Interactions of the systemic and brain renin–angiotensin systems in the control of drinking and the central mediation of pressor responses

Most of the biological actions of the circulating (a.k.a., the systemic or blood-borne) renin–angiotensin system require the generation of the octapeptide angiotensin (ANG) II from the decapeptide ANG I. In the case of circulating ANG I, the lungs are generally considered the major site for this conversion. The present experiments explored the possibility that under conditions of marked elevations of blood-borne ANG I, the generation of ANG II takes place within brain-associated target tissues, most notably circumventricular organs (CVOs) that lack a blood-brain barrier. The first important result of these experiments demonstrates that intracerebroventricular (i.c.v.) infusion of the converting enzyme inhibitor, captopril, completely blocks the drinking response and significantly attenuates the pressor response produced by systemically infused ANG I. This result indicates that under physiological/pathophysiological conditions associated with large elevations of circulating ANG I, an important part of the biological responses derived from blood-borne ANG may result from local conversion of ANG I to ANG II within specific brain target tissues which have high concentrations of converting enzyme. This local conversion process provides an important mechanism that would act to reinforce the “classic” conversion process which takes place in the lungs thereby delivering more ANG II immediately to central target receptors. The second important finding from these studies showed that drinking produced by systemically infused ANG II was not attenuated by an i.c.v. dose of captopril which was effective in blocking a comparable dipsogenic response induced by i.v. ANG I. This observation suggests that drinking induced by systemic ANG II does not require an intact metabolic cascade within the brain for the formation of ANG II (or ANG II-like effector peptide) from ANG I.     

Independent receptors for pressor and drinking responses to central injections of angiotensin II and carbachol.

Angiotensin II and carbachol when injected in the brain ventricles of the rat produce similar responses of an increase in blood pressure and drinking behavior. The question of whether these effects are produced by independent receptors or via a cholinergic circuit is debatable for the drinking behavior and evidence is lacking for the blood pressure effect. We have used a chronic rat preparation for recording blood pressure and drinking at the same time during intraventricular injections (i.v.t.) of both angiotensin and carbachol and i.v.t. or intravenous infusions of appropriate antagonists. The results show that drinking and blood pressure response to angiotensin II can be blocked by P113 (500 ng 1.v.t.) an angiotensin antagonist; they are not blocked by atropine (10 mug i.v.t.) a cholinergic antagonist; carbachol effects, however, are not blocked by P113, but are totally blocked by atropine (10 mug i.v.t.), At high doses of atropine there is inhibition of both agents but this probably represents a general inhibition. The hormone and cholinomimetic administered together interact and both are inhibited by adrenergic stimulation. We conclude from these experiments that angiotensin and carbachol act upon independent receptors in the brain to produce blood pressure and drinking responses but at some point they share common, central effector pathways.     

The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin.

Angiotensin II (Ang II) given centrally produces an increase in blood pressure and motivation to drink. The physiological mechanisms that mediate the pressor response include release of vasopressin (AVP) and activation of the sympathetic nervous system. Using 2 new Ang II receptor antagonists, we were able to investigate the role of AT1 or AT2 receptors in mediating these effects. Adult male Sprague-Dawley rats were cannulated in the lateral ventricle and 5 days later catheterized in the carotid artery for blood pressure measurements. All experiments were carried out in conscious rats. Three treatments were given intraventricularly (i.v.t.), in 2 microliters artificial cerebrospinal fluid (ACSF) at 30 min intervals: (1) 50 ng Ang II, (2) 0.7 micrograms AT1 antagonist Losartan or 7.0 micrograms AT2 antagonist PD123177, followed by 50 ng Ang II, and (3) 50 ng Ang II, to test for recovery. Blood pressure and drinking measurements were recorded. Also, blood samples for assay of AVP were drawn at 1 or 3 min post-injection in 2 separate groups of rats. We found that both Losartan and PD123177 significantly reduced release of AVP to Ang II 1 min post-injection. Losartan significantly blocked the pressor response (P less than 0.001), while PD123177 had no significant effect. Drinking was also antagonized by Losartan (P less than 0.05) and reduced (n.s.) by PD123177. The results suggest that the pressor response to Ang II (i.v.t.) is predominantly AT1 mediated, while the drinking and AVP responses may be mediated by both receptor subtypes.     

Interactions between central monoaminergic systems: dopamine-serotonin.

Concentration of dopamine and serotonin metabolites (HVA and 5-HIAA) in the CSF was evaluated before and after pharmacological treatment in 19 patients with different neuropsychiatric diseases. In every case a reciprocal modification of the two metabolites occurred after treatment. The result supports the hypothesis of a functional balance between the monoaminergic systems in the central nervous system.     

GABA inhibition of central angiotensin II and hypertonic CSF pressor responses

Angiotensin II (AII), hypertonic cerebrospinal fluid (CSF) and serotonin produced an increase in arterial pressure when administered intraventricularly (IVT) in conscious rats. Injection of 25 and 100 μg (IVT) of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), while producing slight hypotension, reduced the pressor effect of centrally administered AII and hypertonic CSF, but not serotonin. IVT-administered muscimol, a potent GABA agonist, also attenuated the pressor effect of IVT AII and hypertonic CSF. Thus, in addition to the profound depressor effect of large doses of centrally administered GABA, very low doses (25–100 μg, IVT) of this amino acid can alter the pressor responses caused by IVT injection of AII and hypertonic CSF.     

Injections of phentolamine into the anterior hypothalamus-preoptic area of rats blocks both pressor and drinking responses produced by central administration of angiotensin II

There are conflicting reports of a possible contribution of noradrenergic projections to the rostral hypothalamus to drinking and blood pressure regulation. The present study investigated the effects of injecting phentolamine into the anterior hypothalamus-preoptic region on drinking and blood pressure responses elicited by injecting angiotensin II into a lateral cerebral ventricle of the rat. Angiotensin II (250 ng or 25 ng) elicited water intakes averaging 9.25 +/- 0.52 ml and 4.35 +/- 0.44 ml respectively in 15 min with latencies of less than 3 min. Phentolamine, an alpha-adrenergic antagonist, injected into the rostral hypothalamus produced a dose-dependent reduction in water intake and number of laps taken accompanied by an increased latency to drink. In the urethane anaesthetized rat, angiotensin II produced significant increases in blood pressure. Injections of phentolamine into rostral hypothalamic sites in which drinking responses to angiotensin II were attenuated, also attenuated the pressor response to angiotensin II. These results indicate that alpha-adrenergic input to the rostral hypothalamus is involved in both the pressor and drinking responses elicited by central angiotensin II.     

Depletion of central catecholamines reduces pressor responses to arginine vasopressin

Previous reports that central administration of arginine vasopressin (AVP) increases turnover of brain catecholamines raise the possibility that the pressor responses which follow central administration of AVP may be mediated, in part, by central catecholamines. To test this hypothesis, rats were given intraventricular injections of vehicle, or of the neurotoxin, 6-hydroxydopamine, which resulted in significant depletions of hypothalamic and medulla oblongata noradrenalin and hypothalamic dopamine, but not of medullary dopamine or of hypothalamic and medullary 5-hydroxytryptamine. Following a one week recovery, these conscious rats, fitted with indwelling arterial catheters, were given intraventricular injections of AVP; the increases in arterial pressure and heart rate were significantly reduced in the catecholamine-depleted animals. These data support the hypothesis that the pressor and tachycardia responses to intraventricular AVP are mediated, in part, by central catecholamine-containing neurons.     

Central ANP attenuates pressor responses to central AVP in WKY and SHR

Blood pressure and heart rate responses to intracerebroventricular (ICV) injections of atrial natriuretic peptide (ANP, 125 ng) arginine vasopressin (AVP, 10 ng), combination of ANP (125 ng) and AVP (10 ng) or artificial cerebrospinal fluid (acsf, 5 microliters) were compared in conscious normotensive (WKY) and spontaneously hypertensive (SHR) rats. In both strains, ICV injection of AVP elicited significant increase of mean blood pressure (MP) and heart rate (HR). Increase of MP but not of HR was significantly greater in SHR than in WKY (p less than 0.05). Injection of acsf or ANP, as well as simultaneous administration of ANP and AVP, did not elicit significant changes of MP either in WKY or in SHR. In SHR, HR was significantly elevated by ICV injections of AVP and ANP + AVP, whereas in WKY HR was increased only after AVP. The data suggest that interaction of ANP and AVP at a central level may result in significant attenuation of central pressor effects of vasopressin.     

Opiate activation suppresses the drinking, pressor and natriuretic responses induced by cholinergic stimulation of the medial septal area.

The present study investigates the participation and interaction between cholinergic and opiate receptors of the medial septal area (MSA) in the regulation of Na+, K+ and water excretion, drinking and blood pressure regulation. Male Holtzman rats were implanted with stainless steel cannulae opening into the MSA. Na+, K+ and water excretion, water intake and blood pressure were measured after injection of carbachol (cholinergic agonist), FK-33824 (an opiate agonist) + carbachol or naloxone (an opiate antagonist) + carbachol into MSA. Carbachol (0.5 or 2.0 nmol) induced an increase in Na+ and K+ excretion, water intake and blood pressure and reduced the urinary volume. FK-33824 reduced the urinary volume and Na+ and K+ excretion. Previous injection of FK-33824 (100 ng) into the MSA blocked the increases in Na+ and K+ excretion, water intake and blood pressure induced by carbachol. Naloxone (10 micrograms) produced no changes in the effect of 2.0 nmol carbachol, but potentiated the natriuretic effect induced by 0.5 nmol dose of carbachol. These data show an inhibitory effect of opiate receptors on the changes in cardiovascular, fluid and electrolyte balance induced by cholinergic stimulation of the MSA in rats.     

Pressor response to CSF sodium in mice: mediation by a ouabain-like substance and renin-angiotensin system in the brain

Intracerebroventricular (i.c.v.) infusion of sodium in rats increases cerebrospinal fluid (CSF) [Na], mimicking the effects of a high salt diet in salt-sensitive strains and causing sympathetic hyperactivity and a pressor response that are mediated via both an endogenous brain ouabainlike substance (OLS) and the brain renin-angiotensin system (RAS). However, the concept that CSF sodium activates both the brain OLS and brain RAS to increase blood pressure has not been tested in any other species besides the rat. In the current study, it was established that continuous i.c.v. infusion of NaCl causes sustained increases in blood pressure and heart rate in both outbred (Swiss Webster, SW) and inbred (C57Bl/6) mouse strains. Subsequently, the mechanisms of the pressor effects were explored. In both SW and C57Bl/6, the i.c.v. administration of Fab fragments of an antibody with high affinity for ouabain and the OLS (Fab) abolished the pressor and tachycardic responses to i.c.v. sodium, as did the angiotensin II AT1 receptor antagonist losartan given i.c.v. In contrast, doses of NaCl, Fab and losartan that were effective i.c.v. were ineffective when given i.v. I.c.v. ouabain also caused the pressor and tachycardic responses, which were abolished by losartan (i.c.v.). In the reciprocal study, i.c.v. Fab had no effect on similar responses to i.c.v. angiotensin II. These studies demonstrate that the sustained blood pressure and heart rate responses caused by increases in CSF [Na] are mediated via both a brain OLS and the brain RAS. The RAS activation occurs downstream of the OLS effect.     

Contribution of nucleus medianus to the drinking and pressor responses to angiotensin II acting at subfornical organ

The contribution of neurons in the nucleus medianus (NM) in mediating the drinking and pressor responses elicited by administration of angiotensin II (AII) either directly into the subfornical organ (SFO) or intravenously was investigated in conscious, unrestrained rats. Microinjection of AII into the SFO elicited a robust drinking (7.9 +/- 0.8 ml in 15 min; n = 24) and pressor (peak rise in mean arterial pressure (MAP), 15 +/- 1 mm Hg; n = 20) response. On the other hand, intravenous infusion of AII elicited an increase in MAP (36 +/- 3 mm Hg; n = 14) accompanied by a marked reflex bradycardia (134 +/- 18 beats/min), but not a significant drinking response. Lesions of NM cells, dorsal to the anterior commissure and between the fornical columns, with the neurotoxin kainic acid significantly (P less than 0.05) attenuated the drinking response (prelesion volume, 8.3 +/- 0.8 ml in 15 min; postlesion volume, 1.9 +/- 1.4 ml in 15 min; n = 7), but did not alter the pressor response to AII injected directly into the SFO. Similarly, kainic acid lesions of NM cells did not significantly effect the pressor response or the associated reflex bradycardia to intravenous administration of AII. Sham lesions of NM cells or control kainic acid lesions of adjacent structures did not alter the AII-induced drinking or pressor responses. These data suggest that neurons in the dorsal NM are part of a forebrain neuronal circuit that is involved in the drinking, but not the pressor responses to AII acting at the SFO in the conscious rat.     

Platelets as central mediators of systemic inflammatory responses

Systemic inflammatory responses are associated with high morbidity and mortality and represent a diverse and clinically challenging group of diseases. Platelets are increasingly linked to inflammation, in addition to their well-known roles in hemostasis and thrombosis. There is agreement that traditional functions of platelets, including adherence, aggregation, and secretion of preformed mediators, contribute to systemic inflammatory responses. However, emerging evidence indicates that platelets function in non-traditional ways. In this review, we focus on new functions of platelets that may be involved in the host response to infection.     

Role of central catecholamines in the control of blood pressure and drinking behavior

The role of central nervous system (CNS) catecholamines in the development of hypertension and the control of drinking behavior was assessed in rats by depleting these amines with 6-hydroxydopamine (6-OHDA). Intraventricular administration of 6-OHDA completely prevented the development of one-kidney renal hypertension and abolished the associated increase in water consumption. 6-OHDA-treated rats showed deficits in drinking behavior when challenged with subcutaneous injections of angiotensin II (AII) and hypertonic sodium chloride. The acute pressor responses produced by intraventricular injections of AII and carbachol were virtually abolished by central catecholamine depletion. However, drinking produced by central cholinergic stimulation remained intact while AII drinking was significantly reduced. These data demonstrate that the integrity of CNS catecholamines is required for the development of one-kidney renal hypertension and the increased drinking which accompanies it. In addition, destruction of central catecholamine-containing neurons allows for a specific dissociation of the pressor and drinking responses produced by central cholinergic but not AII stimulation.     

Central interaction between endothelin and brain natriuretic peptide on pressor and hormonal responses

Interaction between intracerebroventricular (i.c.v.) administration of endothelin (ET) and brain natriuretic peptide (BNP) on pressor and hormonal responses was examined in unanesthetized, freely moving rats. I.c.v. administered ET (5, 20 or 40 pmol/2 microliters) dose-dependently increased arterial pressure. Plasma catecholamine levels were elevated by 40 pmol of ET, and plasma ACTH level was also elevated by centrally administered ET in a dose-dependent manner. I.c.v. administration of BNP (0.2, 1 nmol/3 microliters) dose-dependently attenuated central ET (40 pmol/2 microliter)-induced pressor response, plasma catecholamine and ACTH secretion. These results indicate that ET may be one of the neuropeptides which stimulate both sympathetic nervous system and hypothalamo-pituitary-adrenal axis, and that BNP and ET interact in the central nervous system (CNS) to regulate cardiovascular and hormonal functions. Furthermore, these results raise a possibility that BNP antagonizes the effect of not only angiotensin II but also other neuropeptides in the CNS.     

Selective catecholamine depletion of structures along the ventral lamina terminalis: effects on experimentally-induced drinking and pressor responses

Ablation of the periventricular tissue of the anteroventral third ventricle (AV3V) or injection of the chemical neurotoxin, 6-hydroxydopamine (6-OHDA), into the structures along the ventral lamina terminalis will produce deficits in drinking and pressor responses to exogenous angiotensin II (ANG II). Centrally-applied 6-OHDA has been shown to result in widespread depletions of both adrenergic (i.e. both noradrenaline and adrenaline-containing) and dopaminergic neurons. Questions arise, therefore, as to whether a dopaminergic or adrenergic depletion is critical and the locus where reductions must occur. The present experiment was designed to investigate the specificity of the effects of 6-OHDA administration into lamina terminalis-associated structures on ANG II-induced drinking and pressor responses. The nature of the depletion was manipulated with desmethylimipramine (DMI), a drug which blocks the uptake of 6-OHDA into adrenergic but not dopaminergic nerve terminals and thereby spares adrenergic elements. The experimental results indicate that 6-OHDA administration into structures of the ventral lamina terminalis produced ANG II response deficits and marked reductions in catecholamine histofluorescence in the regions of the injection sites. In contrast, pretreatment with DMI protected against the 6-OHDA-produced functional deficits and minimized the effects on histofluorescence. These findings are consistent with the interpretation that adrenergic but not dopaminergic neurons must be present in the structures of the ventral lamina terminalis in order to elicit normal angiotensin-induced drinking and pressor responses.     

Functional role of brain AT1 and AT2 receptors in the central angiotensin II pressor response

Intracerebroventricular (i.c.v.) angiotensin II (ANG II) increase vascular resistance and elicits a pressor response characterized by sympathetic nervous system activation (SNS component) and increased vasopressin (VP) secretion (VP component). This study examines the role of brain AT1 and AT2 ANG II receptors in mediating the pressor and renal hemodynamic effects of i.c.v. ANG II in conscious Sprague-Dawley rats. Mean arterial pressure, heart rate and renal vascular resistance responses to i.c.v. ANG II (100 ng in 5 μl) were determined 10 min after i.c.v. injection of either the AT1 receptor antagonist, DuP 753 (1.0, 2.5, 5.0, 10.0 μg), the AT2 receptor ligand, PD 123319 (3.5 × [10⁻⁶, 10⁻⁴, 10⁻², 10⁰ μg), or both. In control rats, i.c.v. DuP 753 prevented the pressor response and the increase in renal vascular resistance that occurred following i.c.v. ANG II in a dose-dependent manner (P < 0.05), while i.c.v. PD 123319 was without affect. When the VP- and SNS components were studied individually, by preventing the SNS component with intravenous (i.v.) chlorisondamine or the VP component with a V1 receptor antagonist (i.v.) similar results were obtained; DuP 753 prevented the SNS component and significantly reduced the VP component. These results indicate that both central ANG II pressor components are mediated primarily by brain AT1 receptors. However, doses of DuP 753 were more effective when combined with 3.5 μg of PD 123319 than when given alone (P < 0.05), suggesting that the pressor effects of i.c.v. ANG II may involve activation of multiple ANG II receptor subtypes.     

Interactions between kinases and phosphatases in the rapid control of brain aromatase

Aromatization of testosterone into oestradiol plays a key role in the activation of male sexual behaviour in many vertebrate species. Rapid changes in brain aromatase activity have recently been identified and the resulting changes in local oestrogen bioavailability could modulate fast behavioural responses to oestrogens. In quail hypothalamic homogenates, aromatase activity is down-regulated within minutes by calcium-dependent phosphorylations in the presence of ATP, MgCl2 and CaCl2 (ATP/Mg/Ca). Three kinases (protein kinases A and C and calmodulin kinase; PKA, PKC and CAMK) are potentially implicated in this process. If kinases decrease aromatase activity in a reversible manner, then it would be expected that the enzymatic activity would increase and/or return to baseline levels in the presence of phosphatases. We showed previously that 0.1 mM vanadate (a general inhibitor of protein phosphatases) significantly decreases aromatase activity but specific protein phosphatases that could up-regulate aromatase activity have not been identified to date. The reversibility of aromatase activity inhibition by phosphorylations was investigated in the present study using alkaline and acid phosphatase (Alk and Ac PPase). Unexpectedly, Alk PPase inhibited aromatase activity in a dose-dependent manner in the presence, as well as in the absence, of ATP/Mg/Ca. By contrast, Ac PPase completely blocked the inhibitory effects of ATP/Mg/Ca on aromatase activity, even if it moderately inhibited aromatase activity in the absence of ATP/Mg/Ca. However, the addition of Ac PPase was unable to restore aromatase activity after it had been inhibited by exposure to ATP/Mg/Ca. Taken together, these data suggest that, amongst the 15 potential consensus phosphorylation sites identified on the quail aromatase sequence, some must be constitutively phosphorylated for the enzyme to be active whereas phosphorylation of the others is involved in the rapid inhibition of aromatase activity by the competitive effects of protein kinases and phosphatases. Two out of these 15 putative phosphorylation sites occur in an environment corresponding to the consensus sites for PKC, PKA (and possibly a CAMK) and, in all probability, represent the sites whose phosphorylation rapidly blocks enzyme activity.     

Neural plasticity and the brain renin-angiotensin system

The brain renin-angiotensin system mediates several classic physiologies including body water balance, maintenance of blood pressure, cyclicity of reproductive hormones and sexual behaviors, and regulation of pituitary gland hormones. In addition, angiotensin peptides have been implicated in neural plasticity and memory. The present review initially describes the extracellular matrix (ECM) and the roles of cell adhesion molecules (CAMs), matrix metalloproteinases, and tissue inhibitors of metalloproteinases in the maintenance and degradation of the ECM. It is the ECM that appears to permit synaptic remodeling and thus is critical to the plasticity that is presumed to underlie mechanisms of memory consolidation and retrieval. The interrelationship among long-term potentiation (LTP), CAMs, and synaptic strengthening is described, followed by the influence of angiotensins on LTP. There is strong support for an inhibitory influence by angiotensin II (AngII) and a facilitory role by angiotensin IV (AngIV), on LTP. Next, the influences of AngII and IV on associative and spatial memories are summarized. Finally, the impact of sleep deprivation on matrix metalloproteinases and memory function is described. Recent findings indicate that sleep deprivation-induced memory impairment is accompanied by a lack of appropriate changes in matrix metalloproteinases within the hippocampus and neocortex as compared with non-sleep deprived animals. These findings generally support an important contribution by angiotensin peptides to neural plasticity and memory consolidation.     

Interactions between lysergic acid diethylamide and dopamine-sensitive adenylate cyclase systems in rat brain.

Investigations were carried out on the interactions of the hallucinogenic drug, D-lysergic acid diethylamide (D-LSD), and other serotonin antagonists with catecholamine-sensitive adenylate cyclase systems in cell-free preparations from different regions of rat brain. In equimolar concentration, D-LSD, 2-brono-D-lysergic acid diethylamide (BOL), or methysergide (UML) strongly blocked maximal stimulation of adenylate cyclase activity by either norepinephrine or dopamine in particulate preparations from cerebral cortices of young adult rats. D-LSD also eliminated the stimulation of adenylate cyclase activity of equimolar concentrations of norepinephrine or dopamine in particulate preparations from rat hippocampus. The effects of this hallucinogenic agent on adenylate cyclase activity were most striking in particulate preparations from corpus striatum. Thus, in 10 muM concentration, D-LSD not only completely eradicated the response to 10 muM dopamine in these preparations but also consistently stimulated adenylate cyclase activity. L-LSD (80 muM) was without effect. Significant activation of striatal adenylate cyclase was produced by 0.1 muM D-LSD. Activation of striatal adenylate cyclase of either D-LSD or dopamine was strongly blocked by the dopamine-blocking agents trifluoperazine, thioridazine, chlorpromazine, and haloperidol. The stimulatory effects of D-LSD and dopamine were also inhibited by the serotonin-blocking agents, BOL, 1-methyl-D-lysergic acid diethylamide (MLD), and cyproheptadine, but not by the beta-adrenergic-blocking agent, propranolol. However, these serotonin antagonists by themselves were incapable of stimulating adenylate cyclase activity in the striatal preparations. Several other hallucinogens, which were structurally related to serotonin, were also inactive in this regard, e.g., mescaline, N,N-dimethyltryptamine, psilocin and bufotenine. Serotonin itself produced a small stimulation of adenylate cyclase activity in striatal preparations and, in relatively high concentration (100 muM), partially blocked the activation by 10 muM dopamine, but was without effect on the stimulation by 10 muM D-LSD. The present results indicate that serotonin antagonists, in general, are potent inhibitors of catecholamine-induced stimulation of adenylate cyclase systems in brain cell-free preparations. In addition, these results, coupled with earlier findings on the capacity of D-LSD to interact with serotonin-sensitive adenylate cyclase systems from rat brain23,24 and other neural systems16, strongly suggest that this hallucinogenic agent is capable of acting as an agonist at central dopamine and serotonin receptors, as well as functioning as an antagonist at dopamine, norepinephrine, and serotonin receptors in the brain.     

Localized injections of 6-hydroxydopamine into lamina terminalis-associated structures: effects on experimentally induced drinking and pressor responses

Electrolytic lesions of tissues surrounding the anteroventral third ventricle (AV3V) or injections of the chemical neurotoxin, 6-hydroxydopamine (6-OHDA) into the lateral cerebral ventricles result in virtually identical deficits in response to a variety of dipsogenic and pressor challenges. These observations have led to the hypothesis that the integrity of catecholamine (CA) projections into the AV3V region is a prerequisite for elicitation of these thirst and blood pressure responses. This hypothesis was tested in 6-OHDA-injected rats following protocols designed to deplete CA's in discrete structures associated with the lamina terminalis. Post-injection response deficits, coupled with histofluorescent assessments of CA depletions in specific anterior forebrain nuclei, support the stated hypothesis. In addition, the findings indicate that thirst deficits to systemic as well as central dipsogenic challenges are both selective and dissociable and that 6-OHDA lesions of any of the more ventrally situated target nuclei result in significantly attenuated blood pressure responses to centrally injected angiotensin II.