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PubMed1995

Cholinergic lesions by 192 IgG-saporin and short-term recognition memory: role of the septohippocampal projection.

Two experiments examined the effects of cholinergic basal forebrain lesions by intraventricular and intrahippocampal infusions of the immunotoxin 192 IgG-saporin on recognition memory in an operant delayed-non-matching-to-position task in rats. Intraventricular infusions produced extensive reductions in cortical and hippocampal choline acetyltransferase activity in the first experiment. Behaviourally, a mixed delay-dependent/independent accuracy deficit and increased biased responding was observed post-lesioning. Thus, both mnemonic as well as non-mnemonic processes were affected by the lesion. This performance deficit was indistinguishable from the impairment induced by acute intraventricular injections of the choline uptake inhibitor hemicholinium-3, which suggests that cholinergic damage induced by 192 IgG-saporin disrupted performance. In the second experiment more discrete intrahippocampal 192 IgG-saporin lesions were made, which reduced hippocampal choline acetyltransferase activity about 57%, although this reduction was not as extensive as following intraventricular injections. Although intrahippocampal lesions also impaired non-matching accuracy, this effect failed to reach significance during most stages of the experiment. Scopolamine just failed to significantly impair (P = 0.053) performance in hippocampal lesioned rats more than in controls. The nicotinic antagonist mecamylamine did not affect the lesion-induced changes in performance. These results suggest that the cholinergic basal forebrain, including the septohippocampal system, is important for the mediation of recognition memory, and muscarinic receptor-mediated mechanisms may be of greater importance than alterations of nicotinic receptor-mediated processes in the septohippocampal system.

Acetylcholinesterase↗

PubMed1975

Central effects of clonidine 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride in fowls.

1 The effects of clonidine infused into the IIIrd cerebral ventricle, the hypothalamus or intravenously were studied on behaviour, electrocortical activity, body, comb and leg temperatures, respiration and carbon dioxide elimination in adult and young fowls (Gallus domesticus). 2 Behavioural and electrocortical slow wave sleep were induced by clonidine infused into IIIrd cerebral ventricle, the hypothalamus or intravenously. Suprisingly, sleep elicited by intravenous clonidine was much longer-lasting than that induced by an identical dose given intraventricularly. 3 Body temperature was lowered by clonidine given intraventricularly or infused into the hypothalamus. Depending on initial comb temperature and ambient temperature, comb temperature was elevated, unaffected or lowered as body temperature fell; temperature of the unfeathered legs also rose as body temperature declined after clonidine. 4 Following clonidine, but before any considerable decline of body temperature, tachypnoea and wing abduction developed; during recovery of body temperature, the wings were lowered and applied closely to the trunk and the feathers partly erected. 5 CO2 elimination fell more swiftly than body temperature following intrahypothalamic clonidine in young chicks; initial recovery developed sooner than that of body temperature, but eventual recovery was delayed compared to that for body temperature. The effects of clonidine were much more marked in young chicks studied at an ambient temperature below thermoneutrality as compared to thermoneutrality. 6 The soporific effects of clonidine were attenuated by intraventricular phentolamine; its hypothermic effects were prevented by phenoxybenzamine and prevented or attenuated by phentolamine. Intraventricular atropine, haloperidol, methysergide and propranolol were ineffective. 7 Larger doses of intraventricular phentolamine elicited shivering, tachypnoea and wing abduction; body temperature was elevated, to the extent even of lethal hyperthermia. Intraventricular atropine also elevated body temperature. 8 Clonidine infused intravenously, intraventricularly or into the hypothalamus, replaced the behavioural and electrocortical arousal evoked with dexamphetamine, by sleep associated with slow wave electrocortical activity.

Animals↗

PubMed2000

Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration.

We evaluated the delivery of 14C-cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricular (IVT) infusion, and by 4) convection-enhanced delivery (CED) into the caudate nucleus. Plasma and brain AraC metabolites were measured with HPLC, and distribution and concentration of 14C-AraC in brain sections were measured by quantitative autoradiography. After IV administration, the alpha and beta plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-brain transfer constant of AraC was 2.5+/-1.4 microliter g(-1) min(-1), compatible with high water solubility. After IT and IVT administration, tissue levels were high at the brain and ventricular surfaces, but declined exponentially into brain. After CED, maximum brain levels were up to 10,000 times higher than the IV group, and the distribution pattern was one of high 14C-AraC concentration in the convective component, with exponentially declining concentrations outside this region. The rate loss constant from brain was 0.002+/-0.0004 min(-1), suggesting that AraC was accumulating in brain cells. AraC was metabolized into uracil arabinoside within the brain. 14C-AraC was infused into 1 dog and distributed widely in the ipsilateral hemisphere. These studies suggest that delivery of AraC to brain parenchyma by the IV, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, and maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery.

Animals↗

PubMed2001

Luciferase as a model for the site of inhaled anesthetic action.

UNLABELLED: The in vivo potencies of anesthetics correlate with their capacity to suppress the reaction of luciferin with luciferase. In addition, luciferin has structural resemblances to etomidate. These observations raise the issues of whether luciferin, itself, might affect anesthetic requirement, and whether luciferase resembles the site of anesthetic action. Because the polar luciferin is unlikely to cross the blood-brain barrier (we found that the olive oil/water partition coefficient was 100 +/- 36 x 10(-7)), we studied these issues in rats by measuring the effect of infusion of luciferin in artificial cerebrospinal fluid into the lumbar subarachnoidal space and into the cerebral intraventricular space on the MAC (the minimum alveolar anesthetic concentration required to eliminate movement in response to a noxious stimulus in 50% of tested subjects) of isoflurane. MAC in rats given lumbar intrathecal doses of luciferin estimated to greatly exceed anesthetizing doses of etomidate, did not differ significantly from MAC in rats receiving only artificial cerebrospinal fluid into the lumbar intrathecal space. MAC slightly decreased when doses of luciferin estimated to greatly exceed anesthetizing doses of etomidate were infused intraventricularly (P < 0.05). In contrast to the absent or minimal effects of luciferin, intrathecal or intraventricular infusion of etomidate at similar or smaller doses significantly decreased isoflurane MAC. Luciferin did not affect +-aminobutyric acid type A or acetylcholine receptors expressed in Xenopus oocytes. These results suggest that luciferin has minimal or no anesthetic effects. It also suggests that luciferin/luciferase may not provide a good surrogate for the site at which anesthetics act, if this site is on the surface of neuronal cells. IMPLICATIONS: In proportion to their potencies, anesthetics inhibit luciferin's action on luciferase, and luciferin structurally resembles the anesthetic etomidate. However, in contrast to etomidate, luciferin given intrathecally or into the third cerebral ventricle does not have anesthetic actions, and it does not affect +-aminobutyric acid or acetylcholine receptors in vitro. Luciferase may not provide a good surrogate for the site at which anesthetics act.

Anesthetics, Inhalation↗

PubMed1983

Lowered cerebrospinal fluid sodium antagonizes effect of raised blood sodium on salt appetite.

Moderately Na-deficient sheep (i.e., Na deficit = 300-400 mmol) will correct their deficit when given hypertonic NaHCO3 solution to drink. Access to NaHCO3 was provided by bar press for 2 h only each day following 22 h of salivary loss from a parotid fistula. Each delivery by bar press provided 9 mmol of NaHCO3 and, of the 46.3 +/- 2.5 deliveries made and drunk in 2 h, 80-90% were made in the first 20 min. Ten minutes before access to NaHCO3 commenced an intracarotid infusion of 4 M NaCl at 1.6 ml/min for 30 min was initiated. This infusion reduced intake by approximately 80% and increased both plasma and cerebrospinal fluid sodium concentration (CSF[Na]). Intraventricular (ivt) infusion of 0.7 M mannitol in artificial CSF at 1 ml/h for 3 h begun 1 h before access to Na by bar press lowered CSF[Na] and approximately doubled voluntary Na intake. The combination of the two procedures resulted in NaHCO3 intake similar to base line. That is, the ivt infusion of 0.7 M mannitol counteracted the inhibition of Na appetite produced by the systemic infusion of hypertonic NaCl, and this was associated with attenuation of the effect of the systemic 4 M NaCl infusion on CSF[Na]. The results suggest that the effects of both the ivt and the systemic infusions are mediated via the same sensor system located within the neuropil.

Animals↗

PubMed1975

Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections.

The kinetics and distribution of methotrexate in intraventricular and intrathecal cerebrospinal-fluid spaces were studied in patients with meningeal leukemia and meningeal carcinomatosis after drug administration by intravenous infusion, indwelling intraventricular subcutaneous reservoir (Ommaya), or standard lumbar puncture. Negligible ventricular concentrations followed a single intravenous dose. During an intravenous infusion (500 mg per square meter for 24 hours) the ventricular cerebrospinal-fluid concentration rose to 6 times 10-minus 7 M. Methotrexate administered by Ommaya reservoir, at a dose of 6.25 mg per square meter, rapidly distributed in the subarachnoid space; the peak ventricular concentration of 2 times 10-minus 4 M declined exponentially over 48 hours. Lumbar cerebrospinal-fluid concentration reached a maximum of 5 times 10-minus 5 M four hours after injection and then fell exponentially. Administration by lumbar puncture occasionally produced epidural and subdural leakage; even with successful lumbar puncture, ventricular methotrexate concentration varied considerably from patient to patient despite similar doses. Administration by Ommaya reservoir more reliably produced adequate cerebrospinal fluid distribution than administration by lumbar puncture.

Adolescent↗

PubMed2004

Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey.

Agouti-related peptide (AGRP), an endogenous melanocortin receptor antagonist, is a powerful orexigenic peptide when infused centrally. AGRP and neuropeptide Y (NPY), another orexigenic peptide, are colocated within the same neurons in the arcuate nucleus. Both NPY and AGRP mRNA expression increases during food restriction, a condition that is known to suppress the GnRH pulse generator and reproductive function. Although NPY has been shown previously to suppress LH secretion in the ovariectomized monkey, data on AGRP are lacking. In this study, we examined the effect of AGRP infusion into the third ventricle on pulsatile LH release in five adult monkeys. The 8-h protocol included a 3-h intraventricular saline infusion to establish baseline pulsatile LH release, followed by a 5-h infusion of AGRP (83-132) [5 microg/h (n=1) or 10 microg/h (n=4)]. In separate experiments, each animal received an 8-h saline treatment as a control. Blood samples were collected every 15 min for LH measurements. Cortisol levels were measured every 45 min. AGRP infusion significantly decreased LH pulse frequency (from a baseline of 0.74 +/- 0.07 pulse/h to 0.36 +/- 0.12 during AGRP infusion; P <0.01) and mean LH concentrations (to 41.1 +/- 7.5% of baseline by h 5 of AGRP infusion; P < 0.001). LH pulse amplitude was not modified by AGRP treatment. AGRP infusion also significantly increased cortisol release, as previously reported. The data demonstrate that central administration of AGRP inhibits pulsatile LH release in the monkey and suggest that AGRP, like NPY, may mediate the effect of a negative energy balance on the reproductive system by suppressing the GnRH pulse generator.

Agouti-Related Protein↗

PubMed1994

Effect of intraventricular hemorrhage on pulmonary function in newborn piglets.

Intracranial hemorrhage in the premature infant is often associated with respiratory failure and need for mechanical ventilation. We therefore addressed the question of possible interactions with and pulmonary consequences of intraventricular hemorrhage. Newborn piglets were studied during intraventricular hemorrhage simulated by intraventricular blood infusion. Infusion volume amounted to 8% of estimated brain weight. Respiratory rate, minute ventilation, lung resistance and dynamic lung compliance, as well as arterial blood gases, arterial and intraventricular pressures were measured. The piglets were mechanically ventilated with a low basal rate of 20 breaths per minute throughout the study. All piglets experienced significant rise in intraventricular pressure and respiratory failure during the study. Respiratory failure was mainly a result of a reduction in respiratory frequency and minute ventilation until apnea. However, a rise in lung resistance was also noted while lung compliance did not change. We conclude that increased need for mechanical ventilation during intracranial hemorrhage is primarilty a consequence of hypoventilation. The increase seen in lung resistance could also suggest that intraventricular hemorrhage causes an element of bronchiolar constriction. Furthermore, these effects are not only a result of the increase in intraventricular pressure, but specific effects of blood components within the central nervous system must be considered.

Airway Resistance↗

PubMed1994

I.c.v. infusions of ACPD(1S,3R) attenuate learning in a Morris water maze paradigm.

The functional role of metabotropic glutamate receptors is beginning to be understood. Cognitive effects of metabotropic receptor activation were examined in the present study in a Morris water maze following intraventricular (i.c.v.) infusions of ACPD(1S,3R). I.c.v. infusions of ACPD substantially increased the amount of time animals took to find a hidden platform in a water maze. Current results demonstrate that subtoxic doses of ACPD can produce in vivo effects with functional significance. Spatial learning abilities are impaired following activation of metabotropic receptors with ACPD(1S,3R). Negative implications are provided for the use of cognitive enhancing compounds that stimulate metabotropic glutamate receptors.

Analysis of Variance↗

PubMed1999

Comparison of 14C-sucrose delivery to the brain by intravenous, intraventricular, and convection-enhanced intracerebral infusion.

OBJECT: The authors evaluated convection-enhanced delivery (CED) of 14C-sucrose to the rat brain as a method of enhancing cerebral drug delivery and compared it with intravenous (i.v.) and intraventricular (i.v.t.) routes of administration. METHODS: Groups of rats received 14C-sucrose by bolus i.v. infusion, i.v.t. infusion for 1, 2, or 7 days at 0.17 microl/minute, or CED at rates from 0.01 to 0.5 microl/minute for periods from 1 hour to 7 days. Radioisotope distribution and concentration in tissue were analyzed using quantitative autoradiography. Intravenously administered sucrose reached the entire brain, but levels in tissue were low. After i.v.t. administration, sucrose levels in tissue were high at, and declined exponentially away from, the ventricular surface. Chronic CED administration maintained high levels of sucrose in tissue that focally were up to 10,000 times higher than in the i.v. group. The isotope distribution pattern after chronic CED infusions indicated a central component that resulted from convention and a peripheral component in gray matter that was the result of diffusion. The brain influx (0.42 microl/g/min) and diffusion constants of sucrose (2.8 x 10(-6) cm2/second) were similar to reported values. The total brain efflux constant was 0.0044 minute, whereas the blood-brain barrier (BBB) efflux constant was 0.0016 minute. There were no pathological changes in the brains after CED except those associated with cannula insertion. Sucrose, which was thought to be inert, was found to interact with brain tissue; up to 25% was bound to an unidentified tissue component. CONCLUSIONS: Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.

Animals↗

PubMed1999

Expression of the transcription factor Zif268 in the visual cortex of monocularly deprived rats: effects of nerve growth factor.

Neurotrophins are known to be involved in experience-dependent plasticity of the visual cortex. Here, we have characterized in detail the effects of intraventricular nerve growth factor infusion in monocularly deprived rats by using immunostaining for the immediate-early gene product Zif268 as a marker of functional activity with cellular resolution. We have taken advantage of the rapid regulation of Zif268 by visual input to reveal the cortical units that are responsive to the deprived eye after a period of monocular deprivation. We found that responses to the deprived eye were significantly preserved in the cortex of monocularly deprived rats infused with nerve growth factor. The effects of nerve growth factor were greater for cortical cells located in deep layers and with more peripheral receptive fields. Results from Zif268 staining correlated very well with those obtained by single-cell recordings from the visual cortex. Our results demonstrate that exogenous nerve growth factor preserves the functional input from the deprived eye, enabling cortical neurons to activate immediate-early gene expression in response to stimulation of the deprived eye. Furthermore, we show that the intraventricular infusion of nerve growth factor differentially affects the ocular dominance of cells at various depths and eccentricities in the developing cortex.

Animals↗

PubMed1998

Fatality resulting from intraventricular vincristine administration.

BACKGROUND: Inadvertent intrathecal administration of vincristine has been reported and is uniformly fatal except in two of three cases treated with spinal fluid exchange. We report a case of inadvertent direct intraventricular vincristine administration. CASE REPORT: A 59-year-old woman developed acute lymphocytic leukemia with meningeal involvement and was being treated with intraventricular cytarabine (beta-cytosine arabinoside, Ara-C) injected via an Ommaya reservoir, intravenous (i.v.) vincristine, prednisone, and i.v. daunorubicin. The vincristine (2 mg in 10 mL diluent) was inadvertently injected into her Ommaya reservoir. Within 10 minutes, the error was realized. Despite optimal care, nausea and vomiting developed the first night, followed sequentially by coarse tremor, disorientation, horizontal nystagmus, and stupor. Her mental status waxed and waned until day 9, at which time she became responsive only to noxious stimuli. By day 11, she was deeply comatose and on day 40 she died without regaining any neurological function. CONCLUSION: Despite aggressive and immediate therapy, intraventricular vincristine infusion produced neurologic toxicity, with progressive loss of mental function, followed by coma and death. Systems need to be developed to prevent inadvertent central nervous system administrations.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Encapsulated GDNF-producing C2C12 cells for Parkinson's disease: a pre-clinical study in chronic MPTP-treated baboons.

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor with restorative effects in a variety of rodent and primate models of Parkinson's disease (PD), could be of therapeutic value to PD. In this study, we show that intraventricular chronic infusion of low doses of GDNF using encapsulated genetically engineered C2C12 cells can exert: (1) transient recovery of motor deficits (hypokinesia); (2) significant protection of intrinsic striatal dopaminergic function in the immediate vicinity of the site of implantation of the capsule in the caudate nucleus, and (3) significant-long-lasting-neurotrophic properties at the nigral level with an increase volume of the cell bodies. These observations confirm the potent neurorestorative potential of GDNF in PD and the safety/efficacy of the encapsulation technology as a means to deliver in situ this neurotrophic cytokine even using an intraventricular approach.

Animals↗

PubMed2005

The role of progestin receptors and the mitogen-activated protein kinase pathway in delta opioid receptor facilitation of female reproductive behaviors.

The present study investigated the role of the progestin receptor (PR) and the mitogen-activated protein kinase (MAPK) pathway in the facilitation of lordosis behavior by the delta opioid receptor agonist [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE). Ovariectomized, estrogen-primed rats were treated with the PR antagonist RU486 or the MAPK inhibitor PD98059 prior to intraventricular (icv) infusion of DPDPE. Both RU486 and PD98059 blocked receptive and proceptive behaviors induced by DPDPE at 60 min, and RU486 continued to inhibit estrous behavior at 90 min. Because delta opioid receptors can activate the p42/44 MAPKs, extracellular signal regulated kinases (ERK), we determined the effects of DPDPE on ERK phosphorylation. Icv infusion of DPDPE increased the levels of phosphorylated ERK in the hypothalamus and preoptic area of female rats, assessed by immunoblotting. These results support the participation of the PR and the MAPK pathway in the facilitation of lordosis behavior by delta opioid receptors.

Animals↗

PubMed2006

Pigment epithelium-derived factor is a niche signal for neural stem cell renewal.

Adult stem cells are characterized by self-renewal and multilineage differentiation, and these properties seem to be regulated by signals from adjacent differentiated cell types and by extracellular matrix molecules, which collectively define the stem cell "niche." Self-renewal is essential for the lifelong persistence of stem cells, but its regulation is poorly understood. In the mammalian brain, neurogenesis persists in two germinal areas, the subventricular zone (SVZ) and the hippocampus, where continuous postnatal neuronal production seems to be supported by neural stem cells (NSCs). Here we show that pigment epithelium-derived factor (PEDF) is secreted by components of the murine SVZ and promotes self-renewal of adult NSCs in vitro. In addition, intraventricular PEDF infusion activated slowly dividing stem cells, whereas a blockade of endogenous PEDF decreased their cycling. These data demonstrate that PEDF is a niche-derived regulator of adult NSCs and provide evidence for a role for PEDF protein in NSC maintenance.

Animals↗

PubMed1997

Repeated stress, like vasopressin, sensitizes the excitatory effects of corticotropin releasing factor on the acoustic startle reflex.

In the rat, evidence now suggests a neurotransmitter function for the neuropeptides arginine vasopressin (AVP) and corticotropin releasing factor (CRF), implicating them in various autonomic, behavioral, and neuroendocrine responses to stress. Repeated AVP/CRF release in the pituitary portal circulation, due to stress, sensitizes and potentiates the release of ACTH from the anterior pituitary. Using a neuroanatomically well-defined behavior, the acoustic startle reflex in the rat, we sought to determine whether an interaction between AVP, CRF and stress might also occur centrally as measured by increased behavioral sensitivity to AVP or CRF given directly into the brain. The first experiment tested whether repeated intraventricular (i.c.v.) infusion of AVP would lead to an increase in the excitatory effect of a subthreshold dose of AVP on the acoustic startle reflex when infused 48 h later. Different groups of rats were infused with various doses of AVP (0.3, 3, or 30 ng) or vehicle on Day 1 and tested for startle over the next 60 min. On Day 2, 48 h later, all animals were infused with a single dose of AVP (300 pg) and tested for startle. Infusion of AVP on Day 1 did not increase startle consistently at any dose, but did lead to a sensitized excitatory effect of AVP on startle on Day 2 which was non-monotonically related to the dose of AVP given on Day 1. Experiment 2 tested whether AVP on Day 1 would sensitize the excitatory effects on startle of CRF given i.c.v. on Day 2. Different groups of rats were infused i.c.v. with various doses of AVP (10, 30, 100, 300 pg) or vehicle on Day 1. On Day 2, 48 h later, all rats were infused with a subthreshold dose of CRF (0.25 microg). Infusion of AVP on Day 1 led to a sensitized excitatory effect of CRF on startle on Day 2 which was non-monotonically related to the dose of AVP given on Day 1. In experiment 3, we tested whether footshocks given on Day 1 would sensitize the excitatory effect of CRF on startle tested 48 h later. Different groups were given footshocks (0.2, 0.4, 0.8, 1.6 mA) on Day 1. On Day 2, 48 h later, all rats were infused with a subthreshold dose of CRF (0.25 microg). Footshocks given on Day 1 led to a sensitized excitatory effect of CRF on startle on Day 2 which was non-monotonically related to the intensity of footshock on Day 1. Taken together, these results suggest that an interaction between AVP, CRF and stress may occur centrally, consistent with other studies showing similar interactions peripherally. This may provide a model system for analyzing how prior stress leads to enhanced behavioral reactions to subsequent stressors and a mechanism to explain dysregulation of the stress response.

Acoustic Stimulation↗

PubMed1983

Tetrahydro-beta-carbolines: effect on alcohol intake in rats.

Some beta-carbolines, such as tetrahydro-beta-carboline (THBC) and 6-methoxy-THBC, occur normally in mammalian tissues, and 1-methyl-THBC has been found in human blood after alcohol intake. Continuous intraventricular (ICV) infusion of THBC and 1-methyl-THBC for 14 days was shown to increase voluntary alcohol intake in rats during the second week of infusion. In this study the experimental arrangement was slightly modified. Alcohol was offered for 7 days before the start of the 14 days of ICV infusion with Alzet minipumps and alcohol concentration (3-30% v/v) was increased every second day. The rats consumed less alcohol in the second day with the same concentration. Also, the dose of 47 nmoles/hr of 1-Me-THBC increased the voluntary alcohol intake over the controls, but only during the last 7 days. The same dose of 6-MeO-THBC, a serotonergic beta-carboline, was ineffective. Neither drug changed the total fluid intake. This study suggests that the increased voluntary alcohol intake by THBC's is not due to their serotonergic effect. A hypothesis concerning a possible involvement of opiate receptors is presented.

Alcohol Drinking↗

PubMed1991

Inhibitory interactions between alpha 2-adrenergic and opoid but not NPY mechanisms controlling the CRF-ACTH axis in the rat.

Following a series of investigations supporting the concept that the brain stem catecholaminergic (CA) system played a major stimulatory role on both basal and stress-triggered states of the hypothalamic-pituitary-adrenocortical (HPA) axis, across alpha 1 and beta receptors and also via alpha 2 receptors, the present study was designed to gain a deeper insight into the fine mechanism of functional interactions between the alpha 2 receptors mediated CA system and two peptidergic mechanisms, both shown to take part in the stimulatory control of the HPA axis: beta-endorphin and NPY. All experiments were conducted on rats whose noradrenergic bundles, which directly innervate the CRF neurons and are strongly implicated in the ether stress-induced corticotropic response, had been bilaterally obliterated by an intracerebral (i.c.) injection of 6-OHDA (NAB-X). Results showed that: (1) the blockade of the ether-stress induced ACTH response resulting from NAB-X was entirely reversed by an intraventricular (i.c.v.) infusion of the alpha 2 antagonist idazoxan (10 nmol), which appeared ineffective under basal conditions; (2) the restoration of a normal post-stress ACTH surge by i.c.v. idazoxan was itself blunted by an i.c.v. pretreatment with naloxone (10 nmol), whereas an i.c. pretreatment with an anti-NPY serum appeared ineffective. These data suggest that, in addition to a stimulatory control exerted by postsynaptic alpha 2 receptors directly on CRF neurons, other alpha 2 receptors participate, exclusively under the stress conditions above, in a tonic inhibitory control, indirectly mediated to the HPA axis across a stimulatory opioid, but not NPY regulatory component.

Adrenal Cortex↗