Brain Dopamine Levels Research Articles

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

Parkinson's disease (PD) is a severe neurodegenerative disorder characterised by loss of dopaminergic neurons of the substantia nigra. The pathological hallmarks are cytoplasmic inclusions termed Lewy bodies consisting primarily of aggregated alpha-synuclein (alphaSN). Different lines of transgenic mice have been developed to model PD but have failed to recapitulate the hallmarks of this disease. Since treatment of rodents with the pesticide rotenone can reproduce nigrostriatal cell loss and other features of PD, we aimed to test chronic oral administration of rotenone to transgenic mice over-expressing human alphaSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain beta-synuclein expression and significantly increased levels of the PD-associated oxidative stress response protein, DJ-1, and the E3 ubiquitin ligase enzyme, Parkin. Rotenone treatment of 30 mg/kg for 25 doses over a 35-day period was tolerated in the transgenic mice and resulted in decreased spontaneous locomotor movement and increased cytoplasmic alphaSN expression. The mitochondrial Parkinson's-associated PTEN-induced kinase 1 protein levels were also increased in transgenic mouse brain after rotenone treatment; there was no change in brain dopamine levels or nigrostriatal cell loss. These hA53T alphaSN transgenic mice provide a useful model for presymptomatic Parkinson's features and are valuable for study of associated compensatory changes in early Parkinson's disease stages.

L‐DOPA‐induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson’s disease: temporal and quantitative relationship to the expression of dyskinesia

L-DOPA-induced dyskinesia in Parkinson's disease is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra in dyskinetic and non-dyskinetic animals following a standard dose of L-DOPA. Rats with 6-hydroxydopamine lesions were treated chronically with L-DOPA, monitored on the abnormal involuntary movements scale, and then subjected to intracerebral microdialysis under freely-moving conditions. Following s.c. L-DOPA injection, peak extracellular DA levels in both striatum and substantia nigra were about twice as large in dyskinetic animals compared to non-dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5-HT1A/5-HT1B receptor agonists and tetrodotoxin infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non-dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The 'abnormal involuntary movements output' per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non-dyskinetic cases at most time points examined. The present results indicate that both a high DA release post-L-DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.

The putative antidepressant DOV 216,303, a triple reuptake inhibitor, increases monoamine release in the prefrontal cortex of olfactory bulbectomized rats

The first line of antidepressant treatment nowadays are selective serotonin reuptake inhibitors. Although they are relatively safe to use, selective serotonin reuptake inhibitors (SSRIs) can induce severe side effects. New promising antidepressants may be the triple monoamine reuptake inhibitors, which not only enhance serotonin and norepinephrine neurotransmission, but also increase brain dopamine levels. Recently it has been shown that one of the triple reuptake inhibitors, DOV 216,303 has antidepressant-like effects in the olfactory bulbectomy (OBX) model of depression, but the alterations in monoaminergic neurotransmission in these animals are still unknown. In the present study we investigated not only the effect of acute, but also chronic treatment of DOV 216,303 in OBX rats on monoamine and metabolite levels. The main results are decreased baseline dopamine levels in the prefrontal cortex one day after OBX, while 38 days after OBX no difference could be observed in monoamine levels after vehicle treatment. Treatment with DOV 216,303 leads to increased extracellular levels of serotonin and norepinephrine neurotransmission, but also increased dopamine levels in OBX animals as well as their controls. This increase could be observed after one single administration, but also after chronic treatment. However, a DOV 216,303 challenge in chronically treated animals resulted in lower monoamine concentrations than the same challenge in untreated animals. More research is needed to investigate this seemingly hyporesponsivity to chronic DOV 216,303 treatment.

Roles of Dopamine in Circadian Rhythmicity and Extreme Light Sensitivity of Circadian Entrainment

Light has profound behavioral effects on almost all animals, and nocturnal animals show sensitivity to extremely low light levels [1-4]. Crepuscular, i.e., dawn/dusk-active animals such as Drosophila melanogaster are thought to show far less sensitivity to light [5-8]. Here we report that Drosophila respond to extremely low levels of monochromatic blue light. Light levels three to four orders of magnitude lower than previously believed impact circadian entrainment and the light-induced stimulation of locomotion known as positive behavioral masking. We use GAL4;UAS-mediated rescue of tyrosine hydroxylase (DTH) mutant (ple) flies to study the roles of dopamine in these processes. We present evidence for two roles of dopamine in circadian behaviors. First, rescue with either a wild-type DTH or a DTH mutant lacking neural expression leads to weak circadian rhythmicity, indicating a role for strictly regulated DTH and dopamine in robust circadian rhythmicity. Second, the DTH rescue strain deficient in neural dopamine selectively shows a defect in circadian entrainment to low light, whereas another response to light, positive masking, has normal light sensitivity. These findings imply separable pathways from light input to the behavioral outputs of masking versus circadian entrainment, with only the latter dependent on dopamine.

Poster 23: Pharmacology of the Dopaminergic Stabilizer Pridopidine (ACR16)

Background 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (pridopidine, ACR16) is in development as an agent to target both the motor and behavioral symptoms of Huntington's disease (HD). Pridopidine is a dopaminergic stabilizer, a novel class of drugs that act at dopamine 2 (D2) receptors and display state-dependent behavioral effects. Preclinical studies in vivo suggest that pridopidine has potential efficacy across several clinical domains relevant for HD, including motor function, anxiety, depression, and psychosis. Early clinical studies with pridopidine have been encouraging in terms of reducing HD symptoms, without producing unwanted side effects. Methods Pridopidine was given subcutaneously to male Sprague-Dawley rats. HPLC was used to assess 3,4-dihydroxyphenylacetic acid (DOPAC) levels in brain tissue, and dopamine and noradrenaline levels in brain dialysates. Expression of activity-regulated cytoskeletal protein (Arc) was determined using RT-PCR on brain tissue RNA. Motility meters were used to quantify spontaneous and drug-induced locomotor activity. In vitro D2 radioligand binding and calcium-fluorescence functional studies were performed using human D2 expressing HEK293 cells. Results Pridopidine increased striatal tissue levels of the dopamine metabolite DOPAC (ED50 = 81 μmol/kg) and prefrontal cortex dialysate levels of dopamine and noradrenaline. Arc mRNA in the frontal cortex increased dose-dependently, indicating enhanced N-methyl-D-aspartate receptor-mediated signaling. Pridopidine reduced hyperlocomotion (d-amphetamine: ED50 = 40 μmol/kg; MK801: ED50 = 54 μmol/kg), but preserved spontaneous locomotor activity, confirming state-dependent behavioral effects. In vitro studies with pridopidine revealed surmountable low potency D2 antagonism, no intrinsic activity, and fast recovery of receptor-mediated responses. Conclusions Pridopidine stabilizes psychomotor activity by functional D2 antagonism and strengthening of cortical glutamate functions. Strengthening of cortical glutamatergic transmission may be key to the efficacious in vivo effects of pridopidine in states of hyperdopaminergia and hypoglutamatergia. The dopaminergic stabilizer pridopidine may offer clinical relief of psychomotor symptoms arising from dopaminergic dysfunction in HD.

Limited Potentiation of Blood Pressure in Response to Oral Tyramine by the Anti-Parkinson Brain Selective Multifunctional Monoamine Oxidase-AB Inhibitor, M30

One of the limitations of non-selective monoamine oxidase (MAO) inhibitors as anti-depressant or anti-Parkinson drugs is their ability to potentiate the cardiovascular effect of oral tyramine, resulting from inhibition of systemic MAO-A and release of noradrenaline. We have investigated the cardiovascular effect of oral tyramine in response to the novel multifunctional, brain selective MAO-AB inhibitor, M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], and compared it to the classical non-selective inhibitor tranylcypromine (TCP) in rats. We also measured MAO-A and B in the striatum, hippocampus, liver, and small intestine and determined brain levels of dopamine, noradrenaline, and serotonin. At the doses employed, intraperitoneal (i.p.) M30 (5 and 10 mg/kg) selectively inhibited brain MAO-A and B by more than 85%, with little inhibition of liver and small intestine enzymes while raising striatal levels of dopamine, noradrenaline, and serotonin. In contrast to TCP (10 mg/kg, i.p.), which fully inhibits both enzymes in the brain and systemic organs and significantly potentiates the tyramine pressor effect, M30 had a limited pressor effect as compared to it and controls. The limited potentiation of tyramine pressor effect by M30, its ability to raise brain levels of aminergic neurotransmitters together with its neuroprotective and neurorestorative activities make this drug potentially important as an anti-depressant and anti-Parkinsonian agent, for which it is being developed.

Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse

Oxidative stress is associated with the aging process, a risk factor for neurodegenerative diseases, and decreased by reduced energy intake. Oxidative modifications can affect protein function; the sulfur-containing amino acids, including methionine, are particularly susceptible to oxidation. A methionine sulfoxide can be enzymatically reduced by the methionine sulfoxide reductase (Msr) system. Previously, we have shown that MsrA −/− mice exhibit altered locomotor activity and brain dopamine levels as function of age. Previous studies have demonstrated that a caloric restriction enhances antioxidant defense and reduces the action of reactive oxygen species. Here we examine locomotor behavior and dopamine levels of MsrA −/− mice after caloric restriction starting at eight months of age and ending at 17 months. The MsrA −/− mice did not have any significant difference in spontaneous distance traveled when compared to controls at 17 months of age. In contrast, our previous report showed decreased locomotor activity in the MsrA −/− mice at 12 months of age and older when fed ad-libitum. After completion of the caloric restriction diet, dopamine levels were comparable to control mice. This differs from the abnormal dopamine levels previously observed in MsrA −/− mice fed ad-libitum. Thus, caloric restriction had a neutralization effect on MsrA ablation. In summary, it is suggested that caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.

Orthogonal array design for antidepressant compatibility of polysaccharides from Banxia-Houpu decoction, a traditional Chinese herb prescription in the mouse models of depression

The present study investigated antidepressant-like interaction of five herb polysaccharide fractions from Banxia-Houpu decoction, composed of rhizome pinelliae (PRP), magnolia bark (PMB), poria (PPO), ginger rhizome (PGR) and folium perillae (PFP) by a L(16)(2(5)) orthogonal array design with a two-factor interaction in the tail suspension and forced swimming and tests (TST, FST) in mice. Serotonin (5-HT) and dopamine (DA) levels in whole mouse brain were simultaneously examined after the FST exposure. Polysaccharides PMB, PPO, PFP, and interactions of PRP x PGR, PMB x PFP, PPO x PFP reduced immobility in the mouse FST. Furthermore, PMB and PPO were two principal components of polysaccharides elevating brain 5-HT levels. PFP was an adjuvant component elevating brain DA levels. These results demonstrated that ineffective PRP exhibited antidepressant-like effects when combined with another ineffective PGR, and PFP played a role in assisting effects of PMB and PPO. Therefore, PMB x PFP and PPO x PFP interactions on antidepressant-like effects were the cores in compatibility of polysaccharides from Banxia-Houpu decoction by attenuating abnormalities in the serotonergic and dopaminergic system functions in animal models of depression.

Amphetamine reduces vesicular dopamine content in dexamethasone‐differentiated PC12 cells only following l‐DOPA exposure

Amphetamine (AMPH) increases brain dopamine (DA) levels via reversal of the membrane DA transporter. Additional mechanisms have been suggested, including inhibition of vesicular monoamine transporters and vesicular leakage of DA and Ca(2+). According to the widely-accepted weak base theory, AMPH disrupts the proton gradient required for filling vesicles with DA. As a result, DA and Ca(2+) will leak from vesicles, giving rise to exocytosis of less-filled vesicles. As several contradictions have been described, the aim of the present study was to re-examine this theory using amperometry and Fura-2 imaging to measure AMPH-induced changes in exocytosis and intracellular Ca(2+) levels, respectively, in PC12 and chromaffin cells. Unexpectedly, 15 min exposure to AMPH (20-200 microM) does not affect the amount of DA released per vesicle, the frequency of exocytosis or intracellular Ca(2+) levels in PC12 cells or chromaffin cells. Comparable results were found following prolonged exposure to AMPH (45 min) or at 37 degrees C. When cells were pre-treated with the DA precursor L-DOPA, vesicle content increased to approximately 150%. When these pre-treated cells are exposed to AMPH, vesicle content is strongly reduced. These results indicate that in dexamethasone-differentiated PC12 cells AMPH-induced vesicle leakage occurs only under specific conditions, therefore arguing for re-evaluation of the theory of AMPH-induced vesicular DA leakage.

Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease

BackgroundParkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential.ResultsIn the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level.ConclusionThe present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.

Self-Induced "Therapeutic Seizures" for the Treatment of Depression

Back to table of contents Previous article LETTERFull AccessSelf-Induced “Therapeutic Seizures” for the Treatment of DepressionDonald F. Weaver M.D., Ph.D., F.R.C.P.(C),Donald F. Weaver M.D., Ph.D., F.R.C.P.(C)Search for more papers by this author,Published Online:1 Jul 2009https://doi.org/10.1176/jnp.2009.21.3.355AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Early 20th century research postulated an antagonism between epilepsy and psychosis, leading von Meduna 1 to introduce convulsive therapy for schizophrenia. Although modern research questions this postulate, there is a complex and understudied interplay between seizures and behavioral disorders. I report on a woman with epilepsy who used self-induced seizures to treat her depression. Case ReportA 43-year-old woman was diagnosed with epilepsy at age 29. She experienced 6–8 complex-partial or generalized tonic-clonic seizures per month for many years, failing to respond to a range of anticonvulsant drugs. However, when she was treated with a combination therapy of phenytoin (300 mg/day) and gabapentin (1600 mg/day), her seizures were completely suppressed. Regrettably, after 6 months without seizures, she noticed the onset of depression. Her personality underwent a profound change; she became sad, feeling that life was no longer worth living. She had trouble sleeping and had early morning awakening. Food lost its taste and she lost weight. Although she was depressed, there were no symptoms of psychosis. Her family confirmed the marked change in her mood. Although she had experienced some depressive episodes in her early 20s, since developing epilepsy she had been a happy, positive-thinking person, despite the personal difficulties arising from her seizure disorder.Several antidepressants were tried, but none were of benefit; she remained depressed for more than a year. Ultimately, due to the depression, she quit taking her anticonvulsants stating that “life just is not worth it.” This led to a series of complex partial and generalized tonic-clonic seizures, after which her mood promptly became cheerful and optimistic again. She felt that seizures had done more for her mood than the antidepressant drugs. She was restarted on phenytoin and gabapentin, but did not receive any further antidepressants. After several years of unsupervised self-experimentation, she disclosed a new approach to her seizure disorder. She would abruptly stop taking gabapentin for five consecutive days during the last week of every fourth month. This would result in her having several complex-partial and generalized tonic-clonic seizures (at 3–4 days postwithdrawal); she did not disclose these periodic seizures to family or friends. Since embarking upon this strategy of self-induced “therapeutic seizures,” her depression had completely resolved.Discussion In the 1950s, Landolt 2 observed people with epilepsy who became psychotic when their seizures were controlled—an observation which he attributed to the electroencephalographic phenomenon of “forced normalization.” Conversely, Tellenbach 3 used the term “alternative psychoses” to describe people whose psychosis resolved with the return of seizures. Although these notions are now regarded as outdated and inaccurate, there is a close biological link between seizures and psychiatric (not necessarily psychotic) disorders. This case demonstrates the relationship between seizures and depression. In particular, it demonstrates that the dynamic neurochemical milieu of the postseizure state may exhibit prolonged anticonvulsant properties. Postseizure increases in brain levels of dopamine and serotonin, as well as alterations in norepinephrine metabolism, have been consistently observed in animal models of epilepsy. 4 , 5 Analogously, studies concerning the use of electroconvulsive seizures to treat depression likewise reveal increased release of norepinephrine and increased serotonergic activity (including upregulated 5-HT 2a receptors and increased 5-HT 2a mRNA levels) in the postseizure state. 6 Since such neurochemical changes have antidepressant effects, it is reasonable to assert that “naturally occurring” seizures also produce antidepressant effects. Although abrupt alterations in anticonvulsant dosing cannot be recommended, this woman with epilepsy used periodic self-induced seizures precipitated by intermittent medication withdrawal to treat her depression.Departments of Medicine (Neurology) and Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada

Role of catecholamines in the central actions of medroxyprogesterone acetate.

The role of catecholamines in the mechanism of antiovulatory and other central effects of medroxyprogesterone acetate (MPA) has been studied in adult healthy, non-pregnant female albino rats. It has been observed that a single dose of MPA (100 mg/kg) given intramuscularly did not cause any significant change in brain catecholamine levels after 7 days of treatment. However, there was a significant reduction in brain dopamine levels after 15 days of MPA administration. This reduction in brain dopamine levels may be responsible for the anti-ovulatory activity of MPA. Certain side effects of MPA such as amenorrhoea, galactorrhoea, breast tenderness, breast tumors, inactivity and depression may also be due to decrease in brain dopamine levels.

Structural basis for α-conotoxin potency and selectivity

Parkinson’s disease is a debilitating movement disorder characterized by altered levels of α 6β 2∗ (∗ indicates the possible presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α 6β 2 nAChRs structure and function, but it does not discriminate among closely related α 6∗ nAChR subtypes. Modification of the α-CTx MII primary sequence led to the identification of α-CTx MII[E11A], an analog with 500–5300-fold discrimination between α 6∗ subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α 6 nAChR, a subtype that is selectively lost in Parkinson’s disease. Here, we present the three-dimensional solution structure for α-CTx MII[E11A] as determined by two-dimensional 1H NMR spectroscopy to 0.13 ± 0.09 Ǻ backbone and 0.45 ± 0.08 Ǻ heavy atom root-mean-square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of α-CTx MII[E11A] relative to other members of the α-CTx family may be responsible for its exceptionally high affinity for α6α4β2∗ nAChR as well as discrimination between α 6β 2 and α 3β 2 containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α 6∗ nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson’s disease.

Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge.

Bingeing is one pattern of high dose methamphetamine (METH) abuse which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly-defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats we used a computer-controlled, intravenous METH procedure (dynamic infusion) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life. Animals were treated over 13 weeks with escalating METH doses, using dynamic infusion, and then exposed to a binge in which drug was administered every 3 h for 72h. Throughout the binge, behavioral effects included unabated intense oral stereotypies in the absence of locomotion and in the absence of sleep. Decrements in regional brain dopamine, norepinephrine and serotonin levels, measured at 1 and 10 h after the last injection of the binge, had, with the exception of caudate-putamen dopamine and frontal cortex serotonin, recovered by 48 h. At 10 h after the last injection of the binge, [3H]ligand binding to dopamine and vesicular monoamine transporters in caudate-putamen were reduced by 35% and 13%, respectively. In a separate METH binge treated cohort, post-binge behavioral alterations were apparent in an attenuated locomotor response to a METH challenge infusion at 24h after the last injection of the binge. Collectively, the changes we characterized during and following a METH binge suggest that for humans under similar exposure conditions, multiple time-dependent neurochemical deficits contribute to their behavioral profiles.

Gustatory and Homeostatic Functions of the Rodent Parabrachial Nucleus

Previous studies demonstrate that lesions to the rodent parabrachial nucleus (PBN) disrupt the formation of gustatory-postingestive associations, while preserving gustatory and viscerosensory functions. This suggests that the rodent PBN functions essentially as an integrative circuit, supporting the conditioning of tastants to postingestive factors. In the case of primates, however, anatomical studies have failed to demonstrate gustatory projections from medullary nuclei to PBN. It should therefore be inferred that the primate PBN lacks the associative functions assigned to its rodent counterpart. Moreover, the ability of rodent midbrain dopaminergic systems to respond to the activation of palatable tastants depends on the integrity of the gustatory PBN. However, recent studies demonstrate that caloric palatable compounds do not require taste signaling to produce elevated brain dopamine levels. This raises the possibility that, in rodents, PBN neurons are important for the detection of postingestive effects of nutrients that occur independently of gustatory input. If confirmed, such function would assign non-associative roles to the rodent PBN, approximating its functional organization to its primate counterpart. We are currently testing this possibility by monitoring the behavioral responses to caloric glucose solutions in sweet-blind mice having sustained bilateral lesions to the PBN. Preliminary results indicate that the rodent PBN regulates nutrient intake even when no gustatory inputs are involved. This favors the assignment of non-gustatory, homeostatic functions to the rodent PBN during feeding, a concept that brings an additional perspective on the rodent versus primate functional discrepancy associated with the anatomy of this pontine nucleus.

Dopamine Receptor Activation By Honey Bee Queen Pheromone

Queen mandibular pheromone (QMP) is produced by honey bee queens and used to regulate the behavior and physiology of their nestmates. QMP has recently been shown to block aversive learning in young worker bees, an effect that can be mimicked by treating bees with one of QMP's key components, homovanillyl alcohol (HVA). Although the mechanisms underlying this blockade remain unclear, HVA has been found to lower brain dopamine levels and to alter intracellular levels of cAMP in brain centers involved in learning and memory. These findings led to the hypothesis that HVA targets dopamine pathways in the brain, which are known to play a critical role in the formation of aversive olfactory memories. Here, we investigate the possibility that HVA interacts directly with dopamine receptors in the bee. We show that HVA selectively activates the D2-like dopamine receptor AmDOP3 but has neither agonist nor antagonist activity on the D1-like receptors AmDOP1 or AmDOP2 nor agonist activity on the octopamine receptor AmOA1. These results suggest a direct molecular mechanism by which queen pheromone can modulate dopamine signaling pathways. They also implicate the dopamine receptor AmDOP3 in HVA-induced blockade of aversive learning in young worker bees.

Safflower extracts functionally regulate monoamine transporters

Safflower (HH), the dry flower of Carthamus tinctorius L., has long been used to empirically treat neuropsychological disorders such as stroke and major depression in traditional Chinese medicine, and recently been proven effective for regulating levels of dopamine and serotonin in new-born rat brain. The present study assessed whether HH would be bioactive for functionally regulating monoamine transporters using in vitro drug-screening cell lines. Our current results showed that all solvent-extracted HH fractions, in different degrees, markedly increased both dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing dopamine transporter (DAT) and norepinephrine uptake by CHO cells expressing norepinephrine transporter (NET), and also showed that chloroform (HC), ethyl acetate (HE), and n-butyl alcohol extract strikingly depressed serotonin uptake by CHO cells expressing serotonin transporter (SERT); wherein, the potencies of ethanol extract, HC, HE, and aqueous extract to up-regulate dopamine/norepinephrine uptake and potency of HE to inhibit serotonin uptake were relatively stronger. Further investigation revealed that the enhancement of dopamine/norepinephrine uptake by HC and HE was dependent of DAT/NET activity, and the HE-induced inhibition of serotonin uptake was typical of competition. Thus, HH extracts are novel monoamine transporter modulators functioning as DAT/NET activators and/or SERT inhibitors, and would likely improve neuropsychological disorders through regulating monoamine-transporter activity.

The effect of N‐acetylcysteine on amphetamine‐mediated dopamine release in rat brain striatal slices by ion‐pair reversed‐phase high performance liquid chromatography

The amphetamine (AMPH)-induced alteration in rat brain dopamine levels modified by N-acetylcysteine (NAC) administration has been examined using isocratic ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection. The aim of the development of a novel validated evaluation scheme implying a double AMPH challenge was to enhance the efficiency of AMPH-triggered dopamine release measurements in rat brain striatal slices by improving the reproducibility of the results. The proposed experimental protocol was tested in vivo and proved to be capable of fast and reliable drug screening for tracing the effect of NAC as a model compound in AMPH-mediated dopaminergic response. The subcellular localization of the dopamine mobilizing effect of NAC has been established indirectly by the use of an irreversible dopamine vesicular depletor, reserpine. The antioxidant NAC at 10 mM plays an important role in the complete suppression of acute AMPH-elicited dopamine release. The possible role of this quenching effect is discussed.

Citicoline affects appetite and cortico‐limbic responses to images of high‐calorie foods

Cytidine-5'-diphosphocholine (citicoline) has a variety of cognitive enhancing, neuroprotective, and neuroregenerative properties. In cocaine-addicted individuals, citicoline has been shown to increase brain dopamine levels and reduce cravings. The effects of this compound on appetite, food cravings, and brain responses to food are unknown. We compared the effects of treatment with Cognizin citicoline (500 mg/day versus 2,000 mg/day) for 6 weeks on changes in appetite ratings, weight, and cortico-limbic responses to images of high-calorie foods using functional magnetic resonance imaging (fMRI). After 6 weeks, there was no significant change in weight status, although significant declines in appetite ratings were observed for the 2,000 mg/day group. The higher dose group also showed significant increases in functional brain responses to food stimuli within the amygdala, insula, and lateral orbitofrontal cortex. Increased activation in these regions correlated with declines in appetite ratings. These preliminary findings suggest a potential usefulness of citicoline in modulating appetite, but further research is warranted.

Gonadotropic effects of dopamine in isolated workers of the primitively eusocial wasp, Polistes chinensis

In social insects, biogenic amines are thought to play regulatory roles in the transition between reproductive states in females. To determine the effect of dopamine on the reproductive development of workers in primitively eusocial societies, isolated workers of the paper wasp Polistes chinensis were supplied with oral dopamine. Ovarian development was accelerated in dopamine-fed workers as compared to control workers of the same age fed only sucrose solution. Oral dopamine increased brain levels of dopamine and its metabolite (N-acetyldopamine). Brain levels of tyramine or octopamine were also increased by dopamine application in one of two colonies; levels of the tyramine metabolite N-acetyltyramine were unchanged. These results indicate that dopamine plays a gonadotropic role in isolated workers in the primitively eusocial wasp, similar to the gonadotropic role previously reported for juvenile hormone. This is the first study to report effects of dopamine on ovarian development in workers of the paper wasp.