation of midbrain DA neuronal function.

Effects of mCPP on the Extracellular Concentrations of Serotonin and Dopamine in Rat Brain

Intravenous administration of m-chloro-phenylpiperazine (mCPP) (0.25 or 2.5 mg/kg) induced a marked and dose-related increase in extracellular concentrations of serotonin in hippocampus (300–1,400% of baseline) as measured using in vivo microdialysis in awake male Wistar rats of the spontaneously hypertensive (SH) strain. Indicating that the effect of mCPP was caused by a reversal of the serotonin transporter, it was antagonized by pretreatment with the serotonin re-uptake inhibitor citalopram (10 mg/kg) but was unaffected by local administration of the sodium channel blocker tetrodotoxin (TTX; 1 μm). mCPP was also shown to induce an increase in extracellular concentrations of dopamine in the nucleus accumbens and the striatum of SH rats and in the nucleus accumbens of rats of the Sprague–Dawley (SD) strain; this effect of mCPP was, however, much weaker (125–170% of baseline) than the effect on serotonin; moreover, it seems to be TTX-sensitive. In anesthetized SD rats, mCPP induced a moderate reduction of nigral dopamine cell firing rate; supporting the assumption that this effect is secondary to the observed increase in dopamine release, it was blocked by pretreatment either with the dopamine synthesis inhibitor alpha-methyl-para-tyrosine or with the dopamine D2 receptor antagonist haloperidol. In conclusion, the results suggest that mCPP induces a marked, TTX-insensitive increase in serotonin release in rat brain, but only a modest and TTX-sensitive increase in the extracellular levels of dopamine.

Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons

Microiontophoretic drug application and extracellular recording techniques were used to evaluate the effects of the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate(1S,3R-ACPD) on dopamine (DA) neurons in the substantia nigra zona compacta (SNZC) of chloral hydrate-anesthetized rats. 1S,3R-ACPD had a biphasic effect on the firing rate of DA cells, initially decreasing, then increasing the firing rate. 1S,3R-ACPD also increased the burst-firing activity of DA neurons. Application of the ionotropic receptor (iGluR) agonists (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) increased the firing rates of neurons which had responded to 1S,3R-ACPD, indicating that mGluRs and iGluRs reside on the same neurons. The initial inhibitory period was not antagonized by systemic haloperidol or iontophoretic bicuculline, indicating a lack of DA or gamma-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), and the NMDA antagonist, (I)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), at currents which antagonized AMPA and NMDA, did not antagonize either the inhibitory or excitatory effects of 1S,3R-ACPD. Application of the metabotropic antagonist (S)-4-carboxy-phenylglycine antagonized both the inhibitory and excitatory effects of 1S,3R-ACPD. These results indicate that mGluRs may play a role in the modulation of dopaminergic activity in the SNZC.

The effect of 5-HT 3 receptor antagonists on the morphine-induced excitation of A10 dopamine cells: electrophysiological studies

In extracellular recordings from chloral hydrate anesthetized rats the 5-HT 3 antagonist, BRL 46470A, failed to prevent or reverse the increase in dopamine cell firing rate produced by systemic or iontophoretically applied morphine. A second 5-HT 3 antagonist, tropesitron, was similarly found to be ineffective in antagonizing the effects of systemic morphine. These results suggest that previous microdialysis reports that 5-HT 3 antagonists can prevent the increase in extracellular dopamine levels in the nucleus accumbens produced by morphine are not due to an action of these compounds in suppressing the excitatory effects of morphine on A10 dopamine cell firing rate.

5-HT 3 receptor antagonists fail to block the suppressant effect of cocaine on the firing rate of A10 dopamine neurons in the rat

In the present study, we have shown that cocaine is significantly more potent in suppressing the firing rate of dopamine cells in the ventral tegmental area (VTA or A10) than in the substantia nigra pars compacta (SNC or A9). We have also determined the ability of several 5-HT 3 receptor antagonists to alter the electrophysiological response of A10 dopamine neurons in the rat to cocaine, as these compounds have been implicated in modulating the effects of drugs of abuse on the dopamine system. It was found that the 5-HT 3 receptor antagonists ICS205-930, zacopride and ondansetron do not alter either the firing rate or cocaine-induced suppression of the basal firing rate of A10 dopamine cells.

Electrophysiological, biochemical, and behavioral studies of acute haloperidol-induced depolarization block of nigral dopamine neurons

The electrophysiological, biochemical and behavioral responses produced by administration of haloperidol were studied in intact rats and in rats with 6-hydroxydopamine-induced partial lesions of the nigrostriatal dopamine pathway. In both control rats and rats tested four to 10 days postlesion, the electrophysiological response of nigral dopamine neurons to increasing doses of haloperidol consisted of either: (1) an increase in firing rate which reached a plateau at six to 10 spikes per second, or (2) no response (i.e., less than 20% change in firing rate). Administration of additional doses of haloperidol up to lethal levels did not elicit further changes in dopamine cell firing in these rats. In contrast, in 6-hydroxydopamine-treated rats tested four to six weeks postlesion, acute administration of haloperidol was not only more consistent in producing increases in dopamine cell firing rate, but also caused six out of seven dopamine neurons tested to cease firing upon entering a state of depolarization block. In all cases in which depolarization block was observed, dopamine cell firing was reinstated by either iontophoretic application of γ-aminobutyric acid or intravenous administration of apomorphine. In parallel studies, haloperidol caused an increase in the extracellular dopamine levels measured by microdialysis in the striatum of control rats, whereas administration of the same dose of haloperidol to 6-hydroxydopamine-treated rats four to six weeks postlesion did not elicit any change in extracellular dopamine levels. In addition, administration of haloperidol at a dose which was ineffective in control rats produced gross motor deficits in the 6-hydroxydopamine-treated rats when tested four to six weeks postlesion. These results show that 6-hydroxydopamine-induced dopamine depletions produce a time-dependent change in the responsivity of the nigrostriatal dopamine system to acute haloperidol administration. In this altered system, the induction of depolarization block of spike activity in nigral dopamine neurons by haloperidol was not associated with a corresponding decrease in extracellular dopamine levels measured in the striatum. However, it appeared that depolarization block did prevent haloperidol-induced increases in extracellular dopamine levels. The occurrence of depolarization block in the dopamine-depleted animal may limit the capacity of this system to respond to additional compromise, in spite of the compensatory processes that contribute to maintaining motor function.

Electrophysiological evidence that intrastriatally administered N-methyl-D-aspartate augments striatal dopamine tone in the rat

The firing rate and terminal excitability of identified nigrostriatal dopamine (DA) neurons was determined before, and over a 10-15 min period following, direct intrastriatal administration of the glutamate (GLU) agonist NMDA, or saline. NMDA (0.025 and 0.075 mumol) produced a short latency increase in DA cell firing rate. In 7/8 cases, this increase in firing rate was accompanied by a profound reduction in terminal excitability. The decrease in excitability usually outlasted the increase in firing rate (sometimes by more than 8 min), and was superseded at a later stage by a marked increase in excitability. None of these effects were seen with saline (n = 5), and they could all be blocked by preadministration of the competitive NMDA antagonist AP-7 (0.025 mumol; n = 6). The sequence of events leading to the observed results is argued to be as follows; NMDA initially excites striatal efferents to the DA cell, which through disinhibition and direct stimulation increase DA cell firing rate. Increased firing rate leads to enhanced striatal DA release. Dopamine's inhibitory influence pre-empts any effect NMDA itself may have on the terminals of nigrostriatal neurons, and counteracts NMDA's stimulatory effect on striatal output cells. Furthermore, the marked reduction in terminal excitability suggests that DA becomes the dominant influence in the striatum for a time. Hence, the net outcome of the injection is augmented striatal DA tone. Later, the effect of residual NMDA becomes predominant once more.

σ-Receptors: Implication for the control of neuronal activity of nigral dopamine-containing neurons

Using extracellular single unit recording techniques, we analyzed the significance of σ-receptors in the neuronal control of dopamine (DA) neurons in the zona compacta of the substantia nigra. Administration of racemic trans-9-methoxy-4-benzyl-1,2,3,4,4a,5,6, 10b-octahydrobenzo[f]quinoline (HW 173), a drug displaying high and specific affinity for σ-receptors, was not associated with any change in the firing rate of DA neurons. Furthermore, pretreatment with the drug did not affect the dose-response curve for the inhibitory effects of the DA receptor agonist apomorphine or the mixed DA agonist/σ-receptor ligand (+)-3-(3-hydroxyphenyl)-N-1-propyl)piperidine ((+)-3-PPP). In contrast to the effects of HW 173 on the DA cell firing rate, the firing pattern of the DA cells was significantly changed by the drug. The data suggest that σ-receptors do not play a pivotal role in the control of the firing rate of DA neurons in the substantia nigra. Rather, they may have a function in the regulation of the firing pattern of these neurons.

Neurotensin modulates autoreceptor mediated dopamine effects on midbrain dopamine cell activity

Interactions of neurotensin (NT) with midbrain dopamine (DA) neurons were studied in rats using microiontophoretic techniques. Local ejection of NT significantly increased (30%) the firing rate of a few DA cells (12/106). In most cases, however, iontophoretic NT produced no significant change in spontaneous activity. On the other hand, in these same cells, NT significantly attenuated the inhibition induced by either DA or quinpirole, a specific D 2 agonist. Inhibition induced by DA was not attenuated by either glutamate or cholecystokinin, although both of them increase the firing rate of DA cells. The effect of NT appears to be selective as NT attenuated DA-induced inhibition without a measurable effect on either GABA-induced inhibition or glutamate-induced excitation of the same DA cells. Combined, these results suggest that NT's effect on DA cell activity is primarily a neuromodulatory one. As both NT and D 2 receptors in midbrain DA cell areas are primarily located on DA cells, the above results also suggest that the observed interaction between NT and DA occurred at the DA cell level.

Opposite effects of μ and κ opiates on the firing-rate of dopamine cells in the substantia nigra of the rat

Single unit extracellular recording was carried out in rats to compare the actions of a μ receptor agonist (morphine) to a κ receptor agonist (U50,488) in the substantia nigra pars compacta (SNC). Intravenously administered morphine and U50,488 exhibited opposite effects: morphine excited SNC dopamine cells, and U50,488 inhibited them. Both effects were blocked by naloxone, although significantly more naloxone was necessary to block the effect of the κ agonist. Local administration of U50,488 in the caudate also inhibited the firing of SNC dopamine cells. These results are discussed in terms of the natural functions of the prodynorphinergic striatonigral projection.

In vivo presynaptic control of dopamine release in the cat caudate nucleus—I. Opposite changes in neuronal activity and release evoked from thalamic motor nuclei

Halothane-anaesthetized cats implanted with three push pull cannulae were used to estimate the effects of γ-aminobutyric acid (GABA) application (either 10 −3 M or 10 −5 M ) into the left motor nuclei of the thalamus (either ventralis medialis, or ventralis lateralis) on the firing rate of dopamine cells in the left substantia nigra (caudomedial part) and on the release of [ 3H]dopamine continuously synthesized from [ 3H]tyrosine, in the left substantia nigra (caudomedial part) and the left caudate nucleus. Preliminary experiments were performed to establish the electrophysiological characteristics of dopamine cells and non-dopamine cells in the pars compacta (mediocaudal part of substantia nigra) in groups of animals with the electrode inserted within the nigral push pull cannula or with the electrode inserted in the absence of a push-pull cannula. Dopamine and non-dopamine cells were distinguished according to several criteria (shape of the spike, duration of spike, frequency of discharge, conduction velocity estimated following antidromic activation from the caudate nucleus for dopamine cells or from the ventralis medialis for non-dopamine cells). Data obtained from recordings made within the push pull cannula were identical to those obtained in the absence of the cannula. In addition both the intravenous injection of amphetamine or its local application (10 −6 M) in the substantia nigra inhibited the firing rate of dopamine cells. When GABA was applied at 10 −3 M for 30 min into the ventralis medialis ventralis lateralis the multi-unit activity of thalamic cells recorded within the push pull cannula was inhibited. Single unit activity of dopamine cells was also inhibited and [ 3H]dopamine release was reduced in the caudate nucleus and increased in the substantia nigra. These results suggest that under these conditions, dopamine release from nerve terminals depended upon nerve activity and that dopamine released from dendrites inhibited the activity of dopamine cells. When GABA was applied at 10 −5 M for 30 min into the ventralis medialis-ventralis lateralis, multi-unit activity of thalamic cells was increased, single-unit activity of dopamine cells was inhibited and [ 3H]dopamine release was enhanced in the ipsilateral caudate nucleus and not affected in the left substantia nigra, demonstrating that in this situation the release of dopamine from nerve terminals was not dependent on the firing rate of dopamine cells. In addition, these results indicated that the activity of dopamine cells was not always dependent on the dendritic release of dopamine. Further experiments performed in cats with an acute hemi-transection (left side) made just in front of the substantia nigra to cut through all dopamine fibres confirmed that the GABA (10 −5 M )-evoked release of [ 3H]dopamine in the caudate nucleus was mediated by a presynaptic regulation triggered from thalamic-motor nuclei. Indeed, [ 3H]dopamine release was still enhanced by GABA (10 −3 M) application into the ventralis medialis-ventralis lateralis of such animals. In contrast the application of GABA (10 −3 M) into the ventralis medialis-ventralis lateralis was without effect on [ 3H]dopamine release; n the caudate nucleus of the hemi-transected animals. Results are discussed in the light of the respective contributions of nerve activity and presynaptic regulation in the control of dopamine transmission in the caudate nucleus.

In vivo presynaptic control of dopamine release in the cat caudate nucleus—III. Further evidence for the implication of corticostriatal glutamatergic neurons

In confirmation of previous results, experiments in halothane-anaesthetized cats implanted with push-pull cannulae showed that the unilateral application of GABA (10 −5M for 30 min) into the left thalamic motor nuclei (either ventralis medialis, or ventralis lateralis) markedly stimulated the release of [ 3H]dopamine continuously synthesized from [ 3H]tyrosine in both caudate nuclei and in the contralateral substantia nigra. Three types of experiments confirmed that the changes in [ 3H]dopamine release evoked in both caudate nuclei resulted from a presynaptic facilitation mediated by the bilateral corticostriatal glutamatergic projection: (1) The constant delivery of 2-amino 6-trifluoromethoxy benzothiazole (PK 26124) (10 −5 M) to the left caudate nucleus prevented the increased release of [ 3H]DA evoked by application of γ-aminobutyric acid (GABA) (10 −5M) into ventralis medialis-ventralis lateralis while an enhanced release of [ 3H]dopamine still occurred in the contralateral caudate nucleus. Since PK 26124 is an antagonist of glutamatergic transmission, the presynaptic facilitation may involve glutamatergic neurons. (2) Single unit recordings of dopamine cells in the contralateral substantia nigra indicated that the increased release of [ 3H]dopamine from dendrites evoked by the application of GABA (10 −5M) into ventralis medialis ventralis lateralis was associated with a reduction in the firing rate of dopamine cells. Thus, the enhanced release of [ 3H]dopamine in the contralateral caudate nucleus may involve a presynaptic facilitatory process. (3) Finally, the unilateral lesion of the sensory motor cortex made prior to the superfusion of caudate nucleus with [ 3H]tyrosine prevented the responses evoked in the two caudate nuclei by the application of GABA (10 −5M) into ventralis medialis ventralis lateralis. Taken together, these results suggest that a thalamo-cortico-striatal neuronal loop involving the bilateral corticostriatal glutamatergic projection is responsible for the bilateral presynaptic facilitation of [ 3H]dopamine release induced in both caudate nuclei by the application of GABA (10 −5M) into ventralis medialis ventralis lateralis.

Thalamic control of dopaminergic functions in the caudate-putamen of the rat—I. The influence of electrical stimulation of the parafascicular nucleus on dopamine utilization

A neurochemical response of four dopamine-rich brain regions to unilateral electrical stimulation of the parafascicular thalamic nucleus was examined in the halothane-anaesthetized rat. Tissue concentrations of dopamine and its two major metabolites, 3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid, were assayed by a high performance liquid Chromatographic technique in samples of caudate-putamen complex, nucleus accumbens, prefrontal cortex and substantia nigra. The ratios of metabolite to parent amine concentrations were taken as indices of dopamine utilization. Halothane anaesthesia alone evoked significant bilateral increases of dopamine utilization in every brain region studied. Electrical stimulation of one parafascicular nucleus produced further bilateral elevations of dopamine utilization in the caudate-putamen complex without altering these parameters in the substantia nigra. In the prefrontal cortex, however, thalamic stimulation resulted in significant bilateral decreases of dopamine utilization. Electrical stimulation of cortical or other thalamic areas did not evoke this regional pattern of dopamine utilization. It is argued that these indices of dopamine utilization together serve as reliable indicators of synaptic dopamine release and it is concluded that the parafascicular thalamus is capable of facilitating dopaminergic neurotransmission in the caudate-putamen by a mechanism that is probably independent of changes in dopamine cell firing rate. An anatomical analysis suggests that a thalamo-cortical-striatal route is most likely to mediate this function.

Acute and subchronic effects of Rimcazole (BW 234U), a potential antipsychotic drug, on A9 and A10 dopamine neurons in the rat

The effects of acute and subchronic Rimcazole administration on A9 and A10 dopamine (DA) neurons were examined using extra-cellular single cell recording techniques. Intravenous injections of Rimcazole did not prevent or reverse the inhibition of firing rates of DA cells produced by DA agonist apomorphine (APO). Single intraperitoneal injection of Rimcazole decreased the number of spontaneously active DA cells in A10, but not in A9; it had no effect on the firing rate of DA neurons in either A9 or A10. Following prolonged administration of Rimcazole, 25 mg/kg/day for 28 days, there was a significant increase in the number of spontaneously active A10 DA neurons, but not A9 DA cells. The firing rate of both A9 and A10 DA cells decreased significantly following prolonged Rimcazole administration; however, the firing pattern of these cells did not change. In addition, chronic Rimcazole did not affect the ID 50 of APO for DA neurons. These results suggest that Rimcazole has an indirect effect on DA neurons with a relative selectivity for A10 DA cells; it does not exhibit pharmacological profiles of previously reported antipsychtic drugs.