Quipazine dimaleate

Evidence for serotonin sensitivity of adult rat spinal axons: studies using randomized double pulse stimulation.[Pubmed:9284357]

Neuroscience. 1997 Sep;80(2):559-66.

We have recently shown both inhibitory and excitatory effects of serotonin on neonatal rat dorsal column axons. While neonatal rat dorsal column axons also respond to norepinephrine and GABA, adult rat dorsal columns are insensitive to the actions of both compounds. Therefore, we studied the effects of serotonin agonists on adult rat dorsal column axons using randomized double pulse stimuli at 0.2 Hz with random interpulse intervals of 3, 4, 5, 8, 10, 20, 30, 50 and 80 ms. The serotonin(1A) agonist, 8-hydroxy-dipropylaminotetralin-hydrobromide (8-OH-DPAT), significantly modulated test response amplitudes at 3, 4, 5 and 8 ms interpulse intervals by 29.6+/-4.0%, 17.4+/-2.1%, 9.6+/-2.3%, and 12.4+/-2.2% of conditioning pulse amplitudes, respectively. The mean latencies at 3, 4 and 5 ms interpulse intervals increased by 17.0+/-5.1%, 8.6+/-2.1%, and 5.1+/-1.4%, respectively (P<0.05). However, neither 10 microM 8-OH-DPAT nor 100 microM serotonin hydrochloride affected the compound action potentials evoked by conditioning or test pulses. In contrast, treatment with 100 microM Quipazine dimaleate (a serotonin(2A) agonist) decreased the refractory period. While the response amplitudes to a 3-ms double pulse were reduced by 11.0+/-1.5% during the control period, the test response fell to only 2.4+/-1.8% of the conditioning response amplitudes after exposure to 100 microM quipazine. 8-OH-DPAT decreased the amplitude, prolonged the latency and increased the refractory periods of compound action potentials in the adult rat dorsal column, although a high concentration of the agonist (100 microM) was required for these effects. In contrast, the serotonin(2A) agonist, quipazine, decreased refractory periods. These results suggest that both serotonin(1A) and serotonin(2A) receptor subtypes are present on adult spinal dorsal column axons. Further, these receptors have opposing effects on axonal excitability, despite the fact that their sensitivities are relatively low.

Excitatory and inhibitory effects of serotonin on spinal axons.[Pubmed:7969935]

Neuroscience. 1994 Aug;61(3):645-53.

We studied the effects of serotonin on compound action potentials in dorsal columns isolated from young (nine to 13 days old) rats. Conducting action potentials were activated by submaximal (50%) and supramaximal constant current electrical stimuli and recorded with glass micropipettes. At 10 microM and 100 microM concentrations, serotonin significantly increased mean action potential amplitudes by 9.6 +/- 6.5% (+/- S.D., P < 0.05) and 16.6 +/- 12.2% (+/- S.D., P < 0.005), respectively. Likewise, 10 microM and 100 microM of quipazine (a serotonin2A agonist) increased the amplitudes by 9.6 +/- 2.5% (+/- S.D., P < 0.0005) and 37.7 +/- 8.7% (+/- S.D., P < 0.0005), respectively. In contrast, 10 microM and 100 microM concentrations of 8-hydroxy-dipropylaminotetralin-hydrobromide (a serotonin 1A agonist) reduced axonal excitability by -9.4 +/- 5.5% (+/- S.D., P < 0.05) and -32.9 +/- 10.6% (+/- S.D., P < 0.0005), respectively. At 50 microM concentration, mianserin (a serotonin2A and serotonin2C antagonist) eliminated the excitatory effects of 100 microM Quipazine dimaleate. The combination of 50 microM mianserin and 100 microM serotonin reduced action potential amplitudes by -5.6 +/- 4.9% (+/- S.D., P < 0.05). These results suggest that serotonin1A and serotonin2A receptor subtypes are present on spinal dorsal column axons. These two receptor subtypes have opposing effects on axonal excitability. The ratios and sensitivities of these two axonal receptor subtypes may modulate axonal excitability in rat dorsal column axons and have important implications for both development and injury of axons.

Serotonergic agonists and antagonists affect endurance performance in the rat.[Pubmed:8407063]

Int J Sports Med. 1993 Aug;14(6):330-3.

The purpose of this experiment was to examine the effects of administration of serotonergic (5-HT) agonist and antagonist drugs on run-time to exhaustion (RUN-EXH) in male and female rats. RUN-EXH was reduced (p < 0.05) in a dose related manner by increasing dosages of Quipazine dimaleate (QD: general 5-HT agonist) (0-5 mg.kg-1 i.p.) administered immediately prior to exercise (treadmill running at 20 m.min-1 and 5% grade). Conversely, RUN-EXH was increased (p < 0.05) by the greatest dosage of LY 53,857 (LY: 5-HT1C and 5-HT2 antagonist) (1.5 mg.kg-1 i.p.). Drug effects were similar in male and female rats. The negative effects of QD administration on RUN-EXH were not attenuated by administration of the peripherally restricted antagonist, xylamidine tosylate (up to 200 ug.kg-1 i.p.). The results of this investigation indicated that fatigue during prolonged exercise can be influenced by direct pharmacological administration of a serotonergic agonist and antagonist and that the mechanisms underlying these effects are likely to be central (brain) in nature.

Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue.[Pubmed:8366000]

J Appl Physiol (1985). 1993 Jun;74(6):3006-12.

Pharmacological manipulation of brain serotonergic [5-hydroxytryptamine (5-HT)] activity affects run time to exhaustion in the rat. These effects may be mediated by neurochemical, hormonal, or substrate mechanisms. Groups of rats were decapitated during rest, after 1 h of treadmill running (20 m/min, 5% grade), and at exhaustion. Immediately before exercise rats were injected intraperitoneally with 1 mg/kg of Quipazine dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY 53857 (LY; a 5-HT antagonist), or the vehicle (V; 0.9% saline). LY increased and QD decreased time to exhaustion (approximately 28 and 32%, respectively; P < 0.05). At fatigue, QD animals had greater plasma glucose, liver glycogen, and muscle glycogen concentrations but lower plasma free fatty acid concentration than did V and LY animals (P < 0.05). In general, plasma corticosterone and catecholamine levels during exercise in QD and LY rats were similar to those in V rats. Brain 5-HT and 5-hydroxyindole-3-acetic acid concentrations were higher at 1 h of exercise than at rest (P < 0.05), and the latter increased even further at fatigue in the midbrain and striatum (P < 0.05). Brain dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were higher at 1 h of exercise (P < 0.05) but were similar to resting levels at fatigue. QD appeared to block the increase in DA and DOPAC at 1 h of exercise, and LY prevented the decrease in DA and DOPAC at fatigue (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics of 5-HT3 binding sites in NG108-15, NCB-20 neuroblastoma cells and rat cerebral cortex using [3H]-quipazine and [3H]-GR65630 binding.[Pubmed:1830236]

Br J Pharmacol. 1991 Apr;102(4):919-25.

1. The biochemical and pharmacological properties of 5-HT3 receptors in homogenates of NG108-15 and NCB-20 neuroblastoma cells and rat cerebral cortex have been ascertained by the use of [3H]-quipazine and [3H]-GR65630 binding. 2. In NG108-15 and NCB-20 cell homogenates, [3H]-quipazine bound to a single class of high affinity (NG108-15: Kd = 6.2 +/- 1.1 nM, n = 4; NCB-20: Kd = 3.0 +/- 0.9 nM, n = 4; means +/- s.e.means) saturable (NG108-15: Bmax = 1340 +/- 220 fmol mg-1 protein; NCB-20: Bmax = 2300 +/- 200 fmol mg-1 protein) binding sites. In rat cortical homogenates, [3H]-quipazine bound to two populations of binding sites in the absence of the 5-hydroxytryptamine (5-HT) uptake inhibitor, paroxetine (Kd1 = 1.6 +/- 0.5 nM, Bmax1 = 75 +/- 14 fmol mg-1 protein; Kd2 = 500 +/- 300 nM, Bmax2 = 1840 +/- 1040 fmol mg-1 protein, n = 3), and to a single class of high affinity binding sites (Kd = 2.0 +/- 0.5 nM, n = 3; Bmax = 73 +/- 6 fmol mg-1 protein) in the presence of paroxetine. The high affinity (nanomolar) component probably represented 5-HT3 binding sites and the low affinity component represented 5-HT uptake sites. 3. [3H]-paroxetine bound with high affinity (Kd = 0.02 +/- 0.003 nM, n = 3) to a site in rat cortical homogenates in a saturable (Bmax = 323 +/- 45 fmol mg-1 protein, n = 3) and reversible manner. Binding to this site was potently inhibited by 5-HT uptake blockers such as paroxetine and fluoxetine (pKi s = 8.6-9.9), while 5-HT3 receptor ligands exhibited only low affinity (pK; < 7). No detectable specific [3H]-paroxetine binding was observed in NG108-15 or NCB-20 cell homogenates. 4. [3H]-quipazine binding to homogenates of NG108-15, NCB-20 cells and rat cortex (in the presence of 0.1 microM paroxetine) exhibited similar pharmacological characteristics. 5-HT3 receptor antagonists competed for [3H]-quipazine binding with high nanomolar affinities in the three preparations and the rank order of affinity was: (S)-zacopride > quarternized ICS 205-930 2 granisetron > ondansetron > ICS 205-209 (R)-zacopride > quipazine > renzapride > MDL-72222 > butanopride > metoclopramide. 5. [3H]-GR65630 labelled a site in NCB-20 cell homogenates with an affinity (Kd = 0.7 + 0.1 nms n = 4) and density (B__ = 1800 + 1000 fmol mg- protein) comparable to that observed with [3H]-quipazine. Competition studies also indicated a good correlation between the pharmacology of 5-HT3 binding sites when [3H]-GR65630 and [3H]-quipazine were used in these cells. 6. In conclusion, [3H]-quipazine labelled 5-HT3 receptor sites in homogenates of NG108-15 cells, NCB-20 cells and rat cerebral cortex. In rat cortical homogenates, [3H]-quipazine also bound to 5-HT uptake sites, which could be blocked by 0.1 microM paroxetine. The pharmacological specificity of the 5-HT3 receptor labelled by [3H]-quipazine was similar in the neuroblastoma cells and rat cortex and was substantiated in NCB-20 cells by the binding profile of the selective 5-HT3 receptor antagonist, [3H]-GR65630.

Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve.[Pubmed:3814920]

Br J Pharmacol. 1987 Jan;90(1):229-38.

A study has been made of the pharmacology of the 5-hydroxytryptamine (5-HT)-induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve. Phenylbiguanide (PBG) and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) were found to mimic the effects of 5-HT on the vagus nerve. Their EC50 values were respectively 2.0 fold and 3.9 fold greater than that of 5-HT. Metoclopramide behaved as a reversible competitive antagonist of depolarization induced by PBG and 2-methyl-5-HT, with pKB values of 6.48 +/- 0.04, respectively. These agreed well with the pKB value of 6.60 +/- 0.04 obtained previously for metoclopramide against 5-HT on the rat vagus nerve. 5-HT, PBG and 2-methyl-5-HT had no demonstrable agonist effects at non-5-HT receptors on the rat vagus nerve. Tropacaine and m-chlorophenylpiperazine were found to behave as reversible competitive antagonists of 5-HT-induced depolarization of the vagus nerve. The pKB values were 6.29 +/- 0.03 and 6.90 +/- 0.03, respectively. Quipazine, MDL 72222 and ICS 205-930 were also shown to be effective antagonists of 5-HT on the vagus nerve. However, although these compounds were highly potent, they all caused a marked concentration-dependent reduction in the amplitude of the maximum response to 5-HT. This behaviour was not consistent with a simple reversible competitive mechanism. The results are discussed with reference to the current classification of mammalian peripheral neuronal 5-HT receptors.