Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl)-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg) in three experimental models: 1) blockade of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; 2) the catalepsy test in mice, and 3) apomorphine (1 mg/kg, ip)-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip) and a hypothermic response (30 mg/kg, ip) which was not prevented by haloperidol (0.5 mg/kg, ip). Compound 5 (30 mg/kg, ip) also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip). Only compound 4 (30 mg/kg, ip) significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

Acoustic hypersensitivity in adult rats after neonatal ventral hippocampus lesions

Rats with a bilateral neonatal ventral hippocampus lesion (NVHL) are used as models of neurobiological aspects of schizophrenia. In view of their decreased number of GABAergic interneurons, we hypothesized that they would show increased reactivity to acoustic stimuli. We systematically characterized the acoustic reactivity of NVHL rats and sham operated controls. They were behaviourally observed during a loud white noise. A first cohort of 7 months` old rats was studied. Then the observations were reproduced in a second cohort of the same age after characterizing the reactivity of the same rats to dopaminergic drugs. A third cohort of rats was studied at 2, 3, 4, 5 and 6 months. In subsets of lesioned and control rats, inferior colliculus auditory evoked potentials were recorded. A significant proportion of rats (50-62%) showed aberrant audiogenic responses with explosive wild running resembling the initial phase of audiogenic seizures. This was not correlated with their well-known enhanced reactivity to dopaminergic drugs. The proportion of rats showing this strong reaction increased with rats` age. After the cessation of the noise, NVHL rats showed a long freezing period that did neither depend on the size of the lesion nor on the rats` age. The initial negative deflection of the auditory evoked potential was enhanced in the inferior colliculus of only NVHL rats that displayed wild running. Complementary anatomical investigations using X-ray scans in the living animal, and alizarin red staining of brain slices, revealed a thin layer of calcium deposit close to the medial geniculate nuclei in post-NVHL rats, raising the possibility that this may contribute to the hyper-reactivity to sounds seen in these animals. The findings of this study provide complementary information with potential relevance for the hyper-reactivity noted in patients with schizophrenia, and therefore a tool to investigate the underlying biology of this endophenotype. (C) 2009 Elsevier B.V. All rights reserved.

La perception du contraste de 1er et de 2e ordre chez des personnes atteintes de la maladie de Parkinson sous médication dopaminergique

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Síndrome das pernas inquietas: Diagnóstico e tratamento. Opinião de especialistas Brasileiros

This article contains the conclusions of the November 17-18, 2006 meeting of the Brazilian Study Group of Restless Legs Syndrome (GBE-SPI) about diagnosis and management of restless legs syndrome (RLS). RLS is characterized by abnormal sensations mostly but not exclusively in the legs which worsen in the evening and are improved by motion of the affected body part. Its diagnosis is solely based on clinical findings. Therapeutic agents with efficacy supported by Class I studies are dopamine agonists, levodopa and gabapentine. Class II studies support the use of slow release valproic acid, clonazepan and oxycodone. The GBE-SPI recommendations for management of SPI are sleep hygiene, withdrawal of medications capable of worsening the condition, treatment of comorbidities and pharmacological agents. The first choice agents are dopaminergic drugs, second choice are gabapentine or oxycodone, and the third choice are clonazepan or slow release valproic acid.

Update on restless legs

Restless Legs Syndrome (RLS) has become a well known disorder in the medical community in Switzerland within the last ten years, particularly since the official introduction of dopaminergic drugs as first line treatment. However, even today, in some patients a correct diagnosis is delayed, preventing specific therapy and prolonging discomfort or even painful symptoms over years. It is important to recognise the syndrome of restless legs, and it is essential to search systematically for treatable causes and to treat separately frequent comorbidities such as depression or polyneuropathy. It is important to understand the impact of this progressive disease on the personal and professional life of the patient. In addition, therapy resistance and severe side effects, particularly augmentation and fibrosis, can be minimised by understanding important details of treatment and by an optimal follow up of such patients. Research on the genetic basis of RLS, on purported pathogenetic mechanisms in the dopaminergic and other neurotransmittor systems, on iron metabolism in the brain and spinal cord, and the socioeconomic burden of the disease, are urgently needed.

Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior

BACKGROUND There is ample evidence that a subgroup of Parkinson's disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects. METHODS We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration. RESULTS Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after dopaminergic stimulation. CONCLUSIONS These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.

TIME DEPENDENT ALTERATIONS IN CENTRAL NERVOUS SYSTEM DOPAMINE RECEPTORS INDUCED BY DOPAMINE AGONIST TREATMENT

Levodopa, the precursor of dopamine, is currently the drug of choice in the treatment of Parkinson's disease. Recently, two direct dopamine agonists, bromocriptine and pergolide, have been tested for the treatment of Parkinson's disease because of reduced side effects compared to levodopa. Few studies have evaluated the effects of long-term treatment of dopamine agonists on dopamine receptor regulation in the central nervous system. Thus, the purpose of this study was to determine whether chronic dopamine agonist treatment produces a down-regulation of striatal dopamine receptor function and to compare the results of the two classes of dopaminergic drugs.^ Levodopa with carbidopa, a peripheral decarboxylase inhibitor, was administered orally to rats whereas bromocriptine and pergolide were injected intraperitoneally once daily. Several neurochemical parameters were examined from 1 to 28 days.^ Levodopa minimally decreased striatal D-1 receptor activity but increased the number of striatal D-2 binding sites. Levodopa increased the V(,max) of tyrosine hydroxylase (TH) in all brain regions tested. Protein blot analysis of striatal TH indicated a significant increase in the amount of TH present. Dopamine-beta-hydroxylase (DBH) activity was markedly decreased in all brain regions studied and mixing experiments of control and drug-treated cortices did not show the presence of an increased level of endogenous inhibitors.^ Bromocriptine treatment decreased the number of D-2 binding sites. Striatal TH activity was decreased and protein blot analysis indicated no change in TH quantity. The specificity of bromocriptine for striatal TH suggested that bromocriptine preferentially interacts with dopamine autoreceptors.^ Combination levodopa-bromocriptine was administered for 12 days. There was a decrease in both D-1 receptor activity and D-2 binding sites, and a decrease in brain HVA levels suggesting a postsynaptic receptor action. Pergolide produced identical results to the combination levodopa-bromocriptine studies.^ In conclusion, combination levodopa-bromocriptine and pergolide treatments exhibited the expected down-regulation of dopamine receptor activity. In contrast, levodopa appeared to up-regulate dopamine receptor activity. Thus, these data may help to explain, on a biochemical basis, the decrease in the levodopa-induced side effects noted with combination levodopa-bromocriptine or pergolide therapies in the treatment of Parkinson's disease. ^

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.

Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

BACKGROUND: General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. METHODS: We will look at effects of GA on behavior that is mediated by the dopaminergic system. RESULTS: Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. CONCLUSION: A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system.

Development of natural products as drugs acting on central nervous system

We have recenty studied several natural product constituents which have effects on the CNS. (1) Tetrahydropalmatine (THP) and its analogues were isolated from Corydalis ambigua and various species of Stephania. (+)-THP and (-)-THP posses not only analgesic activity, but also exert sedative-tranquillizing and hypnotic actions. Results of receptor binding assay and their pre-and post-synaptic effects on dopaminergic system indicate that (-)-THP and (-)-stepholidine are dopamine receptor antagonists while (+)-THP is a selective dopamine depletor. (2) 3-Acetylaconitine (AAC) is an alkaloid isolated from Aconitum flavum. The relative potency of analgesic action of AAC was 5.1-35.6 and 1250-3912 times that of morphine and aspirin, respectively. The analgesic effect of AAC was antagonized by naloxone, but was eliminated by reserpine. In monkeys, after AAC was injected for 92 days, no abstinence syndrome was seen after sudden AAC withdrawal or when challenged with nalorphine. (3) Huperzine A (Hup-A) is an alkaloid isolated from Huperzia serrata which was found to be a selective ChE inhibitor and could improve learning and retrieval process. Preliminary clinical studies showed that Hup-A improve short-and long-term memory in patients of cerebral arteriosclerosis with memory impairment. (4) Ranamargarin is a new tetradecapeptide isolated from the skin of the Chines frog Rana margaratae. This peptide may mainly act on NK-1 receptor.

Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence.

Inflammatory processes described in Parkinson’s disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.

Secondary metabolismin in Annonaceae: potencial source of drugs

Several species of Annona (Annonaceae) are used in traditional Mexican medicine by their anti-anxiety, anticonvulsant and tranquilizing properties. It has been reported that the alkaloids isolated from some species of the Annona have affinity to serotonergic 5-HT1A receptors and modulate dopaminergic transmission, which is involved in depressive disorders. In this review it is showed the results of the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice. The antidepressant-like effect was evaluated in the forced swimming test. To elucidate a possible mechanism of action, experiments of synergism with antidepressant drugs, such as imipramine (IMI), clomipramine (CLIMI), and fluoxetine (FLX), were carried out. The neurotransmitter content (DA: dopamine, 5HT: serotonin and its metabolites, HVA: homovanillic acid and 5HIAA:5-hydroxyindoleacetic) in the whole brain of mice were also determined by HPLC method. The results showed that repeated treatment with TA produced antidepressant-like effects in mice. This effect was not related to an increase in locomotor activity. Administration of TA facilitated the antidepressant effect of IMI and CLIMI as well as increased the turnover of DA and 5-HT. The alkaloids: 1,2-dimethoxy-5, 6.6 to 7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine were the main constituents of TA.

Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

The widespread consumption of anorectics and combined anorectic + alcohol misuse are problems in Brazil. In order to better understand the interactive effects of ethanol (EtOH) and diethylpropion (DEP) we examined the locomotion-activating effects of these drugs given alone or in combination in mice. We also determined whether this response was affected by dopamine (DA) or opioid receptor antagonists. A total of 160 male Swiss mice weighing approximately 30 g were divided into groups of 8 animals per group. The animals were treated daily for 7 consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/kg, ip), EtOH (1.2 g/kg, ip), DEP (5.0 mg/kg, ip) or the control solution coadministered with the DA antagonist haloperidol (HAL, 0.075 mg/kg, ip), the opioid antagonist naloxone (NAL, 1.0 mg/kg, ip), or vehicle. On days 1, 7 and 10 after the injections, mice were assessed in activity cages at different times (15, 30, 45 and 60 min) for 5 min. The acute combination of EtOH plus DEP induced a significantly higher increase in locomotor activity (day 1: 369.5 ± 34.41) when compared to either drug alone (day 1: EtOH = 232.5 ± 23.79 and DEP = 276.0 ± 12.85) and to control solution (day 1: 153.12 ± 7.64). However, the repeated administration of EtOH (day 7: 314.63 ± 26.79 and day 10: 257.62 ± 29.91) or DEP (day 7: 309.5 ± 31.65 and day 10: 321.12 ± 39.24) alone or in combination (day 7: 459.75 ± 41.28 and day 10: 427.87 ± 33.0) failed to induce a progressive increase in the locomotor response. These data demonstrate greater locomotion-activating effects of the EtOH + DEP combination, probably involving DA and/or opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH + DEP = 395.62 ± 11.92 and EtOH + DEP + HAL = 371.5 ± 6.76; day 7: EtOH + DEP = 502.5 ± 42.27 and EtOH + DEP + HAL = 281.12 ± 16.08; day 10: EtOH + DEP = 445.75 ± 16.64 and EtOH + DEP + HAL = 376.75 ± 16.4) and NAL (day 1: EtOH + DEP = 553.62 ± 38.15 and EtOH + DEP + NAL = 445.12 ± 55.67; day 7: EtOH + DEP = 617.5 ± 38.89 and EtOH + DEP + NAL = 418.25 ± 61.18; day 10: EtOH + DEP = 541.37 ± 32.86 and EtOH + DEP + NAL = 427.12 ± 51.6) reduced the locomotor response induced by combined administration of EtOH + DEP. These findings also suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by the combination.

Chronic effect of antidopaminergic drugs or estrogen on male Wistar rat lactotrophs and somatotrophs

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean ± SD) 21.3 ± 4.4, haloperidol 27.8 ± 2.2, fluphenazine 34.5 ± 3.6, sulpiride 32.7 ± 3.5, metoclopramide 33.4 ± 5.5 and estrogen 42.4 ± 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 ± 3.0), fluphenazine (22.1 ± 1.1) and metoclopramide (24.2 ± 3.0) compared to control (27.3 ± 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 ± 2.2) and estrogen (27.1 ± 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.

Dopaminergic modulation of grooming behavior in virgin and pregnant rats

Dopamine receptors are involved in the expression of grooming behavior. The pregnancy-induced increase in self-licking observed in rats is important for mammary gland development and lactation. This study focuses on the role of dopamine receptor subtypes in grooming behavior of virgin and pregnant female rats. General and mammary gland grooming were measured in virgin rats treated with 0.25 mg/kg of the D1-like agonist SKF-81297 and antagonist SKF-83566 and the D2-like agonist lisuride and antagonist sulpiride. The effects of 0.01 and 0.25 mg/kg doses of the same agonists and antagonists were evaluated in pregnant rats as well. In virgin animals both SKF-83566 and sulpiride treatments significantly reduced the time spent in general grooming, while none of the dopamine agonists was able to significantly change any parameter of general grooming. Time spent in grooming directed at the mammary glands was not affected significantly by any of the drug treatments in virgin rats. All drugs tested significantly decreased the frequency of and the time spent with general grooming, while SKF-81297 treatment alone did not significantly reduce the duration of mammary gland grooming in pregnant rats. These data show that in female rats the behavioral effects of D1-like and D2-like dopamine receptor stimulation and blockade differ according to physiological state. The results suggest that dopamine receptors may play specific roles modulating grooming behavior in pregnant rats. Since grooming of the mammary gland during pregnancy may influence lactation, this aspect is relevant for studies regarding the perinatal use of dopamine-related drugs.