Hemiparkinsonian rats rotate toward the side with the weaker dopaminergic neurotransmission

Rats with unilateral lesion of the substantia nigra pars compacta (SNpc) have been used as a model of Parkinson`s disease. Depending on the lesion protocol and on the drug challenge, these rats rotate in opposite directions. The aim of the present study was to propose a model to explain how critical factors determine the direction of these turns. Unilateral lesion of the SNpc was induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Separate analysis showed that neither the type of neurotoxin nor the site of lesion along the nigrostriatal. pathway was able to predict the direction of the turns these rats made after they were challenged with apomorphine. However, the combination of these two factors determined the magnitude of the lesion estimated by tyrosine-hydroxylase immunohistochemistry and HPLC-ED measurement of striatal dopamine. Very small lesions did Dot cause turns, medium-size lesions caused ipsiversive turns, and large lesions caused contraversive turns. Large-size SNpc lesions resulted in an increased binding of [H-3] raclopride to D2 receptors, while medium-size lesions reduced the binding of [H-3]SCH-23390 D1 receptors in the ipsilateral striatum. These results are coherent with the model proposing that after challenged with a dopamine receptor agonist, unilaterally SNpc-lesioned rats rotate toward the side with the weaker activation of dopamine receptors. This activation is weaker on the lesioned side in animals with small SNpc lesions due to the loss of dopamine, but stronger in animals with large lesions due to dopamine receptor supersensitivity. (C) 2008 Elsevier B.V. All rights reserved.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Modulation of post-coital dopaminergic tone by prior parity

The aim of this study was to investigate the possible effects of reproductive experience on dopaminergic profile in three different brain tissues, hypothalamus, striatum and cortex in rats on 7th-8th day of pregnancy during the light-dark shift (between 1700-1900h). Results showed that in hypothalamus, dopamine levels increased and DOPAC/DA decreased as a function of parity. In cortex, no differences were observed. In striata, the haloperidol-induced HVA and HVA/DA increases were less intense in experienced animals. These findings suggested that reproductive experience produced functional central changes during pregnancy, with different neurochemical responses depending on the brain region.

Involvement of dopaminergic mechanisms in the nucleus accumbens core and shell subregions in the expression of fear conditioning

The involvement of dopamine (DA) mechanisms in the nucleus accumbens (NAC) in fear conditioning has been proposed by many studies that have challenged the view that the NAC is solely involved in the modulation of appetitive processes. However, the role of the core and shell subregions of the NAC in aversive conditioning remains unclear. The present study examined DA release in these NAC subregions using microdialysis during the expression of fear memory. Guide cannulae were implanted in rats in the NAC core and shell. Five days later, the animals received 10 footshocks (0.6 mA, 1 s duration) in a distinctive cage A (same context). On the next day, dialysis probes were inserted through the guide cannulae into the NAC core and shell subregions, and the animals were behaviorally tested for fear behavior either in the same context (cage A) or in a novel context (cage B). Dialysates were collected every 5 min for 90 min and analyzed by high-performance liquid chromatography. The rats exhibited a significant fear response in cage A but not in cage B. Moreover, increased DA levels in both NAC subregions were observed 5-25 min after the beginning of the test when the animals were tested in the same context compared with accumbal DA levels from rats tested in the different context. These findings Suggest that DA mechanisms in both the NAC core and shell may play an important role in the expression of contextual fear memory. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

In vitro macrophage activity: Biphasic effect of prolactin and indirect evidence of dopaminergic modulation

Objective: Prolactin (PRL), a peptide hormone produced by the pituitary gland, is involved in the interaction between the neuroendocrine and immune system. Since dopamine receptor antagonists increase serum levels of PRL, both PRL and dopamine receptors might be involved in the modulation of macrophage activity, providing means of communication between the nervous and immune systems. This study evaluated the effects of PRL and the dopamine antagonist domperidone (DOMP) on macrophage activity of female rats. Methods: Oxidative burst and phagocytosis of peritoneal macrophages were evaluated by flow cytometry. Samples of peritoneal liquid from female rats were first incubated with PRL (10 and 100 nM) for different periods. The same procedure was repeated to evaluate the effects of DOMP (10 and 100 nM). Results: In vitro incubation of macrophages with 10 nM DOMP decreased oxidative burst, after 30 min, whereas the PMA-induced burst was decreased by DOMP 10 nM after 2 and 4 h. Treatment with PRL (10 and 100 nM) for 30 min decreased oxidative burst and rate of phagocytosis (10 nM). After 2 h of incubation, 10 nM PRL decreased oxidative burst and phagocytosis intensity, but increased the rate of phagocytosis. On the other hand, after 4 h, PRL 10 and 100 nM increased oxidative burst and the rate of phagocytosis, but decreased intensity of phagocytosis. Conclusions: These observations suggest that macrophage functions are regulated by an endogenous dopaminergic tone. Our data also suggest that both PRL and dopamine exert their action by acting directly on the peritoneal macrophage. Copyright (C) 2008 S. Karger AG, Basel.

Alpha-oestrogen and progestin receptor expression in the hypothalamus and preoptic area dopaminergic neurones during oestrous in cycling rats

A secretory surge of prolactin occurs on the afternoon of oestrous in cycling rats. Although prolactin is regulated by ovarian steroids, plasma oestradiol and progesterone levels do not vary during oestrous. Because prolactin release is tonically inhibited by hypothalamic dopamine and modulated by dopamine transmission in the preoptic area (POA), the present study aimed to evaluate whether oestrogen receptor (ER)-alpha and progestin receptor (PR) expression in the dopaminergic neurones of arcuate (ARC), periventricular, anteroventral periventricular (AVPe) and ventromedial preoptic (VMPO) nuclei changes during the day of oestrous. Cycling rats were perfused every 2 h from 10-20 h on oestrous. Brain sections were double-labelled to ER alpha or PR and tyrosine hydroxylase (TH). The number of TH-immunoreactive (ir) neurones did not vary significantly in any area evaluated. ER alpha expression in TH-ir neurones increased at 14 and 16 h in the rostral-ARC and dorsomedial-ARC, 14 h in the caudal-ARC and 16 h in the VMPO, whereas it was unaltered in the ventrolateral-ARC, periventricular and AVPe. PR expression in TH-ir neurones of the periventricular and rostral, dorsomedial, ventrolateral and caudal-ARC decreased transitorily during the afternoon, showing the lowest levels between 14 and 16 h; but it did not vary in the AVPe and VMPO. Plasma oestradiol and progesterone concentrations were low and unaltered during oestrous, indicating that the changes in receptors expression were probably not due to variation in ligand levels. Thus, our data suggest that variations in ER alpha and PR expression may promote changes in the activity of medial basal hypothalamus and POA dopaminergic neurones, even under unaltered secretion of ovarian steroids, which could facilitate the occurrence and modulate the magnitude of the prolactin surge on oestrous.

Activity of Hypothalamic Dopaminergic Neurones During the Day of Oestrus: Involvement in Prolactin Secretion

A secretory surge of prolactin occurs on the afternoon of oestrus in cycling rats. Pituitary prolactin is inhibited by dopamine. We evaluated the activity of the neuroendocrine dopaminergic neurones during oestrus and dioestrus, as determined by dopaminergic activity in the median eminence and neurointermediate lobe of the pituitary, as well as Fos-related antigen expression in tyrosine hydroxylase (TH)-immunoreactive (ir) neurones of the arcuate nucleus (ARC) and periventricular nucleus (Pe). During oestrus, the 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence decreased at 16.00 h, coinciding with the increase in plasma prolactin levels. Similarly, the expression of Fos-related antigen in TH-ir neurones of Pe and rostral-, dorsomedial- and caudal-ARC also decreased at 16.00 h. On dioestrus, 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence and Fos-related antigen expression in TH-ir neurones of Pe and rostral-ARC decreased at 18.00 h, whereas prolactin levels were unaltered. No variation in dopaminergic activity was found in the neurointermediate lobe of the pituitary on either oestrus or dioestrus. The number of TH-ir neurones in the ARC and parameters of dopaminergic activity were found to be generally lower on oestrus compared to dioestrus. The transitory decrease in the activity of neuroendocrine dopaminergic neurones temporally associated with the prolactin surge on the afternoon of oestrus suggests a role for dopamine in the generation of the oestrous prolactin surge.

Kisspeptin Regulates Prolactin Release through Hypothalamic Dopaminergic Neurons

Prolactin (PRL) is tonically inhibited by dopamine (DA) released from neurons in the arcuate and periventricular nuclei. Kisspeptin plays a pivotal role in LH regulation. In rodents, kisspeptin neurons are found mostly in the anteroventral periventricular and arcuate nuclei, but the physiology of arcuate kisspeptin neurons is not completely understood. We investigated the role of kisspeptin in the control of hypothalamic DA and pituitary PRL secretion in adult rats. Intracerebroventricular kisspeptin-10 (Kp-10) elicited PRL release in a dose-dependent manner in estradiol (E2)-treated ovariectomized rats (OVX+E2), whereas no effect was found in oil-treated ovariectomized rats (OVX). Kp-10 increased PRL release in males and proestrous but not diestrous females. Associated with the increase in PRL release, intracerebroventricular Kp-10 reduced Fos-related antigen expression in tyrosine hydroxylase-immunoreactive (ir) neurons of arcuate and periventricular nuclei in OVX+E2 rats, with no effect in OVX rats. Kp-10 also decreased 3,4-dihydroxyphenylacetic acid concentration and 3,4-dihydroxyphenylacetic acid-DA ratio in the median eminence but not striatum in OVX+E2 rats. Double-label immunofluorescence combined with confocal microscopy revealed kisspeptin-ir fibers in close apposition to and in contact with tyrosine hydroxylase-ir perikarya in the arcuate. In addition, Kp-10 was not found to alter PRL release from anterior pituitary cell cultures regardless of E2 treatment. We provide herein evidence that kisspeptin regulates PRL release through inhibition of hypothalamic dopaminergic neurons, and that this mechanism is E2 dependent in females. These findings suggest a new role for central kisspeptin with possible implications for reproductive physiology. (Endocrinology 151: 3247-3257, 2010)

Evaluation of estrogen neuroprotective effect on nigrostriatal dopaminergic neurons following 6-hydroxydopamine injection into the substantia nigra pars compacta or the medial forebrain bundle

Studies involving estrogen treatment of ovariectomized rats or mice have attributed to this hormone a neuroprotective effect on the substantia nigra pars compacta (SNpc) neurons. We investigated the effect of estradiol replacement in ovariectomized rats on the survival of dopaminergic mesencephalic cell and the integrity of their projections to the striatum after microinjections of 1 mu g of 6-hydroxydopamine (6-OHDA) into the right SNpc or medial forebrain bundle (MFB). Estradiol replacement did not prevent the reduction either in the striatal concentrations of DA and metabolites or in the number of nigrostriatal dopaminergic neurons following lesion with 1 mu g of 6-OHDA into the SNpc. Nevertheless, estradiol treatment reduced the decrease in striatal DA following injection of 1 mu g of 6-OHDA into the MFB. Results suggest therefore that estrogen protect nigrostriatal dopaminergic neurons against a 6-OHDA injury to the MFB but not the SNpc. This may be due to the distinct degree of lesions promoted in these different rat models of Parkinson`s disease.

Long-term nitric oxide deficiency causes muscarinic supersensitivity and reduces beta(3)-adrenoceptor-mediated relaxation, causing rat detrusor overactivity

Background and purpose: Overactive bladder is a complex and widely prevalent condition, but little is known about its physiopathology. We have carried out morphological, biochemical and functional assays to investigate the effects of long-term nitric oxide (NO) deficiency on muscarinic receptor and beta-adrenoceptor modulation leading to overactivity of rat detrusor muscle. Experimental approach: Male Wistar rats received No-nitro-L-arginine methyl ester (L-NAME) in drinking water for 7-30 days. Functional responses to muscarinic and b-adrenoceptor agonists were measured in detrusor smooth muscle (DSM) strips in Krebs-Henseleit solution. Measurements of [H-3] inositol phosphate, NO synthase (NOS) activity, [H-3] quinuclidinyl benzilate ([H-3]QNB) binding and bladder morphology were also performed. Key results: Long-term L-NAME treatment significantly increased carbachol-induced DSM contractile responses after 15 and 30 days; relaxing responses to the beta(3)-adrenoceptor agonist BRL 37-344 were significantly reduced at 30 days. Constitutive NOS activity in bladder was reduced by 86% after 7 days and maintained up to 30 days of L-NAME treatment. Carbachol increased sixfold the [H-3] inositol phosphate in bladder tissue from rats treated with L-NAME. [H-3] QNB was bound with an apparent KD twofold higher in bladder membranes after L-NAME treatment compared with that in control. No morphological alterations in DSM were found. Conclusions and implications: Long-term NO deficiency increased rat DSM contractile responses to a muscarinic agonist, accompanied by significantly enhanced KD values for muscarinic receptors and [H-3] inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of beta(3)-adrenoceptor-mediated relaxations indicated that overactive DSM resulted from chronic NO deficiency.

Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

Modelos experimentais baseados no aumento da neurotransmissão dopaminérgica mimetizam aspectos comportamentais e neuroquímicos característicos da esquizofrenia. Psicoestimulantes, como a anfetamina, são utilizados com esta finalidade, pois aumentam os níveis de dopamina extracelular nas vias mesocorticolímbica e mesoestriatal. As limitações da manipulação direta do sistema dopaminérgico nos modelos animais incentivam abordagens complementares. O óxido nítrico (NO), um neurotransmissor atípico que inibe a recaptação de dopamina e estimula sua liberação, parece modular comportamentos controlados pelo sistema dopaminérgico. O teste de inibição pré-pulso revela uma deficiência no filtro sensório-motor, verificada em esquizofrênicos ou após tratamentos com psicotomiméticos, podendo ser prevenida pela inibição do NO. Esta revisão apresenta evidências da interação do NO com o sistema dopaminérgico em modelos para o estudo da esquizofrenia como uma nova ferramenta de investigação desta patologia.

Unconventional neurotransmitters, neurodegeneration and neuroprotection

Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these "new" functions of neurotransmitters in relation to some unconventional neurotransmitters, such as the endocannabinoids and nitric oxide. Data indicating both transcriptional and post-transcriptional modulation of endocannabinoid and nitrinergic systems after neural lesions are discussed in relation to the non-conventional roles of these neurotransmitters. Knowledge of the roles of neurotransmitters in brain functions other than information transfer is critical for a more complete understanding of the functional organization of the brain and to provide more opportunities for the development of therapeutical tools aimed at minimizing neuronal death.

Moxidectin interference on motor activity of rats

The present study investigated the effects of t moxidectin (MXD) in some parameters of rat motor function and neurochemical. The general activity in the open field and the motor coordination in the wooden beam were employed to evaluate the MXD effects. The results showed that, in the open field, even at high doses (2.0 and 20.0 mg/kg), the MXD did not alter the locomotion and the rearing frequencies. However, MXD was able to impair the motor coordination of the animals at wooden beam. Neurochemical studies of striatal GABA and dopamine neurotransmitters showed a reduced levels of dopamine and its metabolite, homovanillic acid, without interference on striatal GABA levels. Since GABAergic receptor stimulation had an inhibitory effect on dopaminergic striatal system, the decreased motor coordination could be attributed to an action of MXD on dopamine system via GABA activation.

Actions of angiotensin II and dopamine in the medial preoptic area on prolactin secretion

Dopamine (DA) is known as a primary regulator of prolactin secretion (PRL) and angiotensin II (Ang II) has been recognized as one brain inhibitory factor of this secretion. In this work, estrogen-primed or unprimed ovariectornized rats were submitted to the microinjection of saline or Ang II after previous microinjection of saline or of DA antagonist (haloperidol, sulpiride or SCH) both in the medial preoptic area (MPOA). Our study of these interactions has shown that 1) estrogen-induced PRL secretion is mediated by Ang II and DA actions in the MPOA, i.e. very high plasma PRL would be prevented by inhibitory action of Ang II, while very low levels would be prevented in part by stimulatory action of DA through D-2 receptors, 2) the inhibitory action of Ang II depends on estrogen and is mediated in part by inhibitory action of DA through D, receptors and in other part by inhibition of stimulatory action of DA through D2 receptors.

Burning mouth syndrome responsive to pramipexol

Burning mouth syndrome (BMS) is characterized by burning discomfort or pain in otherwise normal oral mucosa. It is usually refractory. Treatment modalities are scarce. Herein we report one case of primary disabling BMS, previously refractory to multiple regimens, with complete and persistent improvement with pramipexol, a nonergot dopamine agonist which has high selectivity for dopaminergic D2 receptors. We discuss potential pathophysiological implications of our findings.