Dopamine-dependent tuning of striatal inhibitory synaptogenesis.

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D(1)- and/or D(2)-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABA(A) receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals. These changes result from an increased internalization of GABA(A) receptors, and are mediated by distinct signaling pathways converging at the level of GABA(A) receptors to cause a transient PP2A/PP1-dependent dephosphorylation. Thus, tonic D(1)- and D(2)-receptor activity limits the extent of collateral inhibitory synaptogenesis between medium spiny neurons, revealing a novel role of dopamine in controlling the development of intrinsic striatal microcircuits.

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease.

BACKGROUND: It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. METHODS: Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. RESULTS: EX-4 (0.1 and 0.5 mug/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. CONCLUSION: The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.

The CRF-like peptide urocortin produces a long-lasting recovery in rats made hemiparkinsonian by 6-hydroxydopamine or lipopolysaccharide.

We have recently observed that the corticotropin releasing factor related peptide urocortin (UCN) reverses key features of nigrostriatal neurodegeneration following intracerebral injection of either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS). To determine the potential therapeutic utility of UCN here we have studied whether these effects are sustained for several weeks following peptide injection. In addition we have studied whether UCN still shows efficacy in rats with more pronounced nigrostriatal lesions. Rats were lesioned using 6-OHDA or LPS and injected with UCN either 7 or 14 days later. At different time points animals were tested for rotational behaviour (apomorphine, 0.5 mg/kg) and subsequently implanted with bilateral dialysis probes into the striata. The following day rats were dialysed to estimate extracellular striatal dopamine (DA) and then sacrificed for estimation of striatal tissue DA and subsequent immunohistochemistry of TH(+) cells in the substantia nigra (SN). Toxin treated rats given UCN 7 days later showed clear evidence of reduced nigrostriatal damage both 28 and 84 days following UCN compared with saline injection. In rats given UCN 14 days after toxin injection, by which time deficits were maximal, a restoration of nigrostriatal damage was observed. This suggests that UCN is able to elicit a sustained restoration of functional nigrostriatal integrity and has the ability to produce a recovery in severely lesioned rats. These findings suggest that stimulation of CRF (probably CRF(1)) receptors could have therapeutic utility in PD.

Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease.

We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist alpha-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats.

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.

Chronic treatment with antidepressant drugs reversibly alters NMDA mediated regulation of extracellular 5-HT in rat frontal cortex.

Treatment of depression is largely based upon the monoamine theory of the illness. However, current therapies are only efficacious in 70-80% of patients indicating that other factors are involved. One mechanism could involve glutamatergic NMDA receptors since NMDA receptor antagonists have antidepressant like properties in paradigms of the illness. We have observed that the tricyclic clomipramine given chronically decreases NMDA mediated alterations in extracellular 5-hydroxytryptamine (5-HT). We have now studied whether this observation extends to other antidepressant drugs (AD's), reboxetine and parxoetine and also if the phenomenon is reversible after treatment is discontinued. To do this we have studied cortical extracellular 5-HT in rats using microdialysis. Acutely, none of the AD's altered extracellular 5-HT, while 100 microM NMDA infusion evoked an increase. All three AD's increased extracellular 5-HT after 14 days of treatment, however, at the same time the effects of NMDA on extracellular 5-HT were abolished. In vehicle only treated rats NMDA infusion still evoked a significant increase in extracellular 5-HT. This situation was unchanged after 3 days of drug washout with 5-HT levels remaining high and no response to NMDA infusion occurred. After 14 days of antidepressant washout, however, extracellular 5-HT levels in all three AD drug groups were around basal values. In these groups NMDA infusion now evoked an increase in extracellular 5-HT comparable to that seen in vehicle treated rats. If a reduction in NMDA receptor activity plays a role in AD drug action these observations could be of possible therapeutic significance.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats.

1. Evidence has recently suggested that NMDA receptors may play a role in the aetiology and possible treatment of depression and that weak noncompetitive NMDA receptor antagonists such as amantadine can synergize with conventional antidepressants in a model of the illness. 2. To try to obtain a neurochemical rationale for these findings, we have studied the effects of acute and chronic administration of amantadine or the related drug budipine on cortical release of 5-hydroxytryptamine (5-HT) following the antidepressants reboxitine (REB), paroxetine (PAROX) and clomipramine (CLOM) in freely moving rats by using microdialysis. 3. Acute administration of amantadine (40 mg kg(-1)), budipine (10 mg kg(-1)), REB (10 mg kg(-1)), PAROX (10 mg kg(-1)) or CLOM (10 mg kg(-1)) all failed to significantly alter extracellular 5-HT in the cortex. However, when either amantadine or budipine was administered 30 min prior to any of the three antidepressants, a significant rise in 5-HT was observed. 4. For chronic studies, the effects of the drugs were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular 5-HT at any time point. The three antidepressant drugs all elicited a gradual increase in 5-HT, which became significant after 14 days and tended to plateau thereafter. When either amantadine (20 mg kg(-1)) or budipine (5 mg kg(-1)) was coadministered with any of the three antidepressants, two differences were seen compared with the effects of the antidepressants alone. Firstly, the time required for significant increases in cortical 5-HT was reduced with elevated levels now being observed by 7 days. Secondly, the absolute magnitude of the increase in extracellular 5-HT was markedly greater in these rats from day 7 until the end of the experiment. 5. If, as is widely considered, an increase in extracellular 5-HT represents a critical step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants as well as possibly enhance their efficacy.

Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats.

The antiepileptic drugs sodium valproate (VPA) and lamotrigine (LTG) are increasingly used in combination in patients in whom monotherapy has failed to control seizures. Although these drugs are known to interact pharmacokinetically, several authors have proposed a pharmacodynamic interaction between the two. In order to investigate this we have studied the effects of combined treatment with LTG and VPA on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), gamma amino butyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the hippocampus of freely moving rats using microdialysis. Additionally, we measured the possible effect of VPA on LTG in plasma, whole brain and dialysates. Neither LTG (10 mg/kg) nor VPA (300 mg/kg) given alone significantly altered basal levels of ASP, GLU or TAU. When given together, however, the two drugs significantly reduced extracellular ASP and GLU while increasing TAU levels. In the case of GABA, LTG was without effect on basal levels of the transmitter, but these increased following VPA and this persisted with both drugs. When transmitter release was stimulated by 50 muM veratridine, marked increases in the release of all amino acids occurred and this was decreased by LTG in all cases. VPA alone only altered GABA release, increasing it by approximately the same extent as basal GABA. For all of the amino acids studied, however, VPA reversed the decreases in release seen after LTG. VPA and LTG increased and decreased respectively basal 5-HT and DA. When given together the increase in extracellular 5-HT was greatly prolonged, but no effect on DA release was seen. When 5-HT release was evoked by veratridine this was increased by VPA and no other treatment. With DA, however, neither drug alone altered evoked release, but the two combined led to a marked increase. Co-administration of VPA with LTG showed no significant effect of this combination on LTG in any of the three compartments studied indicating that in this case a significant pharmacokinetic contribution to our findings is unlikely, which suggests that there is a probable pharmacodynamic interaction of the two drugs.

Release of arginine, glutamate and glutamine in the hippocampus of freely moving rats: Involvement of nitric oxide.

Using in vivo microdialysis, we have monitored the release of three amino acids (arginine, glutamate and glutamine) in the hippocampus of freely moving rats in response to various drugs. In response to N-methyl-d-aspartate (NMDA) infusion, extracellular glutamate was increased, glutamine was decreased and arginine remained unchanged. By contrast, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) elicited an increase in arginine release but had no effect on either glutamate or glutamine. When S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was infused into the hippocampus, an increase in glutamate, a decrease in glutamine and no change in arginine were recorded. The effect of SNAP on extracellular glutamine levels was reversed by prior infusion of the guanylate cyclase inhibitor oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), however its effect on glutamate release was unchanged. Interestingly, SNAP was found to promote the release of arginine in the presence of ODQ. We also assessed the effect of two nitric oxide synthase inhibitors, N-nitro-l-arginine methylester (l-NAME) and 7-nitroindazole (7-NI), on the release of these amino acids. l-NAME was found to increase arginine and glutamate levels but decrease those of glutamine. In contrast, 7-NI reduced the release of all three amino acids. The results presented here confirm some but not all of the findings previously obtained using in vitro preparations. In addition, they suggest that complex relationships exist between the release of these amino acids, and that endogenous NO plays an important role in regulating their release.

Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids.

We have studied the effects of treatment with the anticonvulsants lamotrigine (LTG), phenytoin (PHN) and carbamazepine (CBZ) on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), GABA, 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of freely moving rats using microdialysis. All of the drugs investigated have had inhibition of Na(+) channel activity implicated as their principal mechanism of action. Neither LTG (10-20 mg/kg), PHN (20-40 mg/kg) or CBZ (10-20 mg/kg) had an effect on the basal extracellular concentrations of any of the amino acids studied with the exception of glutamate, which was decreased at the highest LTG dose. However, when amino acid transmitter levels were increased with 50 microM veratridine, LTG was found to cause a dose-dependent decrease in dialysate levels of all four amino acids, with the effect being most pronounced for glutamate. In contrast, PHN decreased extracellular aspartate levels but had no effect on evoked-extracellular GLU, TAU or GABA. Somewhat unexpectedly, CBZ did not alter the stimulated increase in the excitatory amino acids, GLU and ASP, but, rather surprisingly for an antiepileptic drug, markedly decreased that of the inhibitory substances TAU and GABA. The three drugs had differing effects on basal extracellular 5-HT and DA. LTG caused a dose-dependent decrease in both, while CBZ and PHN both increased extracellular 5-HT and DA. When extracellular 5-HT and DA was evoked by veratridine LTG had no significant effect on this, while PHN but not CBZ increased stimulated extracellular 5-HT and both PHN and CBZ augmented DA. Thus, the effects of the three drugs studied seemed to depend on whether extracellular transmitter levels are evoked or basal and the particular transmitter in question. This suggests that there are marked differences in the neurochemical mechanisms of antiepileptic drug action of the three compounds studied.

Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat.

1. We have studied the effects of acute and chronic treatment with the anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5-hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus of freely moving rats using in vivo microdialysis. 2. Acute LTG (10 and 20 mg kg(-1)) decreased extracellular 5-HT, but had no effect on its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Dialysate DA was also decreased by LTG as were its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). When transmitter release was stimulated by either 50 microm veratridine or 100 mm K(+), marked increases in the release of both transmitters occurred, but LTG was entirely without effect on this. 3. In chronic experiments, rats were dialysed after 2, 4, 7, 14 and 21 days of LTG treatment (5 mg kg(-1), twice daily). During this period a progressively different response to the drug was seen. After 2 days, basal extracellular 5-HT was significantly greater in treated rats than control rats. This effect persisted up to 14 days, but by 21 days 5-HT levels had returned to control values. 5-HIAA levels were unaltered and there was no effect of LTG on veratridine or K(+) stimulated 5-HT release. 4. Similarly, DA concentrations significantly increased after 2-7 days of LTG treatment, but returned and remained at basal values thereafter. During the treatment period LTG had no effect on extracellular DOPAC, but HVA followed a similar pattern to its parent transmitter. As with 5-HT, at no time point did LTG have any effect on stimulated DA release. 5. These neurochemical findings observed in these experiments are considered in relation to the use of LTG in bipolar disorder.

Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats.

The antiepileptic drug lamotrigine (LTG) is a relatively novel anticonvulsant frequently used in polytherapy and increasingly in monotherapy. LTG is believed to act by reducing excitatory glutamate (GLU) release due to an inhibition of Na(+) channels. In the present study, we have investigated the effects of acute and chronic (up to 21 days) treatment with LTG on basal and either veratridine- or KCl-stimulated release of aspartate (ASP), GLU, taurine (TAU) and GABA in the hippocampus of freely moving rats using microdialysis. Additionally, we have measured LTG concentrations in the plasma, whole brain and extracellular fluid of rats at the same time points. LTG significantly reduced basal ASP and GLU but only at the highest dose used (20 mg/kg) and was entirely without effect on basal TAU or GABA. When either veratridine or 100 mM KCl were added to the infusion medium amino acid release was evoked although the extent of this varied from one amino acid to another. LTG (10 mg/kg) reduced veratridine-evoked release of all four amino acids studied, although this was most marked in the case of GLU. LTG had no effect on KCl-stimulated amino acid release. When given for up to 21 days (2 x 5 mg/kg/day), LTG had no effect on basal amino acid levels. In contrast, LTG demonstrated over the time period studied an increasingly inhibitory effect on veratridine-evoked amino acid release. This effect of the drug was proportionally much greater in the case of GLU than for the other three amino acids studied. Measurement of plasma, whole brain tissue and extracellular LTG showed that in each of these compartments, it had reached an apparent steady state within 4 days of commencement of treatment and appeared to mirror the neurochemical changes measured. Our estimate of plasma LTG indicates that during chronic study, this was well within the therapeutic range, suggesting that the current neurochemical observations are clinically relevant.

Reboxetine modulates norepinephrine efflux in the frontal cortex of the freely moving rat: the involvement of alpha 2 and 5-HT1A receptors.

The effect of reboxetine on norepinephrine (NE) efflux in the frontal cortex of freely moving rats has been studied using in vivo microdialysis. Reboxetine was administered either by injection (10 and 30 mg/kg i.p.) or directly to the frontal cortex via the dialysis probe (10 and 100 microM). To further elucidate the mechanism of action of reboxetine in this region yohimbine (10 microM) was co-infused with reboxetine via the frontal cortex probe. Both routes of administration of reboxetine resulted in a drug-induced, dose-dependent decrease in frontal cortex NE efflux. This effect was reversed following co-infusion of yohimbine, which has been shown to possess both alpha(2)-adrenoceptor antagonist and 5-HT(1A) agonist properties.

Arginine release from rat cerebellar astrocytes: autocrine roles for glutamate and nitric oxide?

In this study we have investigated the relationship between glutamate and arginine release from cultured cerebellar astrocytes. We found that the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) promoted the release of both amino acids in a concentration-dependent manner, and that these responses were partially reversed by a guanylate cyclase inhibitor. Application of the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) resulted in a 60% reduction in basal arginine release but no change in that of glutamate. This effect was not overcome by the subsequent addition of SNAP despite a two-fold increase in glutamate release. Incubation with the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) elicited 40 and 60% reductions in the basal release of glutamate and arginine, respectively. Basal release of both amino acids was restored by the addition of SNAP. We conclude that glutamate released from cerebellar astrocytes in response to increased levels of extracellular NO acts in an autocrine manner to promote arginine release via the activation of non-NMDA receptors. In addition, our data suggest that basal glutamate release is regulated to some extent by tonic NO synthesis in these cells.

Regulatory role of nitric oxide over extracellular taurine in the hippocampus of freely moving rats.

We have studied the effects of drugs which manipulate nitric oxide (NO) levels as well the effect of N-methyl-d-aspartate (NMDA) infusion on extracellular taurine in rat hippocampus using in vivo microdialysis. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased dialysate taurine in a concentration-dependent manner, and this effect was blocked by the inhibitor of soluble guanylate cyclase1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ). NMDA (100 microM) increased hippocampal taurine release, an effect that was reversed by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 10 microM). The non-selective nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME; 100 microM and 1.0 mM) increased extracellular taurine in a concentration-dependent manner while 7-nitroindazole (7-NI), a relatively selective neuronal NOS (nNOS) inhibitor, at the same concentrations decreased extracellular taurine. L-NAME (1.0 mM) infused prior to NMDA did not alter the effect of NMDA on extracellular taurine having an effect essentially identical to that seen with L-NAME infused alone. In contrast, when 7-NI was infused for 30 min prior to NMDA, taurine levels were no longer increased above basal. This suggests to us that taurine efflux is mediated by two different mechanisms: an NMDA-evoked, 7-NI-sensitive pathway which may be dependent on cyclic guanosine monophosphate formation, and an L-NAME-modulated mechanism which presumably involves other members of the NOS group of enzymes than nNOS alone.

Kava lactones and the kava-kava controversy.

Kava-kava is a traditional beverage of the South Pacific islanders and has had centuries of use without major side effects. Standardised extracts of kava-kava produced in Europe have led to many serious health problems and even to death. The extraction process (aqueous vs. acetone in the two types of preparations) is responsible for the difference in toxicity as extraction of glutathione in addition to the kava lactones is important to provide protection against hepatotoxicity. The Michael reaction between glutathione and kava lactones, resulting in opening of the lactone ring, reduces the side effects of the kava kava extracts. This protective activity was demonstrated using Acanthamoebae castellanii in which 100% cell death occurred with 100 mg ml(-1) kava lactones alone, and 40% cell death with a mixture of 100 mg ml (-1)glutathione and 100 mg ml (-1) kava lactones. A comparison of kava lactone toxicity with other pharmaceutical products is discussed and recommendations made for safe usage of kava-kava products

Bitter tastants alter gastric-phase postprandial haemodynamics.

ETHNOPHARMACOLOGICAL RELEVANCE: Since Greco-Roman times bitter tastants have been used in Europe to treat digestive disorders, yet no pharmacological mechanism has been identified which can account for this practice. This study investigates whether the bitter tastants, gentian root (Gentian lutea L.) and wormwood herb (Artemisia absinthium L.), stimulate cephalic and/or gut receptors to alter postprandial haemodynamics during the gastric-phase of digestion. MATERIALS AND METHODS: Normal participants ingested (1) 100 mL water plus capsules containing either cellulose (placebo-control) or 1000 mg of each tastant (n=14); or (2) 100mL of water flavoured with 500 or 1500 mg of each tastant (a) gentian (n=12) and (b) wormwood (n=12). A single beat-to-beat cardiovascular recording was obtained for the entire session. Pre/post-ingestion contrasts with the control were analysed for (1) the encapsulated tastants, in the "10 to 15" minute post-ingestion period, and (2) the flavoured water in the "5 to 10" minute post-ingestion period. RESULTS: Water, the placebo-control, increased cardiac contraction force and blood pressure notwithstanding heart rate decreases. Encapsulated tastants did not further alter postprandial haemodynamics. In contrast gentian (500 and 1500 mg) and wormwood (1500 mg) flavoured water elicited increased peripheral vascular resistance and decreased cardiac output, primarily by reducing stroke volume rather than heart rate. CONCLUSIONS: Drinking 100mL water elicits a pressor effect during the gastric-phase of digestion due to increased cardiac contraction force. The addition of bitter tastants to water elicits an additional and parallel pressor effect due to increased peripheral vascular resistance; yet the extent of the post-prandial blood pressure increases are unchanged, presumably due to baroreflex buffering. The vascular response elicited by bitter tastants can be categorised as a sympathetically-mediated cephalic-phase response. A possible mechanism by which bitter tastants could positively influence digestion is altering gastric-phase postprandial haemodynamics and supporting postprandial hyperaemia.

Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson's disease.

BACKGROUND: Data from an open label randomised controlled trial have suggested possible advantages on both motor and non-motor measures in patients with Parkinson's disease following 12 months exposure to exenatide. OBJECTIVE: Continued follow up of these same patients was performed to investigate whether these possible advantages persisted in the prolonged absence of this medication. METHODS: All participants from an open label, randomised controlled trial of exenatide as a treatment for Parkinson's disease, were invited for a further follow up assessment at the UCL Institute of Neurology. This visit included all 20 individuals who had previously completed twelve months exposure to exenatide 10ug bd and the 24 individuals who had acted as randomised controls. Motor severity of PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the MDS-UPDRS, together with several non-motor tests. This assessment was thus 24 months after their original baseline visit, i.e. 12 months after cessation of exenatide. RESULTS: Compared to the control group of patients, patients previously exposed to exenatide had an advantage of 5.6 points (95% CI, 2.2-9.0; p = 0.002) using blinded video rating of the MDS-UPDRS part 3 motor subscale. There was also a difference of 5.3 points; (95% CI, 9.3-1.4; p = 0.006) between the 2 groups on the Mattis Dementia Rating scale. CONCLUSIONS: While these data must still not be interpreted as evidence of neuroprotection, they nevertheless provide strong encouragement for the further study of this drug as a potential disease modifying agent in Parkinson's disease.

Exenatide and the treatment of patients with Parkinson's disease.

UNLABELLED: BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01174810. FUNDING: Cure Parkinson's Trust.

Caffeine in hot drinks elicits cephalic phase responses involving cardiac activity.

Caffeine stimulates both oropharyngeal and gut bitter taste receptors (hTAS2Rs) and so has the potential to elicit reflex autonomic responses. Coffee containing 130 mg caffeine has been reported to increase heart rate for 30 min post-ingestion. Whereas added-caffeine, in doses of 25 to 200 mg, ingested with decaffeinated coffee/tea decreases heart rate 10 to 30 min post-ingestion. This study aimed to clarify caffeine's chemosensory impact. Double-espresso coffees were compared to a placebo-control capsule in a double-blind between-measures design. Coffees tested were regular coffee (130 mg caffeine) and decaffeinated coffee with added-caffeine (0, 67 and 134 mg). Cardiovascular measures from three post-ingestion phases: 1) 0 to 5; 2) 10 to 15; and 3) 25 to 30 min; were compared to pre-ingestion measures. Participants comprised 11 women in the control group and 10 women in the test group. Decaffeinated coffee elicited no changes. Decaffeinated coffee with 67 mg caffeine: decreased dp/dt in Phase 1. Decaffeinated coffee with 134 mg caffeine: increased heart rate in Phases 1 and 2; decreased spontaneous baroreflex sensitivity in Phase 1; and increased diastolic pressure in Phases 2 and 3. Regular coffee: increased heart rate in Phases 1 and 2; decreased dp/dt in all phases; and decreased systolic pressure in Phase 1. Caffeine is the substance in regular coffee which elicits chemosensory autonomic reflex responses, which involves heart activity and the baroreflex. Compared to the caffeine in regular coffee, added-caffeine elicits somewhat different chemosensory responses including a more pronounced pressor effect and resetting of the baroreflex. Caffeine in commonly consumed amounts, as well as modulating body processes by blocking adenosine receptors, can elicit reflex autonomic responses during the ingestion of caffeinated drinks. It is plausible that caffeine stimulates hTAS2Rs, during the ingestion of coffee, eliciting cephalic phase responses. These cephalic phase responses likely result from vagal withdrawal and it is uncertain whether they enhance digestion or not.