Modulation Of Dopaminergic Function Research Articles

Lorcaserin bidirectionally regulates dopaminergic function site-dependently and disrupts dopamine brain area correlations in rats

Lorcaserin, which is a selective agonist of serotonin2C receptors (5-HT2CRs), is a new FDA-approved anti-obesity drug that has also shown therapeutic promise in other brain disorders, such as addiction and epilepsy. The modulation of dopaminergic function might be critical in the therapeutic effect of lorcaserin, but its exact effect is unknown. Here, we studied the effect of the peripheral administration of lorcaserin on the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) dopaminergic neural activity, dopamine (DA) dialysis levels in the nucleus accumbens and striatum and on DA tissue levels in 29 different rat brain regions. Lorcaserin (5–640 μg/kg, i.v.) moderately inhibited only a subpopulation of VTA DA neurons, but had no effect on the SNc neurons. Lorcaserin (0.3, 3 mg/kg, i.p.) did not change VTA and SNc DA population neural activity but slightly decreased the firing rate and burst firing of the spontaneously active VTA neurons, without altering DA extracellular dialysate levels in both the nucleus accumbens and the striatum. Quantitative analysis of DA and metabolites tissue contents of the 29 areas studied revealed that lorcaserin (0.3 or 3 mg/kg, i.p.) only affected a few brain regions, i.e., increased DA in the central amygdala, ventral hypothalamus and nucleus accumbens core and decreased it in the ventromedial striatum. On the other hand, lorcaserin dramatically changed the direction and reduced the number of correlations of DA tissue content among several brain areas. These effects on DA terminal networks might be significant in the therapeutic mechanism of lorcaserin.This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Effects of Jitai tablet, a traditional Chinese medicine, on spontaneous withdrawal symptoms and modulation of dopaminergic functions in morphine-dependent rats.

Chronic opioid abuse can cause damage to dopamine neurons. However, there are currently no effective pharmacotherapies to reverse this damage, even though progress has been made in the development of therapeutic strategies for opioid dependence. The Jitai tablet (JTT) is a traditional Chinese medicine formulation most commonly used for opioid addiction treatment in China. In a morphine spontaneous withdrawal rat model we investigated the effects of JTT, either given before (pre-treatment) or after (post-treatment) morphine administration, on the dopamine system. Our study has shown the following: (1) pre- and post-treatment with JTT were effective at alleviating the wet dog shakes and episodes of writhing; (2) pre-treatment with JTT inhibited the morphine-induced decreases in dopamine transporter (DAT), dopamine D2 receptor (D2 R) and tyrosine hydroxylase (TH) levels in the striatum (p < 0.01, compared with morphine group) and maintained them at normal levels; and (3) post-treatment with JTT restored the densities of DAT, D2 R and TH in the striatum to normal levels (p < 0.01, compared with morphine group). These results support the notion that modulation of the dopamine system in the striatum may play a role for JTT's therapeutic effect on the alleviation of opioid withdrawal symptoms.

Critical role of Nitric Oxide on Nicotine‐Induced Hyperactivation of Dopaminergic Nigrostriatal System: Electrophysiological and Neurochemical evidence in Rats

Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose-dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N-omega-nitro-l-arginine methyl ester (l-NAME) and 7-nitroindazole (7-NI) were both capable of blocking the nicotine-induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l-NAME and 7-NI-pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions.

Haloperidol impairs auditory filial imprinting and modulates monoaminergic neurotransmission in an imprinting‐relevant forebrain area of the domestic chick

In vivo microdialysis and behavioural studies in the domestic chick have shown that glutamatergic as well as monoaminergic neurotransmission in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) is altered after auditory filial imprinting. In the present study, using pharmaco-behavioural and in vivo microdialysis approaches, the role of dopaminergic neurotransmission in this juvenile learning event was further evaluated. The results revealed that: (i) the systemic application of the potent dopamine receptor antagonist haloperidol (7.5 mg/kg) strongly impairs auditory filial imprinting; (ii) systemic haloperidol induces a tetrodotoxin-sensitive increase of extracellular levels of the dopamine metabolite, homovanillic acid, in the MNH, whereas the levels of glutamate, taurine and the serotonin metabolite, 5-hydroxyindole-3-acetic acid, remain unchanged; (iii) haloperidol (0.01, 0.1, 1 mm) infused locally into the MNH increases glutamate, taurine and 5- hydroxyindole-3-acetic acid levels in a dose-dependent manner, whereas homovanillic acid levels remain unchanged; (iv) systemic haloperidol infusion reinforces the N-methyl-d-aspartate receptor-mediated inhibitory modulation of the dopaminergic neurotransmission within the MNH. These results indicate that the modulation of dopaminergic function and its interaction with other neurotransmitter systems in a higher associative forebrain region of the juvenile avian brain displays similar neurochemical characteristics as the adult mammalian prefrontal cortex. Furthermore, we were able to show that the pharmacological manipulation of monoaminergic regulatory mechanisms interferes with learning and memory formation, events which in a similar fashion might occur in young or adult mammals.

Fixed ratio discrimination training increases in vivo striatal dopamine in neonatal 6-OHDA-lesioned rats.

Massed training in the conditional discrimination task, the fixed ratio discrimination (FRD) task led to elevated extracellular dopamine (DA) concentrations in the neonatal 6-hydroxydopamine (6-OHDA)-treated rat, a model of Lesch-Nyhan disease (LND). Rats neonatally treated with 6-OHDA or its vehicle were, as adults, implanted with microdialysis probes and assessed for basal pretraining concentrations of DA and its major metabolites. Subsequently, microdialysis samples were collected each day following three separate FRD training periods (trained group) or three separate periods of noncontingent food presentations (untrained group). The present study found that there were significant increases in extracellular DA in the caudate-putamen from basal pretraining concentrations in the repeated sample collections of trained 6-OHDA-lesioned animals but not in the samples of untrained 6-OHDA-lesioned animals. Consistent with previous studies [Brain Res. 508 (1990) 30.], there was an increase in the extracellular concentrations as compared to tissue concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC). Similar to our previous studies with long-term FRD training [Pharmacol. Biochem. Behav. 51 (1995) 861; Brain Res. 713 (1996) 246.], there was also an indication of an increase in cortical and striatal tissue concentration of DA in the trained 6-OHDA-lesioned animals as compared to the untrained 6-OHDA-lesioned animals. The elevations in striatal DA concentrations following operant performance in the present study illustrate how operant procedures of the behavior therapy used with individuals with LND and other mental retardation syndromes may interact with the modulation of dopaminergic function by the pharmaceutical application of DA antagonists to suppress aberrant behaviors.

Epigenetic cues in midbrain dopaminergic neuron development

Midbrain dopaminergic (DA) neurons subserve complex and varied neural functions in vertebrate CNS. Their progenitors give rise to DA neurons by the action of two extracellular inducers, Sonic Hedgehog and FGF8. After this first commitment, the function of selectively activated transcription factors, like the orphan steroid nuclear receptor Nurr1, is required for DA final determination. Subsequently, DA function is selectively modulated by specific interaction with the developing striatal target tissue. Committed and determined DA neurons express the key genes involved in DA neurotransmission at different times in development. Synthesis and intracellular accumulation of DA is achieved shortly after expression of Nurr1, while high affinity uptake, responsible for ending the neurotransmission, takes place after a few days. Cell contacts between the presynaptic DA neurons and target striatal neurons are apparently necessary for the fine modulation of DA function, in vivo and in vitro.

Genetic and epigenetic control of midbrain dopaminergic neuron development.

The relatively few dopaminergic (DA) neurons in the mammalian brain regulate many important neural functions, including motor integration, neuroendocrine hormone release, cognition, emotive behaviors and reward. A number of laboratories, including ours, have contributed to unravel the mechanisms of DA phenotype induction and maturation and elucidated the role of epigenetic factors involved in specification, development and maintenance of midbrain dopaminergic functions. DA progenitors are first "committed" to give rise to DA neurons by the action of two secreted factors, Sonic hedgehog and fibroblast growth factor 8 (FGF8). Subsequently, the function of selectively activated transcription factors, Nurr1 and Ptx3, is required for the DA final determination. Further development of DA neurotransmission requires specific interactions with the developing target striatal cells, which modulate key DA functions, namely synthesis and uptake of the neurotransmitter. Committed and determined DA neurons express the key genes involved in DA neurotransmission at different times in development. In rodents, synthesis and intracellular accumulation of DA is achieved shortly after expression of Nurr1, while the onset of high affinity uptake, responsible for ending the neurotransmission, takes place after a few days. Cell contacts between the presynaptic DA neurons and target striatal neurons are apparently necessary for the fine modulation of DA function, in vivo and in vitro. Strikingly, the in situ maturation and phenotypic specialization of DA neurons grafted into the adult striatum/caudate-putamen parallels the normal development of committed fetal dopamine neurons during neurogenesis. The correct matching between the right presynaptic and postsynaptic neurons is required also for grafted DA cells.

Adenosin und Methylxanthine im Zentralnervensystem - zur Bedeutung für Psychiatrie und Neurologie

In the last 15 years the central effects of adenosine and its importance for neurology and psychiatry have increasingly become an object of investigation. Physiology and metabolism of adenosine have been examined by different research groups. The effects of adenosine in the central nervous system and the various mechanisms of these effects have been described by electrophysiologic methods. The inhibition of the release of several neurotransmitters through adenosine has already been described 10 years ago. In this review studies on binding sites for adenosine receptor ligands are discussed thoroughly. The properties and the highly specific distribution of the distinct receptor subtypes are described. For the functioning of the adenosinergic system the different interactions with other centrally active substances such as benzodiazepines, barbiturates, neuroleptics, anti-depressants, opiates, alcohol and carbamazepine have turned out to be of interest. The results of neuropsychiatric investigations on methylxanthines, which are antagonists at the adenosine receptor, are widely considered. Finally the discussion on the importance of the adenosinergic system in different neurological and psychiatric diseases is summed up. The particular significance of adenosine in the modulation of dopaminergic functions is emphasised.

Modulation of striatal dopaminergic function by local injection of 5'-N-ethylcarboxamide adenosine.

Rats rotated to the left when 5'-N-ethylcarboxamide adenosine (NECA) was injected into the left caudate nucleus and apomorphine was administered subcutaneously. The combination of NECA and apomorphine was more potent than L-(phenylisopropyl)adenosine and apomorphine in eliciting rotation, suggesting the involvement of adenosine receptors of the Ra type. The response was reduced when 2',5'-dideoxyadenosine was injected along with NECA into the caudate nucleus or when theorphylline was given intraperitoneally. Higher doses of apomorphine elicited a self-mutilatory response after the injection of NECA into the caudate nucleus. These results suggest that adenosine may be involved in the modulation of dopaminergic function in the striatum.