[Study of the pharmacology of the quipazine maleate. I. General pharmacology of quipazine maleate].
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[Study of the pharmacology of quipazine maleate. II. Effects of quipazine maleate on the central nervous system].
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Animals↗
[Study of the pharmacology of quipazine maleate. 3. Possible analogies between serotonin and quipazine maleate].
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Animals↗
Characteristics of 5-HT3 binding sites in NG108-15, NCB-20 neuroblastoma cells and rat cerebral cortex using [3H]-quipazine and [3H]-GR65630 binding.
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.
Animals↗
The effects of quipazine and fluoxetine on extinction of a previously-reinforced operant response in rats.
Previous studies have shown that treatments that reduce serotonergic neurotransmission lead to enhanced responding during extinction. To evaluate the generality of this effect, the present study examined the effects of the serotonin agonists, quipazine and fluoxetine on responding in extinction. In Experiment 1, 72 rats were trained to lever press on a continuous reinforcement schedule for 5 30-min sessions. Four sessions of extinction followed; 30-min prior to each, 3 groups (n = 16) received quipazine (0, 1.0, 5.0 mg/kg) and 3 groups (n = 8) received fluoxetine (0, 1.0, 5.0 mg/kg). The 5.0 mg/kg dose of quipazine resulted in a significant reduction in responding on day 1; the lower dose of quipazine and both doses of fluoxetine were without significant effect. In Experiment 2, 3 similarly trained groups (n = 8) received either saline or quipazine (5.0 mg/kg) prior to each extinction session; additionally, one quipazine group was injected twice with the 5.0 mg/kg dose in its home cage several days before the beginning of extinction. The results of the drug-naive quipazine group replicated those of that group from Experiment 1 whereas the drug-experienced group showed no significant effect of quipazine in extinction. The results suggested that prior drug experience could modify the effects of quipazine on behaviour. Apart from this drug novelty effect the lack of significant effect of either quipazine or fluoxetine suggested that the effects of manipulations believed to increase and decrease serotonin functioning on responding in extinction may not be symmetrical. These results may be understood with reference to the hypothesis that serotonin plays a role in tuning out or reducing responsiveness to nonreinforced or irrelevant stimuli.
Animals↗
Quipazine increases renin release by a peripheral hemodynamic mechanism.
Systemically administered serotonin (5-HT) agonists have been suggested to act centrally to increase plasma renin activity (PRA) and arterial pressure (AP). To test this hypothesis, hemodynamic responses were determined in conscious male rats after intracerebroventricular (i.c.v.) or intravenous (i.v.) administration of the direct 5-HT agonist quipazine. When administered i.v., quipazine increased AP and PRA, and decreased renal blood flow (RBF); doses of quipazine i.c.v. that increased AP to a similar degree failed to increase PRA. The increase in PRA elicited by i.v. quipazine was not blocked by propranolol, suggesting non-neural mechanisms. The increase in AP and decrease in RBF elicited by i.v. quipazine were not eliminated by prazosin, enalapril, or a V1-vasopressin antagonist administered alone or in combination. LY 53857, a 5-HT2 antagonist that enters the central nervous system (CNS), blocked all responses to i.v. quipazine. In contrast, the peripheral 5-HT2 antagonist xylamidine blocked the renin and RBF responses, but only attenuated the pressor response to quipazine. These data suggest that quipazine can act in the CNS to increase AP, but when administered systemically quipazine also activates vascular 5-HT2 receptors to increase AP further and to decrease RBF. The increase in PRA caused by i.v. quipazine is secondary to renal hemodynamics and is unrelated to CNS actions of this drug.
Angiotensin II↗
The cardiovascular effects of quipazine are mediated by peripheral 5-HT2 and 5-HT3 receptors in anaesthetized rats.
Quipazine (0.5-2 mg/kg i.v.) produced transient hypotension and bradycardia followed by sustained hypertension and variable effects on heart rate in anaesthetized rats. The hypotension, bradycardia and sympatho-inhibitory effects of quipazine were attenuated by bivagotomy. In bivagotomized rats, the hypertension produced by quipazine was not modified by hexamethonium or prazosin but was abolished by ritanserin (1 mg/kg i.v.). In ritanserin-treated rats, section of the carotid sinus nerves and vagus nerves or ICS 205.930 (0.1 mg/kg i.v.) abolished the hypotensive, bradycardic and sympatho-inhibitory effects of quipazine; the action of quipazine was not reproducible in these rats. Quipazine also inhibited the Bezold-Jarish reflex elicited by 5-HT (20 micrograms/kg i.v.). In ICS 205.930-treated rats, the hypertension evoked by quipazine was associated with a reduction in splanchnic nerve activity due to stimulation of baroreceptors. The renin-angiotensin system is not involved in the hypertensive response. The increase in heart rate produced by quipazine in bivagotomized rats was reduced by ritanserin and tertatolol (0.1 mg/kg i.v.) and abolished by a combination of both drugs. We conclude that the bradycardic and sympatho-inhibitory effects of quipazine result from activation of 5-HT3 receptors located in the cardiopulmonary area and of carotid body chemoreceptors. The hypertension and tachycardia are mediated by vascular and myocardial 5-HT2 receptors. No evidence was obtained for a central sympatho-excitatory effect.
Amidines↗
Antagonism of 5-hydroxytryptamine receptors by quipazine.
1 The antagonist actions of quipazine on 5-hydroxytryptamine (5-HT) receptors have been investigated in the rabbit isolated superior cervical ganglion and on the rat isolated spinal cord and stomach strip. 2 Changes in membrane potential induced by 5-HT or by the nicotinic agonist, 1,1-dimethyl-4-phenyl piperazinium (DMPP), were measured in the ganglion by the sucrose-gap technique. At ganglionic receptors, quipazine had little or no agonist activity, but greatly depressed depolarizations evoked by 5-HT but not depolarizations evoked by DMPP or trimethylammonium (TMA). Injections into the superfusion stream to the ganglion of 2 to 5 mumol quipazine in a small volume of Krebs solution prevented all subsequent responses to 5-HT. Superfusion of the ganglion with quipazine at a concentration of 1 microM produced complete blockade of responses to 5-HT in 3 of 6 ganglia and reduced responses by over 90% in 2 others; responses to DMPP were potentiated in amplitude and duration. Superfusion at a concentration of 0.1 microM depressed responses to 5-HT by 75% on average. The threshold concentration for the blocking action was around 0.01 microM, which depressed responses by 42% on average in 6 experiments (range 0 to 75%). 3 5-HT (1 microM or 100 microM) depressed the amplitude of the dorsal root potentials recorded from the isolated, hemisected cord of the neonate rat by 27 +/- 5% (mean +/- s.e. mean, n = 14) and by 45 +/- 6% (n = 14), respectively. In the presence of quipazine (0.01 microM), 5-HT (1 microM or 100 microM) depressed the amplitude by 6 +/- 2% (n = 15) and by 3 +/- 1% (n = 7), respectively. 4 Concentration-response curves of the contractions induced by 5-HT in the fundus of the rat stomach were obtained in the absence and presence of quipazine. Quipazine (1 microM) shifted the concentration-response curve to the right and depressed the maximum, suggesting a non-competitive mode of antagonism. pI50 values were calculated in order to assess the antagonist activity of quipazine at rat fundus 5-HT receptors; the mean pI50 was 6.91 +/- 0.2 (n = 6). 5 It is concluded that quipazine may be an effective antagonist at 5-HT receptors in various tissues.
Animals↗
Spinal cord-transected mice learn to step in response to quipazine treatment and robotic training.
In the present study, concurrent treatment with robotic step training and a serotonin agonist, quipazine, generated significant recovery of locomotor function in complete spinal cord-transected mice (T7-T9) that otherwise could not step. The extent of recovery achieved when these treatments were combined exceeded that obtained when either treatment was applied independently. We quantitatively analyzed the stepping characteristics of spinal mice after alternatively administering no training, manual training, robotic training, quipazine treatment, or a combination of robotic training with quipazine treatment, to examine the mechanisms by which training and quipazine treatment promote functional recovery. Using fast Fourier transform and principal components analysis, significant improvements in the step rhythm, step shape consistency, and number of weight-bearing steps were observed in robotically trained compared with manually trained or nontrained mice. In contrast, manual training had no effect on stepping performance, yielding no improvement compared with nontrained mice. Daily bolus quipazine treatment acutely improved the step shape consistency and number of steps executed by both robotically trained and nontrained mice, but these improvements did not persist after quipazine was withdrawn. At the dosage used (0.5 mg/kg body weight), quipazine appeared to facilitate, rather than directly generate, stepping, by enabling the spinal cord neural circuitry to process specific patterns of sensory information associated with weight-bearing stepping. Via this mechanism, quipazine treatment enhanced kinematically appropriate robotic training. When administered intermittently during an extended period of robotic training, quipazine revealed training-induced stepping improvements that were masked in the absence of the pharmacological treatment.
Animals↗
Activation of serotonin2 (5-HT2) receptors by quipazine increases arterial pressure and renin secretion in conscious rats.
Quipazine, a nonselective serotonin (5-HT) agonist, has been shown to increase plasma renin activity (PRA). The present study examined the effects of quipazine on mean arterial pressure (MAP), heart rate (HR) and PRA in conscious, chronically catheterized male rats. Quipazine caused dose (0.3-3.0 mg/kg i.v.)-and time (up to 30 min)-dependent increases in MAP and PRA. The maximum increases in MAP (control = 94 +/- 2 mm Hg, 3 mg/kg = 155 +/- 1 mm Hg) and PRA (nanograms of angiotensin 1 per milliliter per hour; control = 2.5 +/- 0.2, 3 mg/kg = 25.2 +/- 5.9) were observed 5 min after quipazine. HR tended to decrease, but a significant bradycardia was observed only 15 min after 3 mg/kg. The selective 5-HT2 antagonist LY 53857 (1 mg/kg i.v.) did not affect MAP, HR or PRA per se, but at 0.03 to 1.0 mg/kg totally abolished the pressor response to quipazine (3 mg/kg). At 0.01 mg/kg, LY 53857 attenuated quipazine-induced hypertension, whereas 0.003 mg/kg was ineffective. Total blockade of quipazine-induced renin secretion was produced by LY 53857 at 0.003 mg/kg, and the response was still reduced by 50% at 0.001 mg/kg. In summary, although quipazine increases arterial pressure and renin secretion, endogenous 5-HT does not tonically control MAP or PRA in conscious, unrestrained, normotensive rats through 5-HT2 receptors. The 10-fold difference in the dose of LY 53857 necessary to block the pressor and renin responses may be due to subtle differences in receptor subtypes, or to pharmacokinetic properties favoring antagonism of quipazine-induced renin secretion.
Animals↗
Quipazine-induced head-twitch in mice.
Quipazine has been reported to be a direct serotonin receptor agonist. In this laboratory, quipazine produced head-twitch in mice similar to that produced by the serotonin precursor, 5-hydroxytryptophan (5-HTP). Three antiserotonergic drugs (methiothepin, methysergide, and cinanserin) antagonized both the 5-HTP and quipazine-induced head-twitch responses. In addition, the quipazine response was significantly potentiated by a monoamine oxidase (MAO) inhibitor, pargyline. Since it is not likely that quipazine itself is metabolized by MAO, these results suggested that quipazine might cause release of endogenous serotonin. Parachlorophenylalanine, a serotonin depletor, significantly antagonized the potentiation of quipazine by the MAO inhibitor but failed to antagonize the head-twitch produced by quipazine itself. The present studies suggest that quipazine influences serotonin receptors in the brain to produce head-twitch by two mechanisms of action: (1) by direct serotonin receptor activation, and (2) indirectly by causing a release of endogenous serotonin.
5-Hydroxytryptophan↗
Behavioral effects of quipazine in the cat.
Administration of quipazine to cats elicits a number of behaviors, such as limb flicking abortive grooming, investigatory behavior and hallucinatory-like behavior, which we have previously proposed as an animal behavioral model for studying the actions of LSD and related hallucinogens. While recent studies have indicated that these model behaviors may not be totally specific for hallucinogenic drugs, the model can still be useful for studying drug action. Quipazine (0.5-5.0 mg/kg i.p.) produced significant increases in limb flicking, abortive grooming, investigatory behavior, hallucinatory-like behavior grooming, head and body shakes, staring and yawning. These behavioral changes persisted for 1-6 h, depending on the dose of quipazine employed. Administration of quipazine (5.0 mg/kg per day) for 5 consecutive days produced no significant tolerance effect on any of these model behaviors. These quipazine induced behavioral changes were potentiated by pretreatment with apomorphine, and partially blocked by pretreatment with haloperidol. Quipazine-induced behavioral changes were potentiated by prior serotonin depletion with p-chlorophenylalanine, and completely blocked by pretreatment with a monoamine oxidase inhibitor or the serotonin precursor, L-5-hydroxytryptophan. These quipazine-induced behavioral changes were also blocked by pretreatment with the serotonin receptor blockers, cinnanserin, methysergide or cyproheptadine. The mechanism of action of quipazine, as well as the neuropharmacology of the limb flick model, is discussed in the content of these studies with serotonergic and dopaminergic drugs.
Animals↗
Effects of quipazine on pre- and postsynaptic serotonin receptors: single cell studies in the rat CNS.
Many behavioural and biochemical studies have pointed to an agonistic activity of quipazine on serotonin (5-HT) receptors. In the present electrophysiological study, the effect of quipazine on pre- and postsynaptic 5-HT receptors in the rat was studied. Quipazine, administered intravenously, depressed the firing rate of 5-HT-containing dorsal raphe neurones (ED50 = 0.82 mg/kg). Microiontophoretic applications of quipazine on 5-HT-containing neurones in the dorsal raphe and on neurones of two forebrain regions receiving a 5-HT input (the ventral lateral geniculate nucleus and the dorsal hippocampus) consistently depressed neuronal firing rate as did 5-HT and D-lysergic acid diethylamide (LSD). Quipazine was more potent on 5-HT neurones than on the ventral lateral geniculate nucleus and hippocampal neurones: the post/presynaptic efficacy ratio for quipazine was similar to that of LSD. Following a selective denervation of 5-HT neurones with intraventricular injection of 5,7-di-hydroxy-tryptamine in desipramine-pretreated rats, the responsiveness of neurones in the ventral lateral geniculate nucleus to quipazine, applied microiontophoretically, was increased as was that to 5-HT and to LSD. These results provide direct evidence for the agonistic activity of quipazine on both pre- and postsynaptic 5-HT receptors.
Animals↗
Stimulus generalization by fenfluramine in a quipazine-ketanserin drug discrimination is not dependent on indirect serotonin release.
The purpose of this study was to determine if animals trained to discriminate a serotonin2A (5-HT2A) receptor agonist from a 5-HT2A receptor antagonist would also be sensitive to alterations in serotonin neurotransmission brought about by 5-HT reuptake inhibitors and releasers. Previous work from our laboratory has shown that the quipazine-ketanserin discrimination is mediated solely by the 5-HT2A receptor, thus providing a behavioral continuum of 5-HT2A receptor function. Rats were trained to discriminate quipazine (0.35 mg/kg) from ketanserin (1.0 mg/kg) on a variable interval-30 schedule of reinforcement. Following acquisition, substitution tests were conducted with the training drug, quipazine, and agents that have been shown to alter the synaptic levels of 5-HT, including fenfluramine, norfenfluramine, 5-methoxy-6-methyl-2-aminoindan (MMAI) and fluoxetine. All compounds substituted, except fluoxetine. Antagonist tests with mianserin and MDL 100,907 indicated that fenfluramine's and MMAI's substitution for quipazine was mediated by the 5-HT2A receptor. Animals were pretreated with PCPA to determine whether 5-HT release or direct agonism mediated the discriminative stimulus effects of fenfluramine and MMAI. PCPA blocked the substitution of MMAI but not of fenfluramine for quipazine. Analysis of 3H-IP formation in cells showed that norfenfluramine dose-dependently stimulated phosphoinositide hydrolysis to levels similar to that of serotonin and quipazine. These results indicate that fenfluramine's substitution for quipazine in rats trained on a quipazine-ketanserin discrimination are due to direct agonism at the 5-HT2A receptor likely mediated by norfenfluramine, an active metabolite.
Animals↗
Preweaning cocaine administration alters the adult response to quipazine: comparison with fluoxetine.
This study investigated whether exposure to cocaine during the preweaning period affects the behavioral response to administration of a challenge dose of quipazine, a relatively nonselective serotonin (5-HT) mixed agonist/antagonist, in adulthood. To determine whether selective inhibition of the 5-HT transporter during the preweaning period would produce a cocaine-like pattern of effects, another group of rats was given fluoxetine, a highly selective and potent inhibitor of the 5-HT transporter, and was tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg cocaine HCl (82.5 mumol/kg), 25 mg/kg fluoxetine HCl (72.3 mumol/kg), or vehicle subcutaneous (s.c.) during postnatal days 11-20. Both treatments reduced weight gain during the injection period only. At 60 days of age, subjects were administered a single dose of quipazine (0, 0.4, or 1.0 mg/kg, s.c.) and placed in the Accuscan activity monitor for 1 h of behavioral recording. Overall, distance traveled, vertical activity, and time in the center of the chamber decreased during the initial time blocks of the session and vertical activity decreased with increasing doses of quipazine. Females in general showed greater overall activity levels than males as well as greater responsivity to quipazine. Preweaning cocaine exposure produced different effects in males and females. In males, cocaine enhanced the response to quipazine for vertical activity whereas it had no effect on quipazine-induced alterations on the other two behaviors. On the other hand, cocaine-treated females showed dampened dose-related quipazine responses across all behavioral measures. Fluoxetine administration produced a dampening of the quipazine effect for vertical activity and distance traveled in males and females. Therefore, these data indicate that cocaine administration during the preweaning period of development produced an increase in the effect of a serotonergic drug to alter vertical activity in males and a global dampening of the behavioral responses to that same drug in females. Preweaning fluoxetine treatment produced effects that resembled those produced by cocaine in females, a dampening of serotonergic responsivity, along with an overall decrease in locomotor activity. Because the majority of effects are seen during the initial portion of the behavioral session, a time of heightened activity in response to a novel environment, the data suggest that inhibition of the 5-HT transporter during the preweaning period alters serotonergic influences over novelty-induced activity but that brief periods of inhibition or other actions of cocaine, such as those at the catecholamine transporters, prevent this from happening, particularly in males.
Animals↗
Time- and dose-dependent effects of the serotonergic agent quipazine on regional cerebral metabolism in rats.
The time course and the relation to dose of regional cerebral metabolic rates for glucose (rCMRglc) were measured in awake male adult Fischer-344 rats after administration of quipazine, a serotonin 5-HT2-3 receptor agonist. rCMRglc was determined, using the quantitative autoradiographic [14C]deoxyglucose technique, in 92 brain regions at 30, 60, 90 and 120 min after quipazine 20 mg/kg i.p. and at 60 min after quipazine 5 mg/kg i.p. Peak metabolic effects were observed 60 min after quipazine 20 mg/kg i.p. when rCMRglc was significantly elevated in 27 (29%) brain regions (mean rise 17%). Quipazine increased rCMRglc in brain regions with high densities of 5-HT3 receptors (area postrema, olfactory tubercle, amygdala), in dopaminergic nuclei (substantia nigra pars compacta and pars reticulata) and terminal fields of their projections (zona incerta, subthalamic nucleus, preoptic magnocellular area, nucleus of facial nerve). The topographic distribution and direction of rCMRglc changes induced by quipazine are different from those produced by the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and, consistent with the pharmacological and binding properties of quipazine, suggest a preferential activation of 5-HT3 receptors.
Amphetamines↗
Quipazine-induced hypertension in anaesthetized cats is mediated by central and peripheral 5-HT2 receptors: role of the ventrolateral pressor area.
Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.
Animals↗
Effects of parachlorophenylalanine, quipazine and cyproheptadine on growth hormone and adrenocorticotropin secretion in steers.
Adrenergic and perhaps dopaminergic neurons provide inhibitory regulation of growth hormone (GH) secretion in ruminants. This suggests that either serotonergic or other neurons regulate the stimulatory release of GH. The nature of neurotransmitter control of adrenocorticotropin (ACTH) secretion in ruminants has not been determined. Parachlorophenylalanine (PCPA; serotonin synthesis inhibitor), quipazine (serotonin receptor agonist) and cyproheptadine (serotonin receptor antagonist) were utilized in Holstein steers to determine whether serotonin receptors mediate stimulatory actions on GH and ACTH secretion. PCPA (100 mg/kg BW) administered each day at 1900 hr for three successive days did not alter mean GH concentrations, amplitude of GH peaks, nor the number of GH peaks. Likewise, PCPA altered none of these parameters for ACTH. Quipazine injected iv at .1 or .5 mg/kg BW increased plasma GH (P less than .05) and ACTH (P less than .001) concentrations. There was a dose effect of quipazine on both GH (P less than .05) and ACTH (P less than .0001) secretion. Pretreatment of steers with cyproheptadine (.06 and .6 mg/kg BW) reduced the stimulation of GH by quipazine (P less than .0001) and decreased basal GH concentrations (P less than .0004). Cyproheptadine at .06 mg/kg BW did not alter quipazine effects on ACTH, however, the higher dose decreased the peak ACTH response (P less than .02) to quipazine. Studies with quipazine and cyproheptadine indicated that serotonergic mechanisms are likely involved in the regulation of GH and ACTH secretion in steers.
Adrenocorticotropic Hormone↗