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The effect of ketamine hydrochloride anesthesia on basal and N -methyl-D,L -aspartate induced plasma prolactin secretion in the adult male rhesus monkey
Life Sciences 68 (2001) 1083–1093
Pharmacology letters Accelerated communication
The effect of ketamine hydrochloride anesthesia on basal and N-methyl-D,L-aspartate induced plasma prolactin secretion in the adult male rhesus monkey S.S.R. Rizvia,*, S. Altaf b, A.A. Naseemb, M. Asif b, Z. Rasulb, M. Qayyumc a
b
Pakistan Science Foundation, Constitution Avenue, G-5/2, Islamabad, Pakistan Department of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan c University of Arid Agriculture, Rawalpindi, Pakistan (Submitted February 29, 2000; accepted May 24, 2000; received in final form September 11, 2000)
Abstract The excitatory amino acids (EAAs), glutamate and aspartate, acting predominantly on N-methylD-aspartate (NMDA) receptor, have been shown to be involved in the central regulation of the secretion of several anterior pituitary hormones including prolactin (PRL), whereas ketamine hydrochloride (KH), a widely used anesthetic, has been reported to antagonize a variety of NMDA receptor mediated actions of these EAAs. In the present study, the effect of KH on basal PRL levels as well as on Nmethyl-D,L-aspartate (NMA), an agonist of NMDA receptor, induced plasma PRL secretion was investigated in the adult male rhesus monkey. The values were compared to those obtained from the same animals restrained in primate chairs. The plasma PRL concentrations were higher in animals receiving KH administered either intramuscularly (2.5 mg/kg BW at 30 min intervals) or intravenously (10 mg/kg BW) as compared to those observed in the unanesthetized chair-restrained monkeys. NMA induced an unequivocal increase in plasma PRL concentrations in both conscious chair-restrained and KH anesthetized monkeys, but the response was greater in anesthetized animals than the conscious monkeys. The present findings suggest that KH has stimulatory effects on both basal and NMA induced plasma PRL secretion. © 2001 Elsevier Science Inc. All rights reserved. Keywords: N-methyl-D-aspartate receptor; Ketamine hydrochloride; Prolactin; Male rhesus monkey
Introduction The excitatory neurotransmitters, glutamate and aspartate, acting on glutamate receptors of N-methyl-D-aspartate (NMDA) subtype have been shown to stimulate the release of sev* Corresponding author: Tel.: 92-51-9204033; fax: 92-51-9202468. E-mail address: [email protected] (S.S.R. Rizvi) 0024-3205/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 0 )0 1 0 1 0 -9
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eral anterior pituitary hormones including luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) via the release of their respective releasing factors from the hypothalamus [1,2]. There is substantial evidence demonstrating that N-methyl-D,L-aspartate (NMA), a potent structural analogue of aspartate, elicits the release of pituitary hormones in rodents [3–6] and primates [7–9]. While the increase in LH [3,5] and GH [4,6] secretion in response to NMA has been shown to be mediated via the release of their respective releasing factors, the increased secretion of PRL as a result of NMA stimulation is also presumably occasioned by the discharge of a PRL releasing factor (PRF) from the hypothalamus [1,2]. Evidence has also accumulated indicating that dissociative anesthetic ketamine hydrochloride (KH) and its analogue phencyclidine (PCP) antagonize a variety of behavioral and physiological actions of excitatory amino acids (EAAs) particularly those involving NMDA receptor [10–18]. Furthermore, it has been demonstrated that the antagonistic effect of these anesthetics is also exerted on NMDA receptor mediated release of anterior pituitary hormones [19]. It has been documented that administration of PCP inhibits the release of LH in response to agonists of NMDA receptor such as glutamate and homocysteic acid [19]. On the other hand, PCP, when given alone, has been shown to significantly stimulate the release of LH [19]. These observations suggest that PCP has direct opposite actions on the secretion of LH, stimulating the basal LH secretion, while inhibiting the release of LH in response to NMDA receptor stimulation. Although, KH has been reported to elevate basal circulating levels of PRL in primates [20–23], it is not known whether KH affects the NMDA dependent release of PRL. The present investigation was, therefore, designed to systematically examine the changes in peripheral concentrations of PRL following administration of KH in the male rhesus monkey. In addition, the responses of PRL to NMA stimulation in both the presence and the absence of KH anesthesia were studied in this primate species. Materials and methods Animals Three intact rhesus monkeys weighing 8–12 kg were used in these experiments. The animals maintained under standard colony conditions were housed in individual cages and were provided with standard monkey food supplemented with fresh fruits and vegetables. Water was available ad libitum. Pharmacologic agents Ketamine hydrochloride (Ketavet) and N-methly-D,L-aspartate were purchased from Parke Davis and Company, Freiberg, FRG and Sigma Chemical Company, St. Louis, MO, USA respectively. Catheterization Before handling, the animals were anesthetized (5 mg/kg, im) and while under sedation were fitted with a teflon cannula (Venflon 2, 1.0 mm O.D.; Viggo-Spactramed, Helsingborg, Sweden) in the sephanous vein. The cannula was attached to a 10 cm long extension tube fit-
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ted with a 3-way stopcock (Viggo Product, Viggo AB, Helsingborg, Sweden). A syringe was attached to the stopcock of the extension tube. Blood sampling and the infusion of the drugs were carried out either under KH anesthesia (2.5 mg/kg BW at 30 min intervals) or in conscious animals restrained in primate chairs. For test in the conscious monkeys, the animals under KH sedation were restrained in primate chairs and were allowed to regain full consciousness before the initiation of the blood sampling. The monkeys were accustomed to the primate chairs during 2 mo prior to these experiments by being placed in the chairs for a period of approximately 28 h each wk. Before and during the experiments, the chair-restrained animals were isolated and kept in a quiet room to minimize stress-evoked responses. Bleedings Sequential blood samples (z1.3 ml) were obtained at 10 min intervals for a period of 2 h in heparinized syringes. Following each sampling, an equal volume of heparinized (5 IU/ml) normal saline was injected into the tubing. The bleedings were carried out between 1330 and 1530 h to minimize diurnal variations. Blood samples were immediately centrifuged at 3000 rpm for 10 min. Plasma was separated and stored at 2158C until analyzed. Experimental protocol Effect of multiple intramuscular injections of KH on plasma PRL concentrations in adult male rhesus monkeys Sequential blood samples were obtained at 10 min intervals from 3 conscious chairrestrained adult male rhesus monkeys for a period of 2 h. Three days later, using identical blood sampling regimen, the same animals were bled under multiple intramuscular injections of KH anesthesia (initial dose 5 mg/kg BW followed by 2.5 mg/kg BW at 30 min intervals). Effect of a single iv injection of KH on plasma PRL concentrations in conscious chair-restrained adult male rhesus monkeys Three conscious chair-restrained adult male rhesus monkeys received a single iv injection of KH (10 mg/kg BW) delivered through the sample line. Blood samples were withdrawn at 10 min intervals 50 min before and 70 min after the injection. Effect of a single iv injection of NMA on plasma PRL concentrations in conscious chair-restrained and KH anesthetized adult male rhesus monkeys Three conscious chair-restrained adult male monkeys were injected with NMA (15 mg/kg BW) via the cannula. Blood samples were collected 50 min before and 70 min after the NMA injection at 10 min intervals. Three days later, using identical blood sampling regimen, the same animals were bled under KH anesthesia. Hormonal analysis Plasma PRL was measured by RIA method described previously [24]. All samples were assayed in duplicate. The intra-assay variation for these assays was 6 %. To avoid inter-assay variations, all samples from a serial study were measured in a single assay. All the data from RIA were pooled according to appropriate experimental grouping and statistically analyzed
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by the Student’s t test for comparison of differences between means. A value of p,0.05 was taken as significant. Results Effect of multiple intramuscular injections of KH on plasma PRL concentrations in adult male rhesus monkeys The mean plasma PRL profiles of monkeys treated with either vehicle or multiple intramuscular injections of KH are shown in Fig. 1. Serum PRL levels increased progressively in monkeys, which received multiple intramuscular injections of KH at 30 min intervals. Injections of vehicle (normal saline) alone in the same chair-restrained monkeys did not influence PRL secretion. The mean plasma PRL concentrations in conscious chair-restrained animals were 26263.2 mU/L, which upon receiving multiple intramuscular injections of KH increased to 834656 mU/L. The increase in PRL secretion following multiple intramuscular injections of KH was significant (p,0.05). Effect of a single iv injection of KH on plasma PRL concentrations in conscious chair-restrained adult male rhesus monkeys The mean plasma PRL concentrations before and following a single iv injection of KH in conscious chair-restrained animals are given in Fig. 2. The mean plasma PRL concentrations rose significantly (p,0.05) from 240620 mU/L prior to the administration of the drug to 5786191 mU/L within 20 min of KH injection and reached a maximum of 6786200 mU/L at 30 min of administration. Circulating PRL concentrations then declined progressively to reach levels slightly above the baseline levels at 70 min post injection. Effect of a single iv injection of NMA on plasma PRL concentrations in conscious chair-restrained and KH anesthetized adult male rhesus monkeys The mean plasma PRL concentrations in conscious chair-restrained and KH anesthetized monkeys treated with a single iv injection of NMA are presented in Fig. 3. In conscious chair-restrained animals, the plasma PRL concentrations increased significantly (p,0.05)
Fig. 1. Moment to moment changes in plasma PRL concentration in a group of monkeys (n53) treated with either vehicle (closed circles) or multiple intramuscular injections of KH (closed squares).
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Fig. 2. Moment to moment changes in plasma PRL secretion in a group of monkeys (n53) before and after a single iv injection of KH.
from 289683 mU/L to 612672 mU/L within 10 min of NMA administration. Circulating levels then declined progressively to reach levels of 298683 mU/L at 70 min post injection. In KH anesthetized monkeys treated similarly, a significant increase (p,0.05) in plasma PRL was noticed at 10 min following NMA injection. The mean plasma PRL concentrations rose rapidly from 565651 mU/L to 1396682 mU/L, which declined progressively to 577659 mU/L at 70 min post injection. The release of PRL in response to NMA injection was greater in KH anesthetized animals than the conscious monkeys. Discussion The present data demonstrate a marked increase in PRL secretion following intramuscular or intravenous administration of KH anesthesia to adult male rhesus monkeys. Serum PRL levels showed a marked progressive increase in successive blood samples from monkeys, which received 5 mg/kg BW of KH intramuscularly initially and 2.5 mg/kg BW KH every 30 min thereafter for a period of 2 h. No significant change in serum PRL levels was seen in the blood samples obtained from the conscious chair-restrained controls. An increase in PRL secretion in response to KH has previously been reported in monkeys [20–23]. Wickings and Nieschlag [21] have reported initial lower PRL levels in anesthetized (8–12 mg/kg/h KH, im)
Fig. 3. Moment to moment changes in plasma PRL secretion in conscious chair-restrained (closed circles) and KH anesthetized (closed squares) monkeys (n53) before and after a single iv injection of NMA.
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animals, which increased 2–3 fold after 90 min of the administration of the drug. However, the value at 3 h was not shown to be significantly different from those in conscious animals. In contrast to these observations, our findings indicate higher initial PRL concentrations in anesthetized monkeys as compared to those in conscious animals. Furthermore, we have observed that PRL levels attained a plateau at 90 min post treatment and remained more or less unchanged during the remaining test period. Similar PRL profiles following multiple injections of the anesthetic to male rhesus monkeys have been reported by Puri et al. [22]. Challenge with a single iv injection of KH to unanesthetized chair-restrained adult male rhesus monkeys also resulted in an unequivocal increase in plasma PRL concentrations within 20 min of the injection. A similar pattern of increase in peripheral concentrations of PRL has been reported in male rhesus monkeys following a single injection of the anesthetic administered through the intramuscular route [22]. A comparable PRL response to the acute administration of the anesthetic has also been reported in other species of monkeys. Thus, Aidara et al. [23] noticed a significant, but transient rise of serum PRL following a single intramuscular injection of KH to mangabey and petas monkeys of both sexes. Likewise, intravenous infusion of KH has been shown to increase the plasma concentrations of PRL significantly [17] and dose dependently [18] in young healthy men. In this investigation, NMA induced a significant increase in plasma PRL concentrations in conscious chair-restrained animals. This observation is in agreement with the previous data, which demonstrate that NMA can elicit a several fold increase in plasma PRL levels in unanesthetized normal cycling female [7] and prepubertal GnRH primed male [25] rhesus monkeys. Likewise, NMA evoked an unequivocal increase in plasma PRL secretion in KH anesthetized monkeys in our current study. A marked PRL response to a single iv injection of NMA has earlier been reported in KH anesthetized adult intact and testosterone treated orchidectomized rhesus monkeys [24]. A striking finding of the present study is that the stimulatory effect of KH on plasma PRL secretion is also evident during the challenge dose of NMA to adult male rhesus monkeys. NMA induced a significant increase in plasma PRL secretion in both conscious chair-restrained and KH anesthetized adult male rhesus monkeys. Nevertheless, the magnitude of the rise in plasma PRL levels following NMA injection was markedly greater in anesthetized monkeys as compared to conscious animals. In line with this finding is the observation that KH potentiates the stimulation of PRL release in response to an antagonist of dopamine receptor, haloperidol, in young healthy men [17]. In contrast, PCP, an analogue of KH, has been shown to inhibit the stimulatory effect of the agonists of NMDA receptor on plasma LH release in rats [19]. Although, both KH and NMA induce an increase in PRL release, the temporal patterns of PRL increase following the two treatments are markedly different from each other suggesting that the underlying neuroendocrine mechanisms may be different. Whereas a single iv injection of NMA induced a prompt increase in PRL levels within 10 min of administration, there was no change in circulating PRL concentrations in animals treated with a single iv injection of KH after 10 min of the administration of the drug and peak levels were obtained 30 min post injection. The precise mechanism underlying the stimulation of PRL secretion by NMA is not well understood. The secretion of PRL from the pituitary lactotropes is stimulated by PRF and inhibited by PRL inhibiting factor [26]. The identity of a specific PRF has not yet been confirmed, but many neuropeptides such as thyrotropin releasing hormone (TRH) and
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vasoactive intestinal peptide (VIP) in the paraventricular nucleus and oxytocin in the arcuate nucleus have been shown to stimulate the secretion of PRL [26]. The principal inhibitory factor, dopamine, is released from the tuberoinfundibular dopaminergic neurons directly into the hypophyseal portal vein to inhibit the release of PRL from pituitary lactotropes [26]. Thus, NMA may stimulate plasma PRL secretion through its effects on either TRH, VIP and oxytocin or dopamine, since NMDA has been reported to induce c-Fos immunoreactivity in dopaminergic neurons in the mediobasal hypothalamus [27]. The mechanism whereby KH stimulates basal and NMA induced plasma PRL secretion is also not known. Nevertheless, a number of recent studies have indicated that KH may stimulate PRL secretion by either potentiating the glutamatergic neurotransmission at non-NMDA receptors or by inhibiting the release of dopamine from tuberoinfundibular dopaminergic neurons. It has been demonstrated that low doses of KH increase the release of glutamate in components of cortico-striato-thalamic pathway [28,29]. The increase in glutamate release in response to low doses of KH may stimulate glutamatergic neurotransmission at the nonNMDA receptors, including AMPA and kainate receptors, since the NMDA receptor is already antagonized by KH. That non-NMDA receptors are involved in the control of PRL secretion is evidenced by the observation that treatment of rats with antagonists of AMPA and kainate receptors significantly attenuates the preovulatory PRL surge [30] and sucklinginduced PRL release [31]. On the other hand, the potentiation by KH of haloperidol induced plasma PRL secretion in young healthy men [17] indicates that KH may stimulate PRL secretion by inhibiting the release of dopamine from tuberoinfundibular dopaminergic neurons. A variety of secondary sites of action of KH may also modulate the secretion of PRL in response to KH administration. KH binds to opioidergic [32], sigma [33] and monoaminergic [34] receptor sites in the brain. It has been demonstrated that KH has a modest affinity for and interacts stereoselectively at mu opioid receptors [32], whereas activation of mu opioid receptors has been reported to lead to a sustained increase in glutamate synaptic effectiveness at the NMDA receptor level [35–37]. Furthermore, the agonists of mu opioid receptors have been shown to stimulate basal [38,39] and suckling induced [40] plasma PRL secretion by inhibiting the tuberoinfundibular dopamine turnover [41–43] and release into the hypophyseal portal system [44,45]. Taken together, these observations suggest that KH may stimulate plasma PRL secretion via its effects on mu opioid receptors. Alternatively, the actions of KH at sigma receptor sites may also contribute to KH induced plasma PRL secretion. KH has a high affinity for sigma receptor sites [46,47] and sigma receptor ligands have been reported to antagonize a number of NMDA receptor mediated functions of EAAs [48–50]. Nevertheless, low doses of sigma receptor ligands have been shown to increase the sensitivity of CA3 hippocampal neurons to local administration of NMDA [51,52]. Moreover, sigma receptor ligands have been known to affect the secretion of PRL [53–56]. Finally, the stimulation of plasma PRL secretion by KH may involve its interactions at monoamine uptake sites. At subanesthetic doses, KH has high affinity and activity at the dopamine transporter sites [57–59]. It has been reported that KH specifically and significantly enhances the monoaminergic neurotransmission by inhibiting the transporter proteins for dopamine, norepinephrine and serotonin [60,61]. In summary, the present study suggests that KH exerts a stimulatory effect on both basal and NMDA receptor mediated plasma PRL secretion.
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Acknowledgments This work was supported, in part, by the grants from the UNDP/UNFPA/WHO/World Bank’s Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization.
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Pharmacology letters Accelerated communication
The effect of ketamine hydrochloride anesthesia on basal and N-methyl-D,L-aspartate induced plasma prolactin secretion in the adult male rhesus monkey S.S.R. Rizvia,*, S. Altaf b, A.A. Naseemb, M. Asif b, Z. Rasulb, M. Qayyumc a
b
Pakistan Science Foundation, Constitution Avenue, G-5/2, Islamabad, Pakistan Department of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan c University of Arid Agriculture, Rawalpindi, Pakistan (Submitted February 29, 2000; accepted May 24, 2000; received in final form September 11, 2000)
Abstract The excitatory amino acids (EAAs), glutamate and aspartate, acting predominantly on N-methylD-aspartate (NMDA) receptor, have been shown to be involved in the central regulation of the secretion of several anterior pituitary hormones including prolactin (PRL), whereas ketamine hydrochloride (KH), a widely used anesthetic, has been reported to antagonize a variety of NMDA receptor mediated actions of these EAAs. In the present study, the effect of KH on basal PRL levels as well as on Nmethyl-D,L-aspartate (NMA), an agonist of NMDA receptor, induced plasma PRL secretion was investigated in the adult male rhesus monkey. The values were compared to those obtained from the same animals restrained in primate chairs. The plasma PRL concentrations were higher in animals receiving KH administered either intramuscularly (2.5 mg/kg BW at 30 min intervals) or intravenously (10 mg/kg BW) as compared to those observed in the unanesthetized chair-restrained monkeys. NMA induced an unequivocal increase in plasma PRL concentrations in both conscious chair-restrained and KH anesthetized monkeys, but the response was greater in anesthetized animals than the conscious monkeys. The present findings suggest that KH has stimulatory effects on both basal and NMA induced plasma PRL secretion. © 2001 Elsevier Science Inc. All rights reserved. Keywords: N-methyl-D-aspartate receptor; Ketamine hydrochloride; Prolactin; Male rhesus monkey
Introduction The excitatory neurotransmitters, glutamate and aspartate, acting on glutamate receptors of N-methyl-D-aspartate (NMDA) subtype have been shown to stimulate the release of sev* Corresponding author: Tel.: 92-51-9204033; fax: 92-51-9202468. E-mail address: [email protected] (S.S.R. Rizvi) 0024-3205/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 0 )0 1 0 1 0 -9
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eral anterior pituitary hormones including luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) via the release of their respective releasing factors from the hypothalamus [1,2]. There is substantial evidence demonstrating that N-methyl-D,L-aspartate (NMA), a potent structural analogue of aspartate, elicits the release of pituitary hormones in rodents [3–6] and primates [7–9]. While the increase in LH [3,5] and GH [4,6] secretion in response to NMA has been shown to be mediated via the release of their respective releasing factors, the increased secretion of PRL as a result of NMA stimulation is also presumably occasioned by the discharge of a PRL releasing factor (PRF) from the hypothalamus [1,2]. Evidence has also accumulated indicating that dissociative anesthetic ketamine hydrochloride (KH) and its analogue phencyclidine (PCP) antagonize a variety of behavioral and physiological actions of excitatory amino acids (EAAs) particularly those involving NMDA receptor [10–18]. Furthermore, it has been demonstrated that the antagonistic effect of these anesthetics is also exerted on NMDA receptor mediated release of anterior pituitary hormones [19]. It has been documented that administration of PCP inhibits the release of LH in response to agonists of NMDA receptor such as glutamate and homocysteic acid [19]. On the other hand, PCP, when given alone, has been shown to significantly stimulate the release of LH [19]. These observations suggest that PCP has direct opposite actions on the secretion of LH, stimulating the basal LH secretion, while inhibiting the release of LH in response to NMDA receptor stimulation. Although, KH has been reported to elevate basal circulating levels of PRL in primates [20–23], it is not known whether KH affects the NMDA dependent release of PRL. The present investigation was, therefore, designed to systematically examine the changes in peripheral concentrations of PRL following administration of KH in the male rhesus monkey. In addition, the responses of PRL to NMA stimulation in both the presence and the absence of KH anesthesia were studied in this primate species. Materials and methods Animals Three intact rhesus monkeys weighing 8–12 kg were used in these experiments. The animals maintained under standard colony conditions were housed in individual cages and were provided with standard monkey food supplemented with fresh fruits and vegetables. Water was available ad libitum. Pharmacologic agents Ketamine hydrochloride (Ketavet) and N-methly-D,L-aspartate were purchased from Parke Davis and Company, Freiberg, FRG and Sigma Chemical Company, St. Louis, MO, USA respectively. Catheterization Before handling, the animals were anesthetized (5 mg/kg, im) and while under sedation were fitted with a teflon cannula (Venflon 2, 1.0 mm O.D.; Viggo-Spactramed, Helsingborg, Sweden) in the sephanous vein. The cannula was attached to a 10 cm long extension tube fit-
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ted with a 3-way stopcock (Viggo Product, Viggo AB, Helsingborg, Sweden). A syringe was attached to the stopcock of the extension tube. Blood sampling and the infusion of the drugs were carried out either under KH anesthesia (2.5 mg/kg BW at 30 min intervals) or in conscious animals restrained in primate chairs. For test in the conscious monkeys, the animals under KH sedation were restrained in primate chairs and were allowed to regain full consciousness before the initiation of the blood sampling. The monkeys were accustomed to the primate chairs during 2 mo prior to these experiments by being placed in the chairs for a period of approximately 28 h each wk. Before and during the experiments, the chair-restrained animals were isolated and kept in a quiet room to minimize stress-evoked responses. Bleedings Sequential blood samples (z1.3 ml) were obtained at 10 min intervals for a period of 2 h in heparinized syringes. Following each sampling, an equal volume of heparinized (5 IU/ml) normal saline was injected into the tubing. The bleedings were carried out between 1330 and 1530 h to minimize diurnal variations. Blood samples were immediately centrifuged at 3000 rpm for 10 min. Plasma was separated and stored at 2158C until analyzed. Experimental protocol Effect of multiple intramuscular injections of KH on plasma PRL concentrations in adult male rhesus monkeys Sequential blood samples were obtained at 10 min intervals from 3 conscious chairrestrained adult male rhesus monkeys for a period of 2 h. Three days later, using identical blood sampling regimen, the same animals were bled under multiple intramuscular injections of KH anesthesia (initial dose 5 mg/kg BW followed by 2.5 mg/kg BW at 30 min intervals). Effect of a single iv injection of KH on plasma PRL concentrations in conscious chair-restrained adult male rhesus monkeys Three conscious chair-restrained adult male rhesus monkeys received a single iv injection of KH (10 mg/kg BW) delivered through the sample line. Blood samples were withdrawn at 10 min intervals 50 min before and 70 min after the injection. Effect of a single iv injection of NMA on plasma PRL concentrations in conscious chair-restrained and KH anesthetized adult male rhesus monkeys Three conscious chair-restrained adult male monkeys were injected with NMA (15 mg/kg BW) via the cannula. Blood samples were collected 50 min before and 70 min after the NMA injection at 10 min intervals. Three days later, using identical blood sampling regimen, the same animals were bled under KH anesthesia. Hormonal analysis Plasma PRL was measured by RIA method described previously [24]. All samples were assayed in duplicate. The intra-assay variation for these assays was 6 %. To avoid inter-assay variations, all samples from a serial study were measured in a single assay. All the data from RIA were pooled according to appropriate experimental grouping and statistically analyzed
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by the Student’s t test for comparison of differences between means. A value of p,0.05 was taken as significant. Results Effect of multiple intramuscular injections of KH on plasma PRL concentrations in adult male rhesus monkeys The mean plasma PRL profiles of monkeys treated with either vehicle or multiple intramuscular injections of KH are shown in Fig. 1. Serum PRL levels increased progressively in monkeys, which received multiple intramuscular injections of KH at 30 min intervals. Injections of vehicle (normal saline) alone in the same chair-restrained monkeys did not influence PRL secretion. The mean plasma PRL concentrations in conscious chair-restrained animals were 26263.2 mU/L, which upon receiving multiple intramuscular injections of KH increased to 834656 mU/L. The increase in PRL secretion following multiple intramuscular injections of KH was significant (p,0.05). Effect of a single iv injection of KH on plasma PRL concentrations in conscious chair-restrained adult male rhesus monkeys The mean plasma PRL concentrations before and following a single iv injection of KH in conscious chair-restrained animals are given in Fig. 2. The mean plasma PRL concentrations rose significantly (p,0.05) from 240620 mU/L prior to the administration of the drug to 5786191 mU/L within 20 min of KH injection and reached a maximum of 6786200 mU/L at 30 min of administration. Circulating PRL concentrations then declined progressively to reach levels slightly above the baseline levels at 70 min post injection. Effect of a single iv injection of NMA on plasma PRL concentrations in conscious chair-restrained and KH anesthetized adult male rhesus monkeys The mean plasma PRL concentrations in conscious chair-restrained and KH anesthetized monkeys treated with a single iv injection of NMA are presented in Fig. 3. In conscious chair-restrained animals, the plasma PRL concentrations increased significantly (p,0.05)
Fig. 1. Moment to moment changes in plasma PRL concentration in a group of monkeys (n53) treated with either vehicle (closed circles) or multiple intramuscular injections of KH (closed squares).
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Fig. 2. Moment to moment changes in plasma PRL secretion in a group of monkeys (n53) before and after a single iv injection of KH.
from 289683 mU/L to 612672 mU/L within 10 min of NMA administration. Circulating levels then declined progressively to reach levels of 298683 mU/L at 70 min post injection. In KH anesthetized monkeys treated similarly, a significant increase (p,0.05) in plasma PRL was noticed at 10 min following NMA injection. The mean plasma PRL concentrations rose rapidly from 565651 mU/L to 1396682 mU/L, which declined progressively to 577659 mU/L at 70 min post injection. The release of PRL in response to NMA injection was greater in KH anesthetized animals than the conscious monkeys. Discussion The present data demonstrate a marked increase in PRL secretion following intramuscular or intravenous administration of KH anesthesia to adult male rhesus monkeys. Serum PRL levels showed a marked progressive increase in successive blood samples from monkeys, which received 5 mg/kg BW of KH intramuscularly initially and 2.5 mg/kg BW KH every 30 min thereafter for a period of 2 h. No significant change in serum PRL levels was seen in the blood samples obtained from the conscious chair-restrained controls. An increase in PRL secretion in response to KH has previously been reported in monkeys [20–23]. Wickings and Nieschlag [21] have reported initial lower PRL levels in anesthetized (8–12 mg/kg/h KH, im)
Fig. 3. Moment to moment changes in plasma PRL secretion in conscious chair-restrained (closed circles) and KH anesthetized (closed squares) monkeys (n53) before and after a single iv injection of NMA.
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animals, which increased 2–3 fold after 90 min of the administration of the drug. However, the value at 3 h was not shown to be significantly different from those in conscious animals. In contrast to these observations, our findings indicate higher initial PRL concentrations in anesthetized monkeys as compared to those in conscious animals. Furthermore, we have observed that PRL levels attained a plateau at 90 min post treatment and remained more or less unchanged during the remaining test period. Similar PRL profiles following multiple injections of the anesthetic to male rhesus monkeys have been reported by Puri et al. [22]. Challenge with a single iv injection of KH to unanesthetized chair-restrained adult male rhesus monkeys also resulted in an unequivocal increase in plasma PRL concentrations within 20 min of the injection. A similar pattern of increase in peripheral concentrations of PRL has been reported in male rhesus monkeys following a single injection of the anesthetic administered through the intramuscular route [22]. A comparable PRL response to the acute administration of the anesthetic has also been reported in other species of monkeys. Thus, Aidara et al. [23] noticed a significant, but transient rise of serum PRL following a single intramuscular injection of KH to mangabey and petas monkeys of both sexes. Likewise, intravenous infusion of KH has been shown to increase the plasma concentrations of PRL significantly [17] and dose dependently [18] in young healthy men. In this investigation, NMA induced a significant increase in plasma PRL concentrations in conscious chair-restrained animals. This observation is in agreement with the previous data, which demonstrate that NMA can elicit a several fold increase in plasma PRL levels in unanesthetized normal cycling female [7] and prepubertal GnRH primed male [25] rhesus monkeys. Likewise, NMA evoked an unequivocal increase in plasma PRL secretion in KH anesthetized monkeys in our current study. A marked PRL response to a single iv injection of NMA has earlier been reported in KH anesthetized adult intact and testosterone treated orchidectomized rhesus monkeys [24]. A striking finding of the present study is that the stimulatory effect of KH on plasma PRL secretion is also evident during the challenge dose of NMA to adult male rhesus monkeys. NMA induced a significant increase in plasma PRL secretion in both conscious chair-restrained and KH anesthetized adult male rhesus monkeys. Nevertheless, the magnitude of the rise in plasma PRL levels following NMA injection was markedly greater in anesthetized monkeys as compared to conscious animals. In line with this finding is the observation that KH potentiates the stimulation of PRL release in response to an antagonist of dopamine receptor, haloperidol, in young healthy men [17]. In contrast, PCP, an analogue of KH, has been shown to inhibit the stimulatory effect of the agonists of NMDA receptor on plasma LH release in rats [19]. Although, both KH and NMA induce an increase in PRL release, the temporal patterns of PRL increase following the two treatments are markedly different from each other suggesting that the underlying neuroendocrine mechanisms may be different. Whereas a single iv injection of NMA induced a prompt increase in PRL levels within 10 min of administration, there was no change in circulating PRL concentrations in animals treated with a single iv injection of KH after 10 min of the administration of the drug and peak levels were obtained 30 min post injection. The precise mechanism underlying the stimulation of PRL secretion by NMA is not well understood. The secretion of PRL from the pituitary lactotropes is stimulated by PRF and inhibited by PRL inhibiting factor [26]. The identity of a specific PRF has not yet been confirmed, but many neuropeptides such as thyrotropin releasing hormone (TRH) and
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vasoactive intestinal peptide (VIP) in the paraventricular nucleus and oxytocin in the arcuate nucleus have been shown to stimulate the secretion of PRL [26]. The principal inhibitory factor, dopamine, is released from the tuberoinfundibular dopaminergic neurons directly into the hypophyseal portal vein to inhibit the release of PRL from pituitary lactotropes [26]. Thus, NMA may stimulate plasma PRL secretion through its effects on either TRH, VIP and oxytocin or dopamine, since NMDA has been reported to induce c-Fos immunoreactivity in dopaminergic neurons in the mediobasal hypothalamus [27]. The mechanism whereby KH stimulates basal and NMA induced plasma PRL secretion is also not known. Nevertheless, a number of recent studies have indicated that KH may stimulate PRL secretion by either potentiating the glutamatergic neurotransmission at non-NMDA receptors or by inhibiting the release of dopamine from tuberoinfundibular dopaminergic neurons. It has been demonstrated that low doses of KH increase the release of glutamate in components of cortico-striato-thalamic pathway [28,29]. The increase in glutamate release in response to low doses of KH may stimulate glutamatergic neurotransmission at the nonNMDA receptors, including AMPA and kainate receptors, since the NMDA receptor is already antagonized by KH. That non-NMDA receptors are involved in the control of PRL secretion is evidenced by the observation that treatment of rats with antagonists of AMPA and kainate receptors significantly attenuates the preovulatory PRL surge [30] and sucklinginduced PRL release [31]. On the other hand, the potentiation by KH of haloperidol induced plasma PRL secretion in young healthy men [17] indicates that KH may stimulate PRL secretion by inhibiting the release of dopamine from tuberoinfundibular dopaminergic neurons. A variety of secondary sites of action of KH may also modulate the secretion of PRL in response to KH administration. KH binds to opioidergic [32], sigma [33] and monoaminergic [34] receptor sites in the brain. It has been demonstrated that KH has a modest affinity for and interacts stereoselectively at mu opioid receptors [32], whereas activation of mu opioid receptors has been reported to lead to a sustained increase in glutamate synaptic effectiveness at the NMDA receptor level [35–37]. Furthermore, the agonists of mu opioid receptors have been shown to stimulate basal [38,39] and suckling induced [40] plasma PRL secretion by inhibiting the tuberoinfundibular dopamine turnover [41–43] and release into the hypophyseal portal system [44,45]. Taken together, these observations suggest that KH may stimulate plasma PRL secretion via its effects on mu opioid receptors. Alternatively, the actions of KH at sigma receptor sites may also contribute to KH induced plasma PRL secretion. KH has a high affinity for sigma receptor sites [46,47] and sigma receptor ligands have been reported to antagonize a number of NMDA receptor mediated functions of EAAs [48–50]. Nevertheless, low doses of sigma receptor ligands have been shown to increase the sensitivity of CA3 hippocampal neurons to local administration of NMDA [51,52]. Moreover, sigma receptor ligands have been known to affect the secretion of PRL [53–56]. Finally, the stimulation of plasma PRL secretion by KH may involve its interactions at monoamine uptake sites. At subanesthetic doses, KH has high affinity and activity at the dopamine transporter sites [57–59]. It has been reported that KH specifically and significantly enhances the monoaminergic neurotransmission by inhibiting the transporter proteins for dopamine, norepinephrine and serotonin [60,61]. In summary, the present study suggests that KH exerts a stimulatory effect on both basal and NMDA receptor mediated plasma PRL secretion.
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Acknowledgments This work was supported, in part, by the grants from the UNDP/UNFPA/WHO/World Bank’s Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization.
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