Increased levels of proneurotensin/neuromedin N mRNA in rat striatum and nucleus accumbens induced by 7-OH-DPAT and nafadotride.
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The D3 dopamine receptor has been proposed as a potential antipsychotic site. In this study, the effects of the D3-preferring compounds 7-OH-DPAT and nafadotride on levels of proneurotensin/neuromedin N (proNT/N) were assessed. Adult, male, Sprague-Dawley rats were injected subcutaneously (s.c.) with the agonist 7-OH-DPAT (0.1 mg/kg) or antagonist nafadotride (1 mg/kg) at doses previously shown to produce negligible occupancy of D2 receptors in vivo. As a positive control, an additional group of animals was treated with haloperidol (3 mg/kg, s.c.). ProNT/N mRNA levels were determined by in situ hybridization. 7-OH-DPAT increased proNT/N mRNA in the nucleus accumbens shell. Nafadotride increased proNT/N mRNA levels in the nucleus accumbens shell and dorsomedial caudate nucleus to levels comparable to those produced by haloperidol. Nafadotride also increased proNT/N mRNA in the anterior and dorsal caudate but to a lesser extent than haloperidol. These data indicate that 7-OH-DPAT and nafadotride increase proNT/N mRNA levels in brain areas affected by antipsychotic drugs and suggest that the D3 receptor may regulate proNT/N mRNA expression in the nucleus accumbens shell. (+info)
The role of serotonin in antipsychotic drug action.
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Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptor which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes. (+info)
Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate.
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The measure of changes in synaptic dopamine (DA) concentration in response to the psychostimulant drug methylphenidate (MP) has been used as an indicator of responsiveness of the DA system. The purpose of this study was to assess the reproducibility of these measures. METHODS: Seven healthy subjects were scanned with PET and [11C]raclopride twice in the same day: 7 min after placebo or methylphenidate (0.5 mg/kg) administration. In parallel we also measured the physiologic and behavioral responses to placebo and to methylphenidate. The same procedures were repeated 1-2 wk later to assess test-retest reproducibility. RESULTS: Measures of plasma to brain transfer constant (K1), striatal distribution volume (DVstr) and DA D2 receptor availability (Bmax/Kd), for the placebo condition were similar for the first (E1) and second (E2) evaluations (Bmax/Kd, E1: 2.77+/-0.44; E2: 2.97+/-0.44). MP administration did not change K1, but it significantly decreased DVstr (E1: -25.9%+/-8.7%, P < or = 0.0002; E2: -20.7%+/-11.7%, P < or = 0.007) and Bmax/Kd (E1: -18.4%+/-8.7%, P < or = 0.002; E2: -13.4%+/-9.2%, P < or = 0.008), and the magnitude of these changes, though lower for E2, did not differ significantly. MP increased pulse rate (E1: +64%+/-43%, P < or = 0.002; E2: +69%+/-33%, P < or = 0.001), systolic pressure (E1: +37%+/-19%, P < or = 0.0006; E2: +29%+/-15%, P < or = 0.0009), self reports for drug effects (0: nothing to 10: extreme) of "rush" (E1: +8+/-3, P < or = 0.0004; E2: +6+/-4, P < or = 0.01) and "high" (E1: +8+/-3, P < or = 0.0001, E2: +8+/-3, P < or = 0.0003), anxiety (E1: +5+/-4, P < or = 0.02; E2: +4+/-4, P = 0.1) and restlessness (E1: +4+/-4, P < or = 0.04; E2: +4+/-5, P = 0.1). The magnitude of the cardiovascular and behavioral effects did not differ between E1 and E2. CONCLUSION: MP-induced changes in striatal DV and in Bmax/Kd, as well as the behavioral and cardiovascular effects, were reproducible with repeated administration. (+info)
Effect of tetrahydropalmatine analogs on Fos expression induced by formalin-pain.
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AIM: To study the effect of tetrahydropalmatine (THP) analogs on Fos protein expression induced by formalin-pain and elucidate analgesic mechanism of THP analogs. METHODS: The pain response to Sprague Dawley rats was induced with formalin injected s.c. into the plantar surface of the right hindpaw. Fos protein expression in brain and spinal cord was investigated with immunohistochemistry. The numbers of Fos-like immunoreactive (FLI) neurons were counted with Leica Q570 image analyzer. RESULTS: In the groups of THP analogs and D2 antagonist spiperone, FLI neurons induced by intraperitoneal (i.p.) injection of THP analogs and spiperone were mainly located in the striatum and accumbens nucleus, and a few FLI neurons were also in sensorimotor cortex. In the D1 antagonist, D1 agonist, D2 agonist, saline and vehicle groups, FLI neurons were seldom seen in the striatum and accumbens nucleus. Moreover, the Fos protein expression induced by l-THP and spiperone could be prevented by the pre-treatment of the D2 agonist quinpirole but not D1 agonist SKF38393. In the formalin-pain group, FLI neurons were mainly distributed in ascending pain afferent system (APAS) and descending pain modulation system (DPMS). Following i.p. THP analogs, however, the numbers of FLI neurons induced by formalin-pain in the APAS, such as dorsal horn (mainly laminae I, II, IV-VI) were markedly decreased, while the numbers of FLI neurons in the DPMS, such as periaqueductal gray (PAG) and reticular paragigantocellular lateral nucleus (RPLN) were significantly increased. CONCLUSION: THP analogs enhanced the activity of brainstem DPMS by the blockade of D2 receptors in the striatum and accumbens nucleus, and sequentially inhibited the inputs of peripheral pain afferent message in spinal cord level. (+info)
Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells.
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This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in cloned cells using the cytosensor microphysiometer. Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller than those in adherent CHO cells. The time courses and maximum increases in acidification rate of the agonist responses in adherent CHO cells were different between the three dopamine receptor clones. Responses were blocked by pretreatment of cells with pertussis toxin or amiloride analogues. Most agonists had full intrinsic activity at each of the dopamine receptor subtypes, as compared to quinpirole, however both enantiomers of UH-232 and (-)3-PPP were partial agonists in this assay system. The functional potency of full agonists at each of the three receptors expressed in CHO cells was either higher than, or similar to, the apparent inhibition constants (Ki) determined in [125I]-iodosulpride competition binding studies. Functional selectivities of the agonists were less than radioligand binding selectivities. The rank orders of agonist potencies and selectivities were similar, but not identical, to the rank orders of radioligand binding affinities and selectivities. The dopamine receptor antagonists, iodosulpride and clozapine, had no effect on basal acidification rates but inhibited acidification responses in CHO cells to quinpirole in an apparently competitive manner. Antagonist potencies closely matched their radioligand binding affinities in these cells. (+info)
Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse.
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In this study, the mechanism of nicotine-induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis. Systemic administration of nicotine (0.4 mg kg(-1), s.c.) increased the levels of ACh in hippocampal dialysates. The nicotine-induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg(-1), s.c.) and dihydro-beta-erythrodine (DHbetaE; 4.0 mg kg(-1), s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzaz epine; 0.3 mg kg(-1), s.c.). Local perfusion of mecamylamine (100 microM), DHbetaE (100 microM) or SCH-23390 (10 microM) through microdialysis probe did not increase basal hippocampal ACh release. Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg(-1), s.c.) was antagonized by local perfusion of SCH-23390 (10 microM), but not by MEC (100 microM) or DHbetaE (100 microM). Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co-perfusion of either mecamylamine (100 microM) or SCH-23390 (10 microM). These results suggest that nicotine-induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non-DA-ergic mechanism. (+info)
Calcium channels involved in the inhibition of acetylcholine release by presynaptic muscarinic receptors in rat striatum.
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1. The mechanism of the inhibitory action of presynaptic muscarinic receptors on the release of acetylcholine from striatal cholinergic neurons is not known. We investigated how the electrically stimulated release of [3H]-acetylcholine from superfused rat striatal slices and its inhibition by carbachol are affected by specific inhibitors of voltage-operated calcium channels of the L-type (nifedipine), N-type (omega-conotoxin GVIA) and P/Q-type (omega-agatoxin IVA). 2. The evoked release of [3H]-acetylcholine was not diminished by nifedipine but was lowered by omega-conotoxin GVIA and by omega-agatoxin IVA, indicating that both the N- and the P/Q-type (but not the L-type) channels are involved in the release. The N-type channels were responsible for approximately two thirds of the release. The release was >97% blocked when both omega-toxins acted together. 3. The inhibition of [3H]-acetylcholine release by carbachol was not substantially affected by the blockade of the L- or P/Q-type channels. It was diminished but not eliminated by the blockade of the N-type channels. 4. In experiments on slices in which cholinesterases had been inhibited by paraoxon, inhibition of [3H]-acetylcholine release by endogenous acetylcholine accumulating in the tissue could be demonstrated by the enhancement of the release after the addition of atropine. The inhibition was higher in slices with functional N-type than with functional P/Q-type channels. 5. We conclude that both the N- and the P/Q-type calcium channels contribute to the stimulation-evoked release of acetylcholine in rat striatum, that the quantitative contribution of the N-type channels is higher, and that the inhibitory muscarinic receptors are more closely coupled with the N-type than with the P/Q-type calcium channels. (+info)
Regulation of platelet function by catecholamines in the cerebral vasculature of the rabbit.
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1. 111In-labelled platelets were monitored continuously in the cerebral and pulmonary vascular beds of anaesthetized rabbits. Dopamine can, depending upon the concentration, either potentiate or inhibit thrombin-induced platelet accumulation in the cerebral vasculature of rabbits by unknown mechanisms. The effects of specific adrenergic and dopaminergic receptor antagonists were tested upon dopamine's actions on intracarotid (i.c.) thrombin-induced (80 u kg-1) platelet accumulation in the cerebral vasculature. The effect of adrenaline on the response to thrombin in this vascular bed was also investigated. 2. Thrombin-induced platelet accumulation was significantly (P<0.01) potentiated by dopamine (100 microgkg-1 min-1, i.c.) and this effect was significantly inhibited by infusion of the alpha-adrenoceptor antagonist, phentolamine. 3 A higher dose of dopamine (2 mg kg-1 min-1, i.c.) inhibited thrombin-induced platelet accumulation. The beta-adrenoceptor antagonist, propranolol, did not significantly alter this inhibitory effect whereas it was abolished by the dopamine D1 selective antagonist, SCH23390. 4 Adrenaline (when administered i.c. by bolus injection or infusion) had no significant effect on thrombin-induced accumulation at any of the doses tested. 5 Potentiation of in vivo platelet accumulation by dopamine therefore seems to occur via alpha-adrenergic receptors. However, the inhibitory effect of dopamine appears to be exerted via the activation of dopamine D1 receptors and not via beta-adrenergic receptors. Our findings confirm that dopamine, but not adrenaline, can modify platelet function in the cerebral vasculature and these observations may have implications for current and potential therapeutic uses of dopamine and selective dopaminergic compounds. (+info)