D-2 receptor-mediated inhibition by a substituted quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), of dopaminergic neurons in the ventral tegmental area

A microiontophoretic study was performed to investigate the effects of a newly synthesized quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone (OPC-4392), on neuronal activities of the ventral tegmental area (VTA) of rats anesthetized with chloral hydrate. The VTA neurons, which were identified by antidromic stimulation of the nucleus accumbens (Acc), were classified into type I and type II neurons according to the responses to Acc stimulation: type I neurons had a long spike latency of over 7 msec (9.63 +/- 0.25 msec), and the type II, a short latency of less than 7 msec (2.98 +/- 0.27 msec) upon Acc stimulation. In all of 11 type I neurons, iontophoretically applied OPC-4392 and dopamine inhibited the antidromic spikes elicited by Acc stimulation. This inhibition was antagonized by simultaneous application of domperidone (dopamine D-2 antagonist). However, in 16 out of 19 type II neurons the antidromic spikes were not affected by either OPC-4392 or dopamine. When the effects of iontophoretically applied OPC-4392 and dopamine on spontaneous firings were tested in 32 VTA neurons identified by Acc stimulation (including type I and type II neurons), there was a relationship between the effects of these two drugs. These results suggest that OPC-4392 acts on dopamine D-2 receptors of the dopaminergic neurons in the VTA, thereby inhibiting neuronal activity.     

Excitation by dopamine D-2 receptor agonists, bromocriptine and LY 171555, in caudate nucleus neurons activated by nigral stimulation

Electrophysiological studies using cats anesthetized with alpha-chloralose were carried out to determine whether or not the dopamine D-2 receptor mediates the excitation of the caudate nucleus (CN) neurons activated by stimulation of the substantia nigra (SN). Microiontophoretic application of domperidone (D-2 antagonist) produced a significant inhibition of spikes elicited by SN stimulation in 20 of 27 CN neurons. When bromocriptine and LY 171555 (D-2 agonists) were iontophoretically applied to the CN neurons in which the SN-induced spikes were inhibited by domperidone, an increase in spontaneous firing rate was observed in 18 of 20 neurons and all of 10 neurons tested, respectively. However, no alterations of firing occurred with bromocriptine or LY 171555 in any 7 neurons in which the SN-induced spikes were not affected by domperidone. The increase in firing rate by the D-2 agonists was apparently antagonized during simultaneous application of domperidone and haloperidol, but not affected during application of SCH 23390 (D-1 antagonist). These results strongly suggest that the spike generation of the CN neurons upon SN stimulation is mediated by the dopamine D-2 receptor.     

Presynaptic inhibition of excitatory input from the substantia nigra to caudate nucleus neurons by a substituted quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392)

The effects of a newly synthesized quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl) propoxy]-2(1H)-quinolinone (OPC-4392) on neuronal activities of the caudate nucleus (CN) were investigated in cats anesthetized with alpha-chloralose using a microiontophoretic method. In the CN neurons of which spikes elicited by stimulation of the pars compacta of substantia nigra (SN) were suppressed by iontophoretically applied domperidone, a dopamine D-2 receptor antagonist, application of OPC-4392 (100-200 nA) inhibited the spike generation induced by SN stimulation. Conversely, the CN neurons insensitive to domperidone were unaffected by OPC-4392. Iontophoretic application of CPC-4392 up to 200 nA did not affect glutamate-induced firing of the CN neurons, of which the firing was blocked by dopamine less than 100 nA. In addition, OPC-4392 did not inhibit firing induced by bromocriptine, a dopamine D-2 agonist; while domperidone suppressed the bromocriptine-induced firing without affecting the glutamate-induced firing. These results suggest that OPC-4392 acts on the dopaminergic nerve terminals and inhibits excitatory transmission from the SN to the CN.     

Coexistence of inhibitory dopamine D-1 and excitatory D-2 receptors on the same caudate nucleus neurons

Microiontophoretic studies using cats anesthetized with alpha-chloralose were performed to determine whether or not dopamine D-1 and D-2 receptors co-exist in the same caudate nucleus (CN) neurons that receive inputs from the substantia nigra (SN), and in which spikes elicited by SN stimulation were blocked by domperidone, a selective D-2 antagonist. Iontophoretic application of dopamine produced a dose-dependent inhibition of spontaneous firing in 2 of 4 spontaneously active CN neurons and an increase in firing in the remaining 2 neurons. However, dopamine inhibited the glutamate-induced firing in 31 of 32 CN neurons that were not spontaneously active. Similar inhibition with iontophoretically applied SKF 38393, a selective D-1 agonist, was observed in 33 of 34 spontaneously inactive neurons tested. When the effects of dopamine, SKF 38393 and bromocriptine (D-2 agonist) were examined on the same CN neurons, the inhibitory effects of both dopamine and SKF 38393 were seen in 14 of 15 neurons, and both an inhibition by SKF 38393 and an excitation by bromocriptine were observed in 15 of 17 neurons. The inhibitory effects of dopamine and SKF 38393 were antagonized by haloperidol and SCH 23390 (D-1 antagonist) without being affected by domperidone. Furthermore, the dopamine-induced inhibition was converted to an excitation during simultaneous application of SCH 23390 in 6 of 10 CN neurons, and this excitation was antagonized by domperidone. These results strongly suggest that the inhibitory D-1 and excitatory D-2 receptors co-exist on the same CN neurons receiving inputs from the SN.     

Effects of haloperidol and sulpiride on dopamine-induced inhibition of nucleus accumbens neurons

Microiontophoretic study was performed to elucidate dopaminergic mechanism in the nucleus accumbens (Acc) of rats anesthetized with chloral hydrate. Iontophoretically applied dopamine produced an inhibition of glutamate-induced firing in 28 (62%) out of 45 Acc neurons tested. The dopamine-induced inhibition of 14 Acc neurons was clearly antagonized by simultaneous application of haloperidol, and a partial antagonism by sulpiride was observed in 3 out of 10 Acc neurons. These results indicate that dopamine produces an inhibition of the Acc neuron and that, compared to haloperidol, sulpiride is a less potent blocker of the postsynaptic dopamine receptor involved in the dopamine-induced inhibition.     

Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors

Nicotine elicits dopamine release by stimulating nicotinic acetylcholine receptors (nAChRs) on dopaminergic neurons. However, a modulation of these neurons by endogenous acetylcholine has not been described. We recorded, in vivo, the spontaneous activity of dopaminergic neurons in the VTA of anaesthetized wt and nAChR knockout mice and their response to nicotine injections. Deleting alpha7 or beta2 subunits modified the spontaneous firing patterns, demonstrating their direct stimulation by endogenous acetylcholine. Quantitative analysis further revealed four principal modes of firing, each depending on the expression of particular nAChR subunits and presenting unique responses to nicotine. The prominent role of the beta2 subunit was further confirmed by its selective lentiviral reexpression in the VTA. These data suggest a hierarchical control of dopaminergic neuron firing patterns by nAChRs: activation of beta2*-nAChR switches cells from a resting to an excited state, whereas activation of alpha7*-nAChRs finely tunes the latter state but only once beta2*-nAChRs have been activated.     

Stimulation of midbrain dopaminergic structures modifies firing rates of rat lateral habenula neurons

Ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) are midbrain structures known to be involved in mediating reward in rodents. Lateral habenula (LHb) is considered as a negative reward source and it is reported that stimulation of the LHb rapidly induces inhibition of firing in midbrain dopamine neurons. Interestingly, the phasic fall in LHb neuronal activity may follow the excitation of dopamine neurons in response to reward-predicting stimuli. The VTA and SNpc give rise to dopaminergic projections that innervate the LHb, which is also known to be involved in processing painful stimuli. But it's unclear what physiological effects these inputs have on habenular function. In this study we distinguished the LHb pain-activated neurons of the Wistar rats and assessed their electrophysiological responsiveness to the stimulation of the VTA and SNpc with either single-pulse stimulation (300 μA, 0.5 Hz) or tetanic stimulation (80 μA, 25 Hz). Single-pulse stimulation that was delivered to either midbrain structure triggered transient inhibition of firing of ～90% of the LHb pain-activated neurons. However, tetanic stimulation of the VTA tended to evoke an elevation in neuronal firing rate. We conclude that LHb pain-activated neurons can receive diverse reward-related signals originating from midbrain dopaminergic structures, and thus participate in the regulation of the brain reward system via both positive and negative feedback mechanisms.     

Single unit activity of dopaminergic neurons in freely moving cats

Single unit activity was recorded from the area of the substantia nigra in freely moving cats. A sub-population of these neurons had the following characteristics: long action potential durations (2–4 msec); relatively slow discharge rates (2–6 spikes/sec); firing as single spikes along with periods of bursting activity in which spike amplitude successively decreased; suppression of unit activity by systemic injection of apomorphine and increased activity after systemic injection of haloperidol. These characteristics are similar to those of identified dopamine neurons recorded in chloral hydrate anesthetized or peripherally paralyzed rats. Therefore, based upon these physiological and pharmacological similarities, this study represents the first systematic report providing evidence for recording the activity of dopaminergic neurons in freely moving cats. In addition, when these cells were studied across the sleep-waking cycle they displayed little variation in firing rates between waking, slow wave sleep and REM sleep.     

L-谷氨酸和卡巴胆碱对中脑腹侧被盖区多巴胺能神经元簇放电的影响

中脑腹侧被盖区(ventral tegmental area,VTA)多巴胺能神经元的簇放电会导致其突触末梢多巴胺释放量瞬时大量增加,已被公认是编码奖赏效应的功能相关信号,但诱发多巴胺能神经元产生簇放电的神经调节的具体机制尚不完全清楚。为深入理解诱发VTA多巴胺能神经元产生簇放电介导奖赏信号的递质机制和不同脑区间的协同作用,本实验利用大鼠离体脑片,研究了胆碱能受体激动剂卡巴胆碱单独灌流,兴奋性谷氨酸能受体激动剂L-谷氨酸单独脉冲式给药及二者同时作用时VTA多巴胺能神经元簇放电的产生。结果显示,在离体脑片,卡巴胆碱(10μmol/L)持续灌流或L-谷氨酸(3mmol/L)脉冲式给药均能够诱发多巴胺能神经元产生簇放电。在二者单独作用不能诱发簇放电的神经元,卡巴胆碱和谷氨酸联合用药则可以诱发出簇放电。这些结果提示,卡巴胆碱和L-谷氨酸在诱发多巴胺能神经元簇放电的过程中具有协同作用。     

Dopamine D-2 receptor-mediated excitation of caudate nucleus neurons from the substantia nigra

Microiontophoretic studies using cats anesthetized with alpha-chloralose were performed to elucidate whether the excitatory response of caudate nucleus (CN) neurons upon stimulation of the pars compacta of the substantia nigra (SN) is mediated by the dopamine D-1 or D-2 receptor. There were rare convergent inputs from the SN and motor cortex (MC) in the CN neurons. Iontophoretic application of haloperidol and domperidone (dopamine D-2 receptor antagonist) produced dose-dependent inhibition of spikes elicited by SN stimulation in 25 of 42 and 50 of 82 CN neurons, respectively, however, no alterations of spikes elicited by MC stimulation occurred in any 11 neurons tested. Iontophoretically applied SCH 23390 (D-1 antagonist) did not inhibit the SN-induced spikes in any CN neurons, of which spikes were inhibited by domperidone. These results suggest that the SN-induced spikes are mediated by dopamine, which acts on postsynaptic D-2 receptors.     

Unit responses of the reticular and ventral anterior thalamic nuclei of cats to orbitofrontal cortical stimulation

Responses of 98 neurons of the reticular (R) and 72 neurons of the ventral anterior (VA) thalamic nuclei to stimulation of various zones of the orbitofrontal cortex were investigated in acute experiments on cats immobilized with D-tubocurarine. Not all zones of this cortex were found to be connected equally closely with R and VA. Most of the R (82.7%) and VA (66.7%) neurons responded to stimulation of the proreal gyrus, and fewest (37.3 and 48.9%, respectively) to stimulation of the posterior orbital gyrus. Among the responding neurons, 85.2–86.3% of R cells and 78.2–81.2% of VA cells were excited by cortical stimulation and the rest were inhibited. Excitation was expressed as the appearance of a single spike or of discharges of varied duration in response to each stimulus. The latent period of the spike responses varied from 0.5 to 55.0 msec and the minimal latent period of the discharges was 0.8 msec and its maximal value over 500 msec. The spike frequency in the discharge was 120–250/sec. Unit responses consisting of spikes with a latent period of under 1.3 msec and, it is assumed, some of the responses with a latent period of under 4.0 msec were antidromic. The axons of some R and VA neurons were shown to form branches terminating in different zones of the orbitofrontal cortex.     

Comparison of the effect of morphine on locus coeruleus noradrenergic and ventral tegmental area dopaminergic neurons in vitro

Extracellular single-cell recordings were performed on rat brain slices to compare the effects of morphine on noradrenergic neurons of the locus coeruleus (LC) and on dopaminergic neurons of the ventral tegmental area (VTA). Morphine inhibited the firing of LC neurons at very low concentrations. The mean IC50 was 13.4 +/- 1nM (mean +/- SEM) (n = 7). Moreover, the inhibitory effect of morphine was identical in slices obtained from rats anesthetized with chloral hydrate or from non-anesthetized rats. On the contrary, morphine did not have any influence on the firing of most VTA neurons (N = 20) up to 100 microM, and did not modify the sensitivity of their autoreceptors (N = 8). It is concluded that morphine potently inhibits the firing of LC neurons in vitro both in slices of anesthetized and not anesthetized animals and has no direct excitatory effect on VTA dopaminergic neurons of the rat.     

Physiological characteristics and reflex activation of DUM (octopaminergic) neurons of locust metathoracic ganglion

Intracellular recordings were made from single or pairs of somata of the dorsal unpaired median (DUM) neurons of the metathoracic ganglion of the locust Schistocerca gregaria and the grasshopper Romalea microptera, during reflex actions, direct electric excitation and orthodromic and antidromic neural stimulation. Some, possibly all, of these neurons are unique, identifiable individuals in regard to their targets, which are specific peripheral muscles. Their physiological properties and the ways they are activated synaptically are, however, similar. Large, overshooting action potentials, comprising three components, occur. The first component in time is small and represents an excitatory synaptic potential for orthodromic stimulation or an axon spike (AS) for antidromic stimulation, electrotonically conducted into the soma. The second component is larger, being an electrotonically conducted integrating segment spike (ISS). The final component is the soma spike (SS). Neither AS nor ISS have a late positive phase, but there is a large, prolonged one for SS. The latter, combined with rapid accommodation, determine a low maximum firing rate for the neurons. Most nerves entering the ganglion make excitatory inputs onto each DUM neuron, which is readily driven to spike by electric excitation of either connective. There is a great deal of spontaneous excitatory synaptic input to each DUM neuron and a high proportion of it is common. Although there is no detectable electrical coupling between the cells, there is about 30% synchronous firing, apparently due to the common inputs; independent excitation and inhibition also occur. All sensory modalities tested have inputs to the neurons, which tend to fire constantly at a low rate (1 per 3–4 sec). In reflex actions, DUM neurons tend to fire before motor output occurs. It is suggested that the cells will be found to have many functions serving a general role comparable to that achieved by the release of adrenaline in vertebrates.     

Characteristics of unit responses of the cat cerebellar cortex to acoustic stimuli

Investigation of unit responses of the cerebellar cortex (lobules VI–VII of the vermis) to acoustic stimulation showed that the great majority of neurons responded by a discharge of one spike or a group of spikes with a latent period of 10–40 msec and with a low fluctuation value. Neurons identified as Purkinje cells responded to sound either by inhibition of spontaneous activity or by a "climbing fiber response" with a latent period of 40–60 msec and with a high fluctuation value. In 4 of 80 neurons a prolonged (lasting about 1 sec or more), variable response with a latent period of 225–580 msec was observed. The minimal thresholds of unit responses to acoustic stimuli were distributed within the range from –7 to 77 dB, with a mode from 20 to 50 dB. All the characteristics of the cerebellar unit responses studied were independent of the intensity, duration, and frequency of the sound, like neurons of short-latency type in the inferior colliculi. In certain properties — firing pattern, latent period, and threshold of response — the cerebellar neurons resemble neurons of higher levels of the auditory system: the medial geniculate body and auditory cortex.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 5, No. 1, pp. 3–12, January–February, 1973.     

Unit responses of the first and second somatosensory areas to stimulation of the ventroposterior thalamic nucleus

Single unit responses of the first (SI) and second (SII) somatosensory areas to stimulation of the ventroposterior thalamic nucleus (VP) were investigated in cats immobilized with D-tubocurarine. In response to VP stimulation 12.0% of reacting SI neurons and 9.5% of SII neurons generated an antidromic spike. In most antidromic responses of both SI and SII neurons the latent period did not exceed 1.0 msec. The minimal latent period of spike potentials during orthodromic excitation was 1.5 msec in SI and 1.7 msec in SII. Neurons with an orthodromic spike latency of not more than 3.0 msec were more numerous in SI than those with a latency of 3.1–4.5 msec. The ratio between the numbers of neurons of these two groups in SII was the opposite. In SII there were many more neurons with a latency of 5.6–8.0 msec than in SI. EPSPs appeared after a latent period of 1.1–9.0 msec in SI and of 1.4–6.6 msec in SII. The latent period of IPSPs was 1.5–6.8 msec in SI and 2.2–9.4 msec in SII. The relative importance of different pathways for excitatory and inhibitory influences of VP on SI and SII neurons is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 8, No. 2, pp. 115–121, March–April, 1976.     

Analysis of spike discharge and character of interconnection of identified output neurons in the rat neostriatum

Two populations of neostriatal neurons projecting into the globus pallidus and two neuron populations projecting into the substantia nigra were identified by antidromic testing in acute experiments on immobilized rats. Statistical analysis showed that the firing patterns of the identified output neurons were of either the grouped or single type. Cross-correlation analysis of the spontaneous activity of two neurons, one projecting into the substantia nigra, the other into the globus pallidus, showed that activity of the second neuron was inhibited for 300–400 msec after spike generation by the first neuron.Institute of Biological Physics, Academy of Sciences of the USSR, Pushchino-on-Oka. Computer Research Center, Academy of Sciences of the USSR, Pushchino-on-Oka. Translated from Neirofiziologiya, Vol. 14, No. 5, pp. 470–475, September–October, 1982.     

D-2 dopamine autoreceptor selective drugs: do they really exist?

The catecholamine dopamine plays an important role as a neurotransmitter or neurohormone in the brain and pituitary gland. Dopamine exerts its effects through activation of two types of receptors called D-1 and D-2. These receptors are distinguished by their different pharmacological characteristics and signal transduction mechanism(s). Release of dopamine inhibits the activity of dopaminergic neurons through activation of so-called dopamine autoreceptors which are of the D-2 type. In general, these receptors occur both in the soma-dendritic region of the dopaminergic neuron, where they are involved in the inhibition of the firing rate and on the dopaminergic terminals where they mediate the inhibition of dopamine synthesis and release. D-2 receptors occur also on the target cells of dopaminergic neurons both in the brain (postsynaptic D-2 receptors) and pituitary gland. On the basis of data gathered from in vivo (behavioral- as well as electrophysiological) studies it has been concluded that D-2 agonists are much more potent at dopamine autoreceptors as compared to postsynaptic D-2 receptors, indicating the possibility of a pharmacological distinction between these differentially located D-2 receptors. This concept led to the introduction of a whole group of drugs allegedly displaying a selective agonist profile at the dopamine autoreceptor. In contrast, biochemical (in vitro) studies with brain tissue as well as the pituitary gland, did not reveal any significant difference between the pharmacological profiles of autoreceptors and postsynaptic D-2 receptors. In the present minireview a balanced discussion is presented of these in vivo and in vitro findings and it is concluded that both autoreceptors as well as postsynaptic D-2 receptors are similar if not identical entities.     

Effects of ibogaine,and cocaine and morphine after ibogaine,on ventral tegmental dopamine neurons

Ibogaine, an indole containing alkaloid, has been shown to reduce the rate of injection of morphine and cocaine in self-administration protocols. Since morphine- and cocaine-induced modulation of dopamine release is impulse dependent and essential for their reinforcing effects, disruption of dopamine neuronal activity by ibogaine could explain its purported ‘antiaddictive’ properties. Therefore, the present study was designed to determine: (1) the acute effects of ibogaine on the activity of VTA dopamine neurons, and (2) whether ibogaine pretreatment causes a persistent modification of the dopamine neuronal response to morphine and cocaine. Extracellular recordings in anesthetized animals found that intravenous ibogaine markedly excited VTA dopamine neuronal firing. However, ibogaine pretreatment (6–8 hr and 19 hr before) failed to alter either the spontaneous activity of VTA neurons, or the response of these dopamine neurons to morphine or cocaine. Thus, ibogaine's excitatory effect on VTA neurons is not longlasting nor does it persistently alter cocaine- or morphine-induced changes in dopamine neuron impulse activity. Therefore, other mechanisms must be explored to account for the proposed antiaddictive properties of ibogaine.     

Functional diversity of ventral midbrain dopamine and GABAergic neurons

Recent findings indicate that VTA and SN dopaminergic (DA) and GABAergic neurons form subpopulations that are divergent in their electrophysiological features, vulnerability to neurodegeneration, and regulation by neuropeptides. This diversity can be correlated with the anatomical organization of the VTA and SN and their inputs and outputs. In this review we describe the heterogeneity in ion channels and firing patterns, especially burst firing, in subpopulations of dopamine neurons. We go on to describe variations in vulnerability to neurotoxic damage in models of Parkinson’s disease in subgroups of DA neurons and its possible relationship to developmental gene regulation, the expression of different ion channels, and the expression of different protein markers, such as the neuroprotective marker calbindin. The electrophysiological properties of subgroups of GABAergic midbrain neurons, patterns of expression of protein markers and receptors, possible involvement of GABAergic neurons in a number of processes that are usually attributed exclusively to dopaminergic neurons, and the characteristics of a subgroup of neurons that contains both dopamine and GABA are also discussed.     

Analysis of evoked discharges in hypothalamic neurons to somatosensory,acoustic, and photic stimulation

Single unit activity in the supramammillary, mammillary, and anterior hypothalamic areas in response to acoustic, photic, and sciatic nerve stimulation was recorded in cats anesthetized with chloralose and immobilized with succinylcholine. In response to sensory stimulation the spontaneous firing rate was increased or decreased, and silent neurons were activated. Evoked potentials of the silent neurons had the shortest latent period to acoustic and somatosensory stimulation (15 msec), and rather longer to photic stimulation (30 msec); in some cases their latent period was 200 msec. Histograms of interspike interval distribution showed a maximum for intervals of up to 50 msec. Histograms of spike distribution relative to the beginning of stimulation showed maximal density between 100 and 200 msec. A high degree of convergence of excitation was found on units of the anterior as well as the posterior hypothalamus. Unit responses in the hypothalamus to sensory stimuli of all three modalities are regarded as being of secondary, nonspecific type.L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 3, No. 6, pp. 592–598, November–December, 1971.