Interactions between p-tyramine, m-tyramine, or beta-phenylethylamine and dopamine on single neurones in the cortex and caudate nucleus of the rat

p-Tyramine, applied to cortical and caudate neurones with weak iontophoretic currents (0-10 nA), did not usually cause any alteration of base-line firing rate. However, neuronal responses to dopamine (DA) during such weak applications of p-tyramine were greatly enhanced. Cortical neurone responses to noradrenaline (NA) were similarly potentiated, but both cortical and caudate neurone responses to alpha-aminobutyric acid were unaffected by p-tyramine. In addition, weak background applications of DA which did not affect cell firing rate were also without effect on the neuronal responses to the standard application of DA. The responses of cortical neurones to DA were also potentiated by m-tyramine and beta-phenylethylamine applied with weak cationic currents. The results may suggest that trace amines can enhance NA and DA transmission in the central nervous system.     

The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity

Atypical antipsychotics show preferential 5-HT 2A versus dopamine (DA) D2 receptor affinity. At clinical doses, they fully occupy cortical 5-HT2 receptors, which suggests a strong relationship with their therapeutic action. Half of the pyramidal neurones in the medial prefrontal cortex (mPFC) express 5-HT 2A receptors. Also, neurones excited through 5-HT 2A receptors project to the ventral tegmental area (VTA). We therefore hypothesized that prefrontal 5-HT 2A receptors can modulate DA transmission through excitatory mPFC-VTA inputs. In this study we used single unit recordings to examine the responses of DA neurones to local (in the mPFC) and systemic administration of the 5-HT 2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl-2-aminopropane] (DOI). Likewise, using microdialysis, we examined DA release in the mPFC and VTA (single/dual probe) in response to prefrontal and systemic drug administration. The local (in the mPFC) and systemic administration of DOI increased the firing rate and burst firing of DA neurones and DA release in the VTA and mPFC. The increase in VTA DA release was mimicked by the electrical stimulation of the mPFC. The effects of DOI were reversed by M100907 and ritanserin. These results indicate that the activity of VTA DA neurones is under the excitatory control of 5-HT 2A receptors in the mPFC. These observations may help in the understanding of the therapeutic action of atypical antipsychotics.     

Effects of hypothalamic releasing hormones and biogenic amines on identified neurones in the circumoesophageal ganglia of the water snail (Planorbis corneus)

1. The effect of locally applied releasing hormones, thyrotropin-releasing hormone (TRH) and luteinizing-hormone-releasing hormone (LHRH) and the putative neurotransmitters, acetylcholine (ACh) and dopamine (DA), on the neuronal excitability of identified invertebrate giant dopaminergic neurone (GDN) and serotoninergic neurone (5-HT) (Planorbis corneus) were investigated by intracellular recording in vitro. 2. The membrane potential of GDN was of the order of -60 to -70 mV. The microiontophoretically applied substances produced membrane depolarization as well as spike activation. Their order of efficacy was as follows: TRH greater than ACh greater than DA greater than LHRH. 3. The effects of the tested TRH, ACh, LHRH and DA on serotoninergic neurones were less pronounced. 4. During ACh depolarization the membrane resistance of GDN was found to be strongly reduced, whereas TRH produced only a small reduction in membrane resistance. 5. Dihydro-beta-erythroidin (DHE) added to the bath solution reversibly blocked ACh depolarization without influencing TRH depolarization. Concentrations of atropine sulfate required to block the ACh depolarization were higher by at least 100 order of magnitude. 6. These effects are discussed in relation to the immunoreactive TRH detected earlier in the central nervous system of invertebrates and vertebrates. The results are consistent with the postulate that TRH acts as a neuromodulator and/or neurotransmitter on invertebrate and vertebrate neurones.     

A comparison of domperidone and haloperidol effects on different dopaminergic neurons in the rat brain

Domperidone, a dopamine (DA) receptor antagonist with reportedly preferential actions outside of the blood-brain barrier, and haloperidol, a centrally active DA antagonist, were compared with respect to their abilities to increase the activity of dopaminergic neurons in the rat brain. The activity of nigrostriatal, mesolimbic, tuberohypophyseal and tuberoinfundibular dopamine nerves was estimated by measuring the $\text{in vivo}$ rate of DA synthesis (dihydroxyphenylalanine accumulation following administration of an inhibitor of aromatic L-amino acid decarboxylase) in the striatum, olfactory tubercle, posterior pituitary and median eminence, respectively. In an initial study, the rates of DA synthesis in striatum, olfactory tubercle, and posterior pituitary were determined at 2, 8, and 16 h after subcutaneous administration of 0.25, 2.5, or 25 mg/kg domperidone. At the lowest dose of domperidone, DA synthesis was increased only in the posterior pituitary at 8 and 16 h; at the intermediate dose, DA synthesis increased in the posterior pituitary at 8 and 16 h and in the olfactory tubercle at 8 h. Only at 8 h after the highest dose of domperidone was DA synthesis increased in the striatum. When 2.5 mg/kg of doperidone or haloperidol were administered, DA synthesis in posterior pituitary and median eminence was increased in a similar fashion (in the latter region only at 16 h). In contrast, domperidone promoted only modest and delayed increases in DA synthesis in the olfactory tubercle and had no effect in the striatum. These results indicate that systemically administered domperidone preferentially increases DA synthesis in neurons terminating outside the blood-brain barrier, but after a pronounced delay, high doses of the drug can also activate DA neurons which project to the forebrain.     

The role of dopamine and serotonin in modulating the defensive behavior of the edible snail

Dopamine application in concentration of 10(-5)-10(-6) M into saline around the snail CNS leads to decrease of excitability of LPa7 neurone which is presynaptic in relation to defensive behaviour command neurones, and to decrease of amplitude of monosynaptic excitatory postsynaptic potential (EPSP) in the command neurones elicited by intracellular stimulation of LPa7 neurone. Besides, the dopamine causes a decrease of summated EPSP amplitude in the studied neurones in response to intestinal nerve stimulation (70% in average), a change of rest potential towards hyperpolarization for 6-8 mV, a reduction of the command neurones input resistance (20% in average). The described influences can lead to a general increase of the threshold of defensive system reaction to stimulation. Dopamine action on the defensive behaviour command neurones is significantly weakened in serotonine presence. Against the dopamine background, the efficiency of serotonine influence on the value of EPSP in command neurones in response to testing stimulus is reduced. According to the obtained data, a conclusion is made that interrelation of dopamine and serotonine concentrations can be a base for formation of behaviour choice in snail.     

Effect of cold exposure on synthesis of cerebral dopamine (author's transl)]

The synthesis of dopamine (DA) has been studied in the striatum and cortex of rats exposed to a temperature of 40C for 2.5 or 24 h. The synthesis rate has been estimated 30 mn after an i.v. injection of 3H tyrosine (TY), by the evaluation of the ratio: 3H-DA specific activity 3H-TY specific activity. Cold exposure modified DA synthesis differently in the two brain areas. In the striatum, DA synthesis was multiplied by a factor of 1.5 after 2.5 h of cold exposure and returned to normal value after 24 h. In the cortex, cold exposure did not significantly change DA synthesis (at any of the two times studied).     

Activation of nociceptin/orphanin FQ-NOP receptor system inhibits tyrosine hydroxylase phosphorylation, dopamine synthesis, and dopamine D(1) receptor signaling in rat nucleus accumbens and dorsal striatum

Nociceptin/orphanin FQ (N/OFQ) has been reported to inhibit dopamine (DA) release in basal ganglia mainly by acting on NOP receptors in substantia nigra and ventral tegmental area. We investigated whether N/OFQ could affect DA transmission by acting at either DA nerve endings or DA-targeted post-synaptic neurons. In synaptosomes of rat nucleus accumbens and striatum N/OFQ inhibited DA synthesis and tyrosine hydroxylase (TH) phosphorylation at Ser40 via NOP receptors coupled to inhibition of the cAMP/protein kinase A pathway. Immunofluorescence studies showed that N/OFQ preferentially inhibited phospho-Ser40-TH in nucleus accumbens shell and that in this subregion NOP receptors partly colocalized with either TH or DA D(1) receptor positive structures. In accumbens and striatum N/OFQ inhibited DA D(1) receptor-stimulated cAMP formation, but failed to affect either adenosine A(2A) or DA D(2) receptor regulation of cAMP. In accumbens slices, N/OFQ inhibited DA D(1)-induced phosphorylation of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, whereas in primary cultures of accumbal cells, which were found to coexpress NOP and DA D(1) receptors, N/OFQ curtailed DA D(1) receptor-induced cAMP-response element-binding protein phosphorylation. Thus, in accumbens and striatum N/OFQ exerts an inhibitory constraint on DA transmission by acting on either pre-synaptic NOP receptors inhibiting TH phosphorylation and DA synthesis or post-synaptic NOP receptors selectively down-regulating DA D(1) receptor signaling.     

Differential effects of d-amphetamine, β-phenylethylamine,cocaine and methylphenidate on the rate of dopamine synthesis in terminals of nigrostriatal and mesolimbic neurons and on the efflux of dopamine metabolites into cerebroventricular perfusates of rats

The $\text{in}$$\text{vivo}$ of four psychomotor stimulants (d-amphetamine, β-phenylethylamine, cocaine and methylphenidate) were determined on: 1) the rate of dopamine (DA) synthesis, as measured by the accumulation of dihydroxyphenylalanine (DOPA) after aromatic L-amino acid decarboxylase inhibition, in the striatum (terminals of nigrostriatal neurons) and in the nucleus accumbens and olfactory tubercle (terminals of mesolimbic neurons) and 2) the efflux of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) into cerebroventricular perfusates of conscious, freely-moving rats. d-Amphetamine and β-phenylethylamine produced biphasic responses with lower doses of each drug increasing both the efflux of DOPAC and the rate of DA synthesis in the striatum. Higher doses of each drug either had no effect or actually decreased the efflux of DOPAC and also decreased the rate of DA synthesis in the striatum. Higher doses of each drug either had no effect only decreased the efflux of DOPAC and the rate of DA synthesis in the striatum. The effects of the drugs on the rate of DA synthesis in the nucleus accumbens and olfactory tubercle were similar to, but less pronounced than those seen in the striatum. These results are consistent with the following suggestions: 1) low doses of d-amphetamine and β-phenylethylamine facilitate the neuronal release of DA while higher doses of both drugs facilitate release and inhibit neuronal reuptake of the amine, and 2) cocaine and methylphenidate preferentially block the neuronal reuptake of DA.     

The effects of monoamine oxidase B inhibition on dopamine metabolism in rats with nigro-striatal lesions

The purpose of this study was to examine whether monoamine oxidase type B (MAO-B) has a role in striatal dopamine metabolism in animals with a unilateral lesion of the medial forebrain bundle, and whether 2-phenylethylamine (PE) could have a role in amplification of dopamine (DA) responses in DA depleted striatum. Inhibition of MAO-B did not alter DA metabolism in lesioned striata. PE accumulation decreased with loss of DA as long as there was no DA dysfunction. In lesioned striata with dysfunction of DA transmission at the synaptic level, PE accumulation increased,suggesting a compensatory increase in PE synthesis. This increase in PE levels does not appear to be mediated by an increase in the total striatal aromaticl-amino acid decarboxylase (AADC) activity. We conclude that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that PE could be involved in the antiparkinsonian action of MAO-B inhibitors.     

Nicotinamide N-methyltransferase expression in SH-SY5Y neuroblastoma and N27 mesencephalic neurones induces changes in cell morphology via ephrin-B2 and Akt signalling

Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to produce 1-methylnicotinamide (MeN). We have previously shown that NNMT expression protected against neurotoxin-mediated cell death by increasing Complex I (CxI) activity, resulting in increased ATP synthesis. This was mediated via protection of the NDUFS3 subunit of CxI from degradation by increased MeN production. In the present study, we have investigated the effects of NNMT expression on neurone morphology and differentiation. Expression of NNMT in SH-SY5Y human neuroblastoma and N27 rat mesencephalic dopaminergic neurones increased neurite branching, synaptophysin expression and dopamine accumulation and release. siRNA gene silencing of ephrin B2 (EFNB2), and inhibition of Akt phosphorylation using {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, demonstrated that their sequential activation was responsible for the increases observed. Incubation of SH-SY5Y with increasing concentrations of MeN also increased neurite branching, suggesting that the effects of NNMT may be mediated by MeN. NNMT had no significant effect on the expression of phenotypic and post-mitotic markers, suggesting that NNMT is not involved in determining phenotypic fate or differentiation status. These results demonstrate that NNMT expression regulates neurone morphology in vitro via the sequential activation of the EFNB2 and Akt cellular signalling pathways.     

Differential effects after repeated treatment with haloperidol, clozapine, thioridazine and tefludazine on SNC and VTA dopamine neurones in rats

The effects of repeated treatment (21 days) with different antipsychotic compounds (haloperidol, clozapine, thioridazine and tefludazine) on dopamine (DA) neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) were studied in rats using single unit recording techniques. A dose-dependent decrease in the number of spontaneously active DA neurones in SNC and in VTA was observed with haloperidol. Clozapine showed no significant effect on the activity in SNC while a dose-dependent decrease in the number of active DA neurones in VTA was observed. Thioridazine showed no or weak effect in SNC while repeated treatment induced a marked inhibitory effect on the DA neurones in VTA. Tefludazine, a potential antipsychotic compound, induced a dose-dependent decrease in both SNC and VTA DA activity. However, the effect on the DA neurones in VTA was more pronounced at all doses. Since the classical neuroleptic haloperidol is equally effective in both regions, while the atypical neuroleptics clozapine and thioridazine have selective or predominant effect in the VTA area it has previously been thought that the inhibition of spontaneously active DA neurones in VTA should indicate an antipsychotic effect of a compound while the inhibition of DA neurones in SNC should account for the development of neurological side effects. The data suggests that the potential antipsychotic compound tefludazine should not induce neurological side effects at lower doses but still has an antipsychotic activity while repeated treatment with higher doses of tefludazine might cause extrapyramidal side effects.     

Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.     

The in vivo modulation of dopamine synthesis by calcium ions: influences on the calcium independent release

To investigate the contribution of the dopamine (DA) synthesis to both the calcium-dependent and the carrier-mediated, mechanisms of DA release in the striatum, anaesthetized rats were locally superfused in the striatum with a push–pull cannula supplied with an artificial CSF containing tritiated tyrosine. DA, dihydroxyphenylacetic acid (DOPAC) and their respective specific activity were measured in effluent and used to evaluate changes in the DA synthesizing rate. Excluding calcium ions from the CSF only partially reduced spontaneous DA release (70%) still leaving a possible carrier-mediated DA release. This effect was not additive with a local superfusion with 0.1 mM a-methyl-p-tyrosine, a blocker of DA synthesis, suggesting that synthesis could already be reduced by calcium-free superfusion. Local superfusion with 100 μM cadmium in the presence or not of calcium ions, increased the DA release (220 and 350%, respectively), simultaneously reducing DA synthesis. Local application of 1 μM calcium ionophore (A23187) was without effect on the basal release of DA but enhanced DA synthesis and increased the amphetamine-evoked and carrier-mediated amine release. We conclude that DA synthesis can be a modulatory process of the firing-independent and carrier-mediated amine release while it weakly affects the classical calcium-dependent release.     

Spermidine synthase is prominently expressed in the striatal patch compartment and in putative interneurones of the matrix compartment

The ubiquitous polyamines spermidine and spermine are known as modulators of glutamate receptors and inwardly rectifying potassium channels. They are synthesized by a set of specific enzymes in which spermidine synthase is the rate-limiting step catalysing the formation of the spermine precursor spermidine from putrescine. Spermidine and spermine were previously localized to astrocytes, probably reflecting storage rather than synthesis in these cells. In order to identify the cellular origin of spermidine and spermine synthesis in the brain, antibodies were raised against recombinant mouse spermidine synthase. As expected, strong spermidine synthase-like immunoreactivity was obtained in regions known to express high levels of spermidine and spermine, such as the hypothalamic paraventricular and supraoptic nuclei. In the striatum, spermidine synthase was found in neurones and the neuropil of the patch compartment (striosome) as defined by expression of the micro opiate receptor. The distinct expression pattern of spermidine synthase, however, only partially overlapped with the distribution of the products spermidine and spermine in the striatum. In addition, spermidine synthase-like immunoreactivity was seen in patch compartment-apposed putative interneurones. These spermidine synthase-positive neurones did not express any marker characteristic of the major striatal interneurone classes. The neuropil labelling in the patch compartment and in adjacent putative interneurones may indicate a role for polyamines in intercompartmental signalling in the striatum.     

Comparison of alterations in tyrosine hydroxylase,dopamine levels,and dopamine uptake in the striatum of the weaver mutant mouse

Previous reports have shown that among the markers for the nigro-striatal dopamine (DA) system measured in the striatum, dopamine uptake seems to be more severely affected than the others in the weaver mutant mouse. In the present study we examined DA levels, tyrosine hydroxylase (TH) activity, and high-affinity DA uptake to determine if the DA uptake is most affected when all the measurements are made in the same striatal homogenate in the same laboratory. We found that the DA uptake activity was most altered (93% lower) compared to DA levels (68% lower) and TH activity (64% lower). The DA uptake was so low in the weaver that we could not obtain reliable kinetic parameters. For TH activity we found that the Vmax was 36% lower while the Km forl-tyrosine was 92% higher in the weaver striatum. This lower affinity for substrate suggests that the TH enzyme itself may be altered in the nigro-striatal system of the weaver mutant mouse.Special issue dedicated to Dr. Morris H. Aprison.     

Effect of Transient Cerebral Ischaemia and Cardiac Arrest on Brain Extracellular Dopamine and Serotonin as Determined by In Vivo Dialysis in the Rat

The effects of 20-min transient, global, forebrain ischaemia and cardiac arrest on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their respective metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in vivo by dialysis of rat striatum and hippocampus. During the ischaemic period, striatal DA content increased (250-fold basal concentrations) with parallel but much less marked increases of both striatal and hippocampal 5-HT content (eight- to 10-fold). Baseline values were restored during reperfusion. Subsequent increases of DA and 5-HT levels on cardiac arrest were comparable after both sham operation and ischaemia. Significant decreases of HVA and 5-HIAA levels were observed following ischaemia or cardiac arrest. The differential effects of ischaemia on DA and 5-HT suggest selective alterations in disposition or metabolism of the two transmitters and that dopaminergic neurones may be more vulnerable to ischaemic insults.     

Identification and pharmacological characteristics of giant neurones situated in the buccal ganglia of an African giant snail (Achatina fulica Férussac)

1. The following four giant neurones were identified on the dorsal surface of the left buccal ganglion of an African giant snail (Achatina fulica Ferussac): d-LBAN (dorsal-left buccal anterior neurone), d-LBMN (dorsal-left buccal medial neurone), d-LBCN (dorsal-left buccal central neurone) and d-LBPN (dorsal-left buccal posterior neurone). The axonal pathways of the neurones were studied by the intracellular injection of Lucifer Yellow; their pharmacological characteristics with respect to common putative neurotransmitters were also investigated.2. The axonal pathways of d-LBAN and d-LBCN were simple, innervating some left lateral buccal nerves or the left accessory connective buccal nerve. On the other hand, those of d-LBMN and d-LBPN were much more widespread, projecting not only to the left buccal nerves, but also to the right buccal nerves through the buccal commissure.3. No direct axonal pathway from any of the four buccal neurones tested to the other ganglioncomplexes through the cerebral buccal connectives was demonstrated.4. The pharmacological characteristics of the four neurones tested were not identical. Only 5-hydroxytryptamine excited all of the neurones, whereas dopamine, l-epinephrine and acetylcholine inhibited all of them. However, the other effective substances, such as dl-octopamine, GABA, l-homocysteic acid, erythro-β-hydroxy-l-glutamic acid and histamine, were either excitatory or inhibitory according to the neurone.