A10 Dopamine Cells Research Articles

The Orexin-1 Receptor Antagonist SB-334867 Blocks the Effects of Antipsychotics on the Activity of A9 and A10 Dopamine Neurons: Implications for Antipsychotic Therapy

Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day x 21 days, s.c.) or olanzapine (10 mg/kg/day x 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.

Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups.

Estrogen modulates dopamine synthesis, release, and metabolism in corticolimbic and striatal targets of midbrain dopamine neurons. The relevant sites of receptor-mediated action, however, had been elusive, because all available evidence suggested a paucity of intracellular estrogen receptors in the A8, A9, and A10 dopamine regions and their afferent targets. More recent evidence of a relative abundance of the beta isoform of the estrogen receptor (ER) in the substantia nigra and ventral tegmental area (VTA), however, suggests that this newly described receptor may be important in estrogen's stimulation of midbrain DA systems. It is unknown, however, precisely how ERbeta is distributed with respect to the functionally and neurochemically diverse cell populations of the ventral midbrain. To address these issues, this study used single- and double-label immunocytochemistry to detail the regional, subregional, and cellular distributions of ERbeta immunoreactivity in and around midbrain dopamine-containing cell groups in hormonally intact adult male and female rats. These analyses revealed that ERbeta-immunoreactive nuclei were found only in neurons, more specifically, within subsets of both dopaminergic and nondopaminergic neurons in the dorsal VTA, the parabrachial pigmented nucleus, the substantia nigra pars lateralis, the retrorubral fields, and to a lesser extent the linear midline nuclei. These regional and cellular receptor distributions thus place the ERbeta isoform in anatomical register with midbrain dopamine systems known to participate in a spectrum of motor, cognitive, and affective functions.

Localization of 5-HT 2A receptors on dopamine cells in subnuclei of the midbrain A10 cell group

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT 2A receptors. It is currently unknown if 5-HT 2A receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT 2A receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT 2A receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT 2A receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT 2A immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT 2A receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT 2A receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT 2A receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT 2A receptor activation may modulate reward-related behavior in rodents. 5-HT 2A receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT 2A receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.

Xanomeline, an M 1/M 4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice

Xanomeline is an M 1/M 4 preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.

Electrophysiological effects of E-5842, a σ 1 receptor ligand and potential atypical antipsychotic, on A9 and A10 dopamine neurons

Extracellular single unit recording techniques were used to study the effects of the novel potential atypical antipsychotic E-5842, (4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-il)butyl]pyridine citrate), a preferential σ 1 receptor ligand, on the activity of dopamine cells in substantia nigra pars compacta (A9) and ventral tegmental area (A10) in anesthetized rats. Acute i.v. administration of E-5842 (up to 3.2 mg kg −1) did not change the spontaneous activity of the dopamine neurons, which still responded to the inhibitory effect of a subsequent administration of high dose of apomorphine. Acute administration of E-5842 (20 mg kg −1, i.p.) did not change the number of spontaneously active A9 or A10 dopamine cells. Chronic administration of E-5842 (20 mg kg −1 day −1×21 days, s.c.) decreased the number of spontaneously active A10, but not A9, dopamine neurons. This effect was reversed by the administration of apomorphine, thus, indicating a possible depolarization inactivation phenomenon. Our results suggest an influence of E-5842 on dopaminergic neurotransmission, although the exact mechanism remains unknown. The effect of E-5842 on A10 is similar, in some ways, to the effects observed with several atypical antipsychotics and suggest the atypicality of the compound and that E-5842 may exert its antipsychotic effects without causing significant extrapyramidal side effects.

Rewarding brain stimulation induces only sparse Fos-like immunoreactivity in dopaminergic neurons

In this study, c-fos immunohistochemistry was used to identify the brain regions activated by rewarding brain stimulation in rats. Rats had monopolar electrodes implanted in the medial forebrain bundle and were allocated to either a self-stimulation (n=4), yoked stimulation (n=4) or no stimulation (n=6) group. In a single 1h test session, each rat in the self-stimulation group made 1 000 nose poke responses with each response followed by a 0.5s train of brain stimulation. Rats in the yoked-stimulation group were paired with a partner in the self-stimulation group and received brain stimulation whenever their partner did. However, their nose poke responses did not trigger stimulation. This yoked procedure was thus used to identify any Fos-like immunoreactivity due to operant responding. Rats in the no stimulation group were placed in the same apparatus as the other rats but received no brain stimulation and were thus used to assess baseline Fos-like immunoreactivity. Results showed that stimulation increased Fos-like immunoreactivity in many areas of the brain in both the self-stimulation and yoked groups. The areas with the highest Fos-like immunoreactivity were ipsilateral to the electrode site and included the medial prefrontal cortex, lateral septum, nucleus accumbens (shell), the medial and lateral preoptic areas, bed nucleus of the stria terminalis, central amygdala, lateral habenula, dorsomedial hypothalamus, lateral hypothalamus and the anterior ventral tegmental area. Bilateral Fos-like immunoreactivity was evident in the nucleus accumbens core, paraventricular nucleus of the hypothalamus, the retrorubral fields and the locus coeruleus. A double-labelling procedure identifying both Fos and tyrosine hydroxylase was used to show that very few (<5%) of the A10 dopamine cell bodies in the ventral tegmental area expressed Fos following brain stimulation. In contrast, most of the noradrenergic neurons of the locus coeruleus (A6), rubrospinal tract (A5) and pontine tegmental area (A7) were Fos positive.Overall, the results show that rewarding brain stimulation induces Fos-like immunoreactivity in many forebrain regions but only sparsely in mesolimbic and mesocortical dopamine neurons. The similar patterns of Fos-like immunoreactivity seen in the self-stimulation and yoked-stimulation groups suggests that the operant responding for brain stimulation causes minimal Fos expression in itself.

Infusion of quinpirole and muscimol into the ventral tegmental area inhibits fear-potentiated startle: implications for the role of dopamine in fear expression

Dopamine (DA) D 2 and γ-aminobutyric acid (GABA) A somatodendritic receptors tonically inhibit mesolimbic projection neurons in the A10 DA cell grouping of the ventral tegmentum. In the present study we determined the contribution of the ventral tegmental area (VTA) to the expression of a classically conditioned fear-induced increase in the acoustic startle reflex. Saline applied to VTA neurons did not modify the capacity of a light previously associated with footshock to potentiate acoustic startle amplitudes; conversely, bilateral administration of the DA D 2/3 agonist quinpirole or the GABA A receptor agonist muscimol into the ventral tegmentum blocked fear-potentiated startle without altering baseline acoustic startle responding. It was suggested that DA VTA neurons regulate the excitatory aspects of fear expression by gating levels of aversive emotional arousal within the amygdala-based fear system.

Examination of the action of 3,4-methylenedioxymethamphetamine on rat A10 dopamine neurons

Extracellular single cell recording was used to examine the effect of intravenous administration of (-), (+), and (+/-)-3,4-methylenedioxymethamphetamine (MDMA) on A10 dopamine (DA) neurons in chloral hydrate anesthetized male rats. Both (+/-)-MDMA and (+)-MDMA inhibited the firing rate of most (79%) A10 DA cells. By contrast, (-)-MDMA induced either no effect or a slight increase in the firing rate of these cells. Analysis of the effects of (+/-)-MDMA on the firing pattern of the DA cells revealed on overall decrease in the percentage of spikes in bursts but both increases and decreases were seen in the coefficient of variation of interspike intervals. To determine the contribution of 5-HT and DA to the (+/-)-MDMA-induced inhibition of A10 DA cells rats were pretreated either with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or the DA synthesis inhibitor alpha-methyl-p-tyrosine (AMPT). Pretreatment of rats with PCPA did not reduce the ability of (+/-)-MDMA to inhibit the DA cells. However, in rats pretreated with AMPT, the (+/-)-MDMA-induced inhibition was blocked and some cells (44%) showed instead an increase in firing rate following administration of (+/-)-MDMA. The administration of l-3,4-dihydroxyphenylalanine (L-DOPA) to AMPT-treated rats rapidly restored the inhibition of cell firing by (+/-)-MDMA. In conclusion, the results reported here demonstrate that MDMA has an overall inhibitory effect on A10 DA cells. Despite MDMA's greater potency in releasing 5-HT compared to DA, the inhibitory effect of this drug on A10 DA cells appears to be mediated by the latter transmitter.

Examination of the action of 3,4‐methylenedioxymethamphetamine on rat A10 dopamine neurons

Extracellular single cell recording was used to examine the effect of intravenous administration of (−), (+), and (±)-3,4-methylenedioxymethamphetamine (MDMA) on A10 dopamine (DA) neurons in chloral hydrate anesthetized male rats. Both (±)-MDMA and (+)-MDMA inhibited the firing rate of most (79%) A10 DA cells. By contrast, (−)-MDMA induced either no effect or a slight increase in the firing rate of these cells. Analysis of the effects of (±)-MDMA on the firing pattern of the DA cells revealed an overall decrease in the percentage of spikes in bursts but both increases and decreases were seen in the coefficient of variation of interspike intervals. To determine the contribution of 5-HT and DA to the (±)-MDMA-induced inhibition of A10 DA cells rats were pretreated either with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or the DA synthesis inhibitor α-methyl-p-tyrosine (AMPT). Pretreatment of rats with PCPA did not reduce the ability of (±)-MDMA to inhibit the DA cells. However, in rats pretreated with AMPT, the (±)-MDMA-induced inhibition was blocked and some cells (44%) showed instead an increase in firing rate following administration of (±)-MDMA. The administration of l-3,4-dihydroxyphenylalanine (L-DOPA) to AMPT-treated rats rapidly restored the inhibition of cell firing by (±)-MDMA. In conclusion, the results reported here demonstrate that MDMA has an overall inhibitory effect on A10 DA cells. Despite MDMA's greater potency in releasing 5-HT compared to DA, the inhibitory effect of this drug on A10 DA cells appears to be mediated by the latter transmitter. © 1996 Wiley-Liss, Inc.

Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons

This study examined the effects of the novel atypical antipsychotic olanzapine (LY170053) on the activity of substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine cells in anesthetized rats. Acute administration of olanzapine (10, 20 mg/kg sc) increased the number of spontaneously active A10, but not A9, dopamine cells. Chronic administration of olanzapine (10, 20 mg/kg/day x 21 days) decreased the number of spontaneously active A10, but not A9, dopamine cells. Administration of the dopamine agonist apomorphine reversed the effects of chronic olanzapine on A10 cells, indicating a possible depolarization-inactivation mechanism. In conclusion, olanzapine has selective effects on A10 versus A9 dopamine cells following acute and chronic administration. These effects of olanzapine on dopamine cells are similar to the effects observed with clozapine and may play an important role in the atypical antipsychotic profile of olanzapine.

3H]WIN 35,428 [2β-Carbomethoxy-3β-(4-fluorophenyl)tropane] binding to rat brain membranes : Comparing dopamine cell body areas with nerve terminal regions

Potential differences between somatodendritic and axonal dopamine transporters were examined by comparing the binding constants of [ 3H]WIN 35,428 [2β-carbomethoxy-3β-(4-fluorophenyl)tropane] binding to membranes prepared from the rat ventral mesencephalon, containing A9 and A10 dopamine cell bodies, and from the nucleus accumbens. Saturation analysis of [ 3H]WIN 35,428 binding, in the presence of compounds to occlude norepinephrine and serotonin transporters, was performed by both the “unlabeled” method (varying unlabeled ligand) and “labeled” method (varying radioligand). The density of binding was substantially lower in the ventral mesencephalon than in the nucleus accumbens, but the binding affinity was only slightly different. Likewise, the differences between the two regions in the inhibitory potency of cocaine and GBR 12909 [1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine] were not substantial. The results suggest that somatodendritic and axonal dopamine transporters in the ventral mesencephalon and nucleus accumbens are not very different as far as their binding domains for uptake blockers such as cocaine and GBR 12909 are concerned.

The depletion of brain serotonin levels by para‐chlorophenylalanine administration significantly alters the activity of midbrain dopamine cells in rats: An extracellular single cell recording study

In this study, we examined the effect of 5-HT depletion produced by the acute administration of para-chlorophenylalanine (PCPA) on the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in the rat. We also determined the effect of PCPA administration on the spike discharge pattern of midbrain DA cells. This was accomplished using standard extracellular single cell recording techniques. The administration of PCPA (400 mg/kg, i.p., 24 h before the experiment) produced a significant decrease in the number of spontaneously active DA cells in both the A9 (52%) and A10 (63%) areas compared to controls. The burst firing analysis indicated that there was a significant increase in the mean interspike interval of A9 and A10 DA neurons in PCPA treated animals compared to controls. Furthermore, a decrease in the percentage of A10 DA neurons exhibiting a burst firing pattern and the number of bursts was observed in the PCPA treated animals compared to controls. The intravenous (i.v.) administration of 5-hydroxytryptophan (40 mg/kg) and the peripheral aromatic acid decarboxylase inhibitor benserazide (10 mg/kg) which restores 5-HT content, reversed the decrease in the number of spontaneously active A9 and A10 DA neurons, as well as the decrease in the percentage of A10 DA neurons exhibiting a bursting pattern. In contrast, the i.v. administration of benserazide (10 mg/kg) and L-DOPA (40 mg/kg) did not reverse the decrease in the number of spontaneously active midbrain DA neurons produced by PCPA treatment. The pretreatment of animals with PCPA did not alter the sensitivity of spontaneously active A9 or A10 DA cells to the intravenous administration of (+)-apomorphine (1–32 μg/kg) compared to controls. Overall, our results indicate that the depletion of brain 5-HT by PCPA produces a decrease in the activity of midbrain DA cells, suggesting that endogenous 5-HT is required to maintain DA tone. © 1996 Wiley-Liss, Inc.

The depletion of brain serotonin levels by para-chlorophenylalanine administration significantly alters the activity of midbrain dopamine cells in rats: an extracellular single cell recording study.

In this study, we examined the effect of 5-HT depletion produced by the acute administration of para-chlorophenylalanine (PCPA) on the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in the rat. We also determined the effect of PCPA administration on the spike discharge pattern of midbrain DA cells. This was accomplished using standard extracellular single cell recording techniques. The administration of PCPA (400 mg/kg, i.p., 24 h before the experiment) produced a significant decrease in the number of spontaneously active DA cells in both the A9 (52%) and A10 (63%) areas compared to controls. The burst firing analysis indicated that there was a significant increase in the mean interspike interval of A9 and A10 DA neurons in PCPA treated animals compared to controls. Furthermore, a decrease in the percentage of A10 DA neurons exhibiting a burst firing pattern and the number of bursts was observed in the PCPA treated animals compared to controls. The intravenous (i.v.) administration of 5-hydroxytryptophan (40 mg/kg) and the peripheral aromatic acid decarboxylase inhibitor benserazide (10 mg/kg) which restores 5-HT content, reversed the decrease in the number of spontaneously active A9 and A10 DA neurons, as well as the decrease in the percentage of A10 DA neurons exhibiting a bursting pattern. In contrast, the i.v. administration of benserazide (10 mg/kg) and L-DOPA (40 mg/kg) did not reverse the decrease in the number of spontaneously active midbrain DA neurons produced by PCPA treatment. The pretreatment of animals with PCPA did not alter the sensitivity of spontaneously active A9 or A10 DA cells to the intravenous administration of (+)-apomorphine (1-32 micrograms/kg) compared to controls. Overall, our results indicate that the depletion of brain 5-HT by PCPA produces a decrease in the activity of midbrain DA cells, suggesting that endogenous 5-HT is required to maintain DA tone.

Nicotine withdrawal leads to increased firing rates of midbrain dopamine neurons

In order to explore the neurophysiology of nicotine withdrawal, we examined the activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine cells in rats undergoing withdrawal from chronic exposure to nicotine. Animals were exposed to nicotine (6 mg kg-1 day-1 base) via s.c. implanted osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal. Rats were anesthetized on various days of the procedure and single-unit recordings were made from A9 and A10 dopamine cells. Chronic administration of nicotine led to a decreased firing rate of A10, but not A9, dopamine cells. Upon withdrawal from the chronic exposure to nicotine, the firing rates of A10 dopamine cells returned to control levels, while the firing rate of A9 dopamine cells significantly increased above control levels. This increased dopamine neuronal activity may play a role in some behavioural symptoms of nicotine withdrawal.

Nicotine withdrawal leads to increased firing rates of midbrain dopamine neurons

In order to explore the neurophysiology of nicotine withdrawal, we examined the activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine cells in rats undergoing withdrawal from chronic exposure to nicotine. Animals were exposed to nicotine (6 mg kg−1 day−1 base) via s.c. implanted osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal. Rats were anesthetized on various days of the procedure and single-unit recordings were made from A9 and A10 dopamine cells. Chronic administration of nicotine led to a decreased firing rate of A10, but not A9, dopamine cells. Upon withdrawal from the chronic exposure to nicotine, the firing rates of A10 dopamine cells returned to control levels, while the firing rate of A9 dopamine cells significantly increased above control levels. This increased dopamine neuronal activity may play a role in some behavioural symptoms of nicotine withdrawal.

Comparison of the action of the stereoisomers of the psychostimulant 4-methylaminorex (4-MAX) on midbrain dopamine cells in the rat: an extracellular single unit study.

In this study, we examined and characterized the action of the stereoisomers of 2-amino-4-methyl-delta 2-5-phenyl-oxazoline (4-methylaminorex, 4-MAX) on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10) in anesthetized male rats. This was accomplished using the technique of extracellular single unit recording. The intravenous (i.v.) administration of the stereoisomers of 4-MAX (0.1-6.4 mg/kg) produced a dose-dependent suppression of the basal firing rate of A10 DA cells with the following rank order of potency: trans 4S,5S > cis 4R,5S approximately cis 4S,5R >> trans 4S,5S 4-MAX. The rank order of potency of the isomers of 4-MAX to suppress the firing of A9 DA cells was trans 4S,5S = cis 4R,5S = cis 4S,5R >> trans 4R,5R. The trans 4S,5S isomer was 5-fold more potent in suppressing DA cell firing in the A10 compared to the A9 area. The suppressant action of the isomers on A9 and A10 DA cells was reversed by the i.v. administration of haloperidol and the D2/D3 receptor antagonists (-)-sulpiride and (-)-eticlopride but not by the D1 receptor antagonists SCH 23390 and SCH 39166. In addition, the suppressant action of the trans 4S,5S isomer on A10 DA cells was not antagonized or reversed by the i.v. administration of the receptor antagonists granisetron (5-HT3), ritanserin (5-HT2A,C), idazoxan (alpha 2), phentolamine (peripheral alpha 1), (+/-)-pindolol (5-HT1A,B beta) or prazosin (alpha 1). The pretreatment of animals with either alpha-methyl-p-tyrosine (AMPT) or reserpine, but not p-chlorophenylalanine (PCPA), (+/-)-fluoxetine or tomoxetine, significantly attenuated the suppression of A10 DA cell firing produced by trans 4S,5S 4-MAX. Overall, our results suggest that the suppressant action of 4-MAX on midbrain DA cell firing may be mediated by the release of DA, which subsequently interacts with D2/D3 receptors.

Olanzapine, a novel atypical antipsychotic, has electrophysiological effects on A9 and A10 dopamine cells similar to clozapine

The role of neurotensin (NT) in a putative model of tardive dyskinesia (TD) was examined in the rat. When administered directly into the ventrolateral striatum of neuroleptic-naive animals, NT (2.5 μg/side) elicited vacuous chewing movements. This response was not seen following administration of NT into other striatal regions or the substantia nigra and was suppressed by the NT antagonist SR 48692 (100 μg/kg i.p.). Vacuous chewing movements were also seen following chronic administration of fluphenazine decanoate. These movements were likewise suppressed by SR 48692 (10–100 μg/kg i.p.), which failed to affect other behavioural responses and was without effect in neuroleptic-naive animals. Our data suggest that increased levels of endogenous NT within the ventrolateral striatum may play a critical role in the development of TD following chronic neuroleptic administration and that NT antagonists may be beneficial for the treatment of this disorder.

Effects of neurotensin on midbrain dopamine neuronal activity

AbstractThe effects of acute intracerebroventricular administration of the tridecapeptide, neurotensin, and a pseudopeptide analog of neurotensin‐(8‐13) were compared to the effects of haloperidol and clozapine on the spontaneous activity of dopamine cells in both the ventral tegmental area (A10) and the substantia nigra compacta (A9). Unlike the typical antipsychotic haloperidol, which causes a non‐selective increase in both A9 and A10 cell activity, both neurotensin and a neurotensin analog, H‐Lys (CH2NH)Lys‐Pro‐Tyr‐lle‐Leu‐OH, in like manner to clozapine, at low doses selectively increase the number of spontaneously active A10 dopamine cells. These data provide the first in vivo evidence that acute administration of neurotensin can produce changes in spontaneous activity of midbrain dopamine cells similar to the atypical antipsychotic, clozapine.

Effect produced by acute and chronic administration of the selective 5‐HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

AbstractThis study examined the effect of acute and chronic administration of the selective 5‐HT3 receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose‐response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01‐0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)‐apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2‐fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose‐response curve of BRL 46470A. © 1994 Wiley‐Liss, Inc.

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.