Central Catecholamine Depletion Research Articles

Mechanisms mediating the ability of caffeine to influence MDMA (‘Ecstasy’)‐induced hyperthermia in rats

Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction. Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration. Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia. A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Tyrosine supplementation mitigates working memory decrements during cold exposure

In rats, dietary supplementation with the amino acid tyrosine (TYR) prevents depletion of central catecholamines observed during acute environmental stress. Concomitant changes in the animals' behavioral responses to stress suggest that TYR might have similar effects on central catecholamines and cognition in humans exposed to environmental stress. This study aimed to determine if severe cold exposure impairs human cognition and if dietary supplementation with TYR would ameliorate such deficits. Volunteers ( N = 19) completed three test sessions on different days (35 °C control/placebo, ∼ 10 °C/placebo, ∼ 10 °C/TYR) using a double-blind, within subjects design. During each session, volunteers completed two 90-minute water immersions and consumed a food bar (150 mg/kg TYR or placebo) before each immersion (total TYR 300 mg/kg). Cognitive performance, mood, and salivary cortisol were assessed. Cortisol was elevated in the cold ( p < .01). Volunteers made fewer correct responses on a Match-to-Sample memory measure ( p < .05) and reaction time (RT) and errors increased on a choice RT test ( p < .01) in the cold. Self-reported tension ( p < .01), depression ( p < .05) and confusion ( p < .01) also increased in the cold. When volunteers consumed TYR, correct responses increased on a Match-to-Sample memory measure ( p < .05) and study time for the sample was shorter ( p < .05), indicative of more rapid and accurate information processing. Finally, RT on the memory measure revealed a similar pattern across immersions for TYR and thermoneutral conditions, but not cold/placebo ( p < .05). This study demonstrates cold exposure degrades cognitive performance and supplementation with TYR alleviates working memory decrements.

Benzo( α)pyrene-induced up-regulation of CYP1A2 gene expression: Role of adrenoceptor-linked signaling pathways

CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo( α)pyrene (B( α)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B( α)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of α 1-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral α 1- and α 2-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B( α)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via α 1- and α 2-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications.

Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression

Alpha2-adrenoceptor agents as well as stress affect the activity of several hepatic monoxygenases including those related to CYP1A enzymes. This study was therefore designed to assess the role of central and/or peripheral catecholamines and, in particular, of adrenoceptors in the regulation of B(α)P-induced cytochrome CYP1A1 expression. In order to discriminate the role of central from that of peripheral catecholamines in the regulation of CYP1A1 induction, the effect of central and peripheral catecholamine depletion using reserpine versus only peripheral catecholamine depletion using guanethidine was assessed. By using selected agonists and antagonists, the role of alpha and beta-adrenoceptors in the regulation of CYP1A1 induction was evaluated. The results showed that the central catecholaminergic system has a negative regulatory effect on 7-ethoxyresorufin O-deethylase (EROD) inducibility by benzo(α)pyrene (B(α)P), and that this may be mediated via α1-, α2- and β-adrenoceptors. Specifically, stimulation of α2-adrenoceptors with dexmedetomidine and blockade of α1- or β-adrenoceptors with prazosin or propranolol respectively, resulted in a further increase of EROD inducibility. Adrenoceptors were found to be involved in the regulation of the CYP1A1 gene at mRNA level. Both, reduced noradrenaline release in central nervous system induced with dexmedetomidine and central catecholamine depletion, as well as blockade of central α1-adrenoceptors induced with prazosin, all were associated with up-regulation of CYP1A1 expression. In contrast, stimulation of central beta-adrenoceptors with isoprenaline resulted in a down-regulation of CYP1A1 expression. Our observations indicate that drugs, which stimulate or block adrenoceptors and catecholamine release may lead to complications in drug therapy and modulate the toxicity or carcinogenicity of drugs that are substrates for the CYP1A1.

Central catecholamine depletion inhibits peripheral lymphocyte responsiveness in spleen and blood.

Experimental and clinical evidence has demonstrated extensive communication between the CNS and the immune system. To analyse the role of central catecholamines in modulating peripheral immune functions, we injected the neurotoxin 6-hydroxydopamine (6-OHDA) i.c.v. in rats. This treatment significantly reduced brain catecholamine content 2, 4 and 7 days after injection, and in the periphery splenic catecholamine levels were reduced 4 days after treatment. Central catecholamine depletion induced an inhibition of splenic and blood lymphocyte proliferation and splenic cytokine production and expression (interleukin-2 and interferon-gamma) 7 days after injection. In addition, central treatment with 6-OHDA reduced the percentage of spleen and peripheral blood natural killer (CD161 +) cells, and T-cytotoxic (CD8 +) cells in peripheral blood. The reduction in splenocyte proliferation was not associated with a glucocorticoid alteration but was completely abolished by prior peripheral sympathectomy. These data demonstrate a crucial role of central and peripheral catecholamines in modulating immune function.

Damage to ceruleo-cortical noradrenergic projections impairs locally cued but enhances spatially cued water maze acquisition

A series of 4 experiments tested the effects of central catecholamine depletion on acquisition of an escape response in a spatial water maze. In Expt. 1, local infusions of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DNAB) enhanced efficient acquisition of the spatial water maze in a stressful condition (cold water), but had no effect in warm water. In Expt. 2, lesions of the ventral noradrenergic bundle did not affect acquisition of the maze, indicating that the changes observed in Expt. 1 were unlikely to have been the result of incidental damage to the noradrenergic innervation of the hypothalamus. Measures of core body temperature and plasma corticosterone were taken in parallel with the behavioral experiments and revealed that central noradrenaline (NA) depletion did not alter these responses to cold or warm water swims. Expt. 3 revealed a contrasting pattern of effects following dopamine (DA) depletion from the caudate-putamen: swimming speed was reduced in warm, but not cold water and maze acquisition was impaired, to an equal extent in warm and cold water. Finally, in Expt. 4, rats with 6-OHDA lesions of the DNAB were impaired in discriminating local cues in a simultaneous visual discrimination water maze. These results support the hypothesis that ceruleo-cortical NA depletion broadens the span of attention, particularly under stressful circumstances. In contrast, the results also indicate that striatal DA depletion mainly affects vigour of responding, as measured by swim speed, and that this effect can be reversed by the stressful effects of cold water.

Hypotensive Effects of 5-HT1A Receptor Agonists on the Ventrolateral Medullary Pressor Area in Dogs

An attempt to determine the central site of the sympathoinhibitory effects of 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, has been made in normotensive anesthetized dogs. Intravenous and central (cisterna magna, vertebral artery) administration of 8-OH-DPAT induced dose-dependent decreases in blood pressure and sympathetic (splanchnic and renal) nerve activity in intact and baroreceptor denervated dogs. In contrast, 8-OH-DPAT was ineffective when injected into the nucleus tractus solitarii or into the raphe nuclei. Administration of 8-OH-DPAT into the ventrolateral pressor area (VLPA) decreased blood pressure and renal sympathetic nerve activity. The sympathoinhibitory effects of 8-OH-DPAT injected into the vertebral artery (v.a.) were antagonized by methiothepin and (+/-)pindolol injected into the v.a. Likewise, the effects of 8-OH-DPAT administered into the VLPA were antagonized by methiothepin injected into the same site. Depletion of central catecholamines and 5-HT content did not change the sympathoinhibitory effects of 8-OH-DPAT. These results suggested that 8-OH-DPAT has a direct effect on 5-HT1A receptors located in the VLPA in dogs.

Central catecholamine depletion impairs in vivo immunity but not in vitro lymphocyte activation

We have previously shown that depletion of central nervous system (CNS) catecholamines by injecting the neurotoxin 6-hydroxydopamine (6-OHDA) into the cisterna magna of C57B1/6 mice markedly impairs the humoral immune response to sheep red blood cells. This work extends these observations by showing that 6-OHDA treatment also inhibits the humoral antibody response to the T-cell-dependent antigen trinitrophenyl-keyhole limpet hemocyanin, but does not affect the response to the T-independent antigen trinitrophenyl-lipopolysaccharide. This treatment also impairs humoral responsiveness at peripheral lymphoid sites in addition to inhibiting natural killer cell activity. However, 6-OHDA treatment in vivo does not affect in vitro mixed lymphocyte responsiveness, mitogen-induced lymphocyte activation or antigen presentation by macrophages.

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 posibility 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.

Reserpine and the monoaminergic regulation of adrenal dopamine β-hydroxylase activity

The systemic administration of reserpine to rats increases adrenal dopamine β-hydroxylase activity, but is without significant effect on the K m (tyramine). This induction is partially blocked by hemisplanchnicotomy and by impairment of translation. The combined administration of (a) α-methyl-p-tyrosine and p-chlorophenylalanine; (b) 6-hydroxydopamine and p-chlorophenylalanine; or (c) α-methyl-p-tyrosine and 5,7-dihydroxytryptamine increases adrenal dopamine β-hydroxylase activity. These results suggest that the simultaneous depletion of central serotonin and catecholamines, as achieved by reserpine alone or by conjoint action of two specific drugs, is necessary for the induction. p-Chlorophenylalanine (intraperitoneal) or 5,7-dihydroxytryptamine (intracerebroventricular or injected into the medial raphe nucleus) increases the effect of reserpine, but the use of a catecholamine-depleting agent with reserpine does not alter the increase of adrenal dopamine β-hydroxylase obtained with reserpine alone. The potentiation by 5,7-dihydroxytryptamine is abolished by hemisplanchnicotomy, a result that demonstrates neural mediation of its effect. Although intravenous administration of 6-hydroxydopamine alone increases the activity of adrenal dopamine β-hydroxylase, the combination of this treatment with p-chlorophenylalanine does not elevate it further, as occurs with intra- cerebroventricular injections; this suggests a specific role of central catecholamine depletion. The serotonin agonists 5-hydroxytryptophan, fenfluramine and 5-methoxy-N,N-dimethyltryptarnine abolish the in- ducing effect of reserpine. This work sheds light on the action of reserpine as inducer and provides evidence for the role of monoaminergic pathways, with net inhibitory effects, that are involved in the regulation of the activity of an adrenal enzyme.

Brain catecholamine alterations accompanying development of anorexia in rats bearing the walker 256 carcinoma

In the present study, the relationship between central catecholamine levels and the anorexia induced by Walker 256 carcinoma was investigated. Results indicate that the anorexia is not due to depletion of central catecholamines. Tumor bearing rats sacrificed at night, when spontaneous food intake is selectively depressed, showed increased norepinephrine levels in the hypothalamus, cortex and hippocampus and increased dopamine levels in the striatum, midbrain, and cortex. Increased nighttime hypothalamic norepinephrine levels were positively correlated with the magnitude of spontaneous food intake in tumor rats.

Tolerance following the repeated administration of high doses of phencyclidine: No relation to central catecholamine depletion

The tolerance which develops following the repeated administration of phencyclidine has been attributed to both pharmacological and behavioral adaptations. In the present study, the possibility that neurochemical alterations induced by the repeated administration of phencyclidine might account for some portion of the observed tolerance was examined. Specifically, it was postulated that the repeated administration of high doses of phencyclidine might result in long lasting depletion of central catecholamine stores and that this neurochemical perturbation might result in tolerance to the drug's effects. It was observed that phencyclidine disrupted the performance of rats on a fixed-interval schedule maintained by water presentation. The repeated administration of high doses of phencyclidine (but not of a comparable volume of saline) during a period when subjects were not engaged in the fixed-interval task resulted in the development of a long lasting tolerance, but this tolerance could not be accounted for in terms of a depletion of central catecholamine stores.

Central catecholamine depletion, vasopressin, and blood pressure in the DOCA/NaCl rat

To determine whether impaired arginine vasopressin (AVP) release occurs when DOCA-NaCl hypertension is prevented following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), male Sprague-Dawley rats treated with intraventricular injections of 6-OHDA (250 micrograms X 2) or Merlis solution received deoxycorticosterone acetate (DOCA) implants (100 mg/kg) and drank 0.5% saline. Systolic blood pressure in the 6-OHDA-treated DOCA/NaCl group (139 +/- 4 mmHg) was lower (P less than 0.001) than in the Merlis-DOCA/NaCl group (183 +/- 7 mmHg). 6-OHDA treatment produced widespread catecholamine depletion throughout the central nervous system, including the supraoptic and paraventricular nuclei, the cells of which are known to produce AVP, but hypothalamic, pituitary, and plasma AVP levels were similar in both experimental groups, the latter values averaging 1.5-2 times those of controls. Both groups of rats suppressed AVP secretion appropriately when water loaded. Such suppression, however, had no effect on blood pressure in the hypertensive animals and, furthermore, administration of the AVP antagonist d(CH2)5Tyr(Me)AVP produced small decrements in mean blood pressure of both groups that were not significantly different from responses seen in control normotensive rats. These data demonstrate that 6-OHDA does not prevent DOCA-NaCl hypertension by decreasing AVP levels and suggest that AVP is not necessary for the maintenance of hypertension in this model.

Deficits in locomotor behaviour and motor performance after central 6-hydroxydopamine or peripheral L-DOPA

Intracerebral injections of 6-hydroxydopamine (6-OHDA) which produce deficits in locomotor behaviour and motor performance cause localized accumulation of monoamines as well as depletion of central catecholamines (CA). To determine whether the localized increases in monoamines could be contributing to the behavioural deficits seen after intracerebral 6-OHDA injection, the behavioural and biochemical effects of peripherally administered L-DOPA were compared to those which occurred after central injections of 6-OHDA. Forty-five minutes after the injection of 40 mg/kg of L-DOPA, in animals pretreated with 50 mg/kg of R044602, the ability to step down, to retract a limb and to ambulate were significantly impaired. Locomotor behaviour and body temperature of L-DOPA-injected animals were similar to those displayed by animals receiving intracerebral injections of 6-OHDA. Fluorescent histochemical and biochemical assessment of diencephalic CA revealed that depletion of CA was not related to the severity of the motor deficits which occurred, but that increased diencephalic CA were present in impaired animals injected with either 6-OHDA or L-DOPA. These findings support the contention that increased CA in degenerating hypothalamic neurones may contribute to behavioural deficits seen after the injection of 6-OHDA.

Adrenomedullary secretory response to midbrain stimulation in rat: effects of depletion of brain catecholamines or serotonin.

Electrical stimulation of the periaqueductal gray substance (PAG) of the rostral midbrain of the rat produced biphasic or monophasic pressor responses depending on the duration of the stimulus train. Marked increases in plasma noradrenaline (NA) and adrenaline (A) levels accompanied the pressor responses, indicating the participation of the adrenal medulla. Depletion of central catecholamines (CA) by intraventricular administration of 6-hydroxydopamine (6-OHDA) did not affect the primary vasomotor component but markedly depleted adrenal CA levels and attenuated the adrenomedullary component of the response to brain stimulation. The intraperitoneal administration of p-chlorophenylalanine (pCPA) not only depleted brain serotonin (5-HT) levels but also reduced brain CA levels significantly. The adrenaline (A) levels were reduced in the adrenal glands of these rats and the adrenal secretory response to brain stimulation was attenuated. In contrast, the selective destruction of central 5-HT neurons by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) in rats pretreated with desmethylimipramine (DMI) did not influence either the pressor nor the plasma CA responses to brain stimulation. Furthermore, the adrenal glands of these rats were normal. The results suggest that: (i) the central catecholaminergic neurons play an important role in the regulation of the adrenal glands but are not essential for the activation of the sympathetic vasoconstrictor fiber system: (ii) the pressor and plasma CA responses to PAG stimulation are not dependent on the central serotonergic system.

Effects of reduced central and peripheral catecholamines on avoidance learning.

Adult male Sprague-Dawley rats were randomly divided into 3 groups of 10. Using an independent-groups design the 6-hydroxydopamine animals received intraventricular and IP injections of the drug. The sham drug rats received intraventricular and IP injections of a vehicle solution while the control subjects were not injected. When administered either centrally or peripherally, 6-hydroxydopamine specifically and extensively depletes catecholamine levels. All rats were consequently given 30 trials per day over a 5-day period on a one-way active avoidance jump task. Using latency of response and number of avoidance responses as criteria, drug-induced depletion of central and peripheral catecholamines significantly retarded and in half the rats totally inhibited the acquisition of the one-way avoidance response. The results were discussed in relation to recent empirical findings on reduced catecholamine levels and avoidance behavior. Theoretically the results were interpreted as supporting Mowrer's two-factor learning theory and in conflict with DiGiusto and King's hypothesis about “difficulty of task.”

Central catecholamine depletion: effects on physiological growth hormone and prolactin secretion.

The effects of depletion of central nervous system (CNS) catecholamines (CA) upon growth hormone (GH) and prolactin (Prl) secretion were examined in unanaesthetized male rats. Animals were chronically implanted with cannulae for blood sampling and for intracerebroventricular (i.c.v.) injections. GH and Prl secretory profiles were obtained by radioimmunoassay of blood samples drawn every 15 min for a 6-hour period. Hormone profiles were obtained before, 1 day (day 1) and 7 days (day 7) after i.c.v. injection of 6-hydroxydopamine (6-OHDA, total dose 600 microgram). GH secretion on day 1 was almost completely abolished (mean GH concentrations 25.2 +/- 10.1 vs. baseline 177.2 +/- 34.1 ng/ml), but secretory patterns tended to return towards normal by day 7. Prl secretion was markedly increased at day 1 (18.8 +/- 5.1 vs. 6.7 +/- 1.9 ng/ml), but levels had fallen by day 7. Treatment of animals at day 8 with the norepinephrine antagonist phentolamine (7.5 mg/kg i.v.) suppressed GH secretion, but stimulated Prl secretion. The administration of the dopamine antagonist butaclamol (1 mg/kg i.v.) on day 9 had no effect on Gh secretion, but stimulated Prl release. Histofluorescence examination of tissue sections confirmed extensive disruption of CA structures throughout the CNS. These findings indicate that central CA neurons are facilitatory to GH secretory rhythms, but inhibitory to Prl secretion. Furthermore, it is apparent that the effects of i.c.v. 6-OHDA treatment are transient, recovery being due to re-establishment of functional CA mechanisms.

Depletion of central catecholamines alters amphetamine- and fenfluramine-induced taste aversions in the rat.

Conditioned taste aversions induced by pairing the consumption of saccharin with an amphetamine injection are attenuated in rats with depletion of central catecholamines caused by intraventricular administration of 6-hydroxydopamine (6-OHDA). The hypothesis that dopamine (DA) depletion is responsible for this effect was tested. The reduction in conditioning caused by intraventricular 6-OHDA could not be duplicated either with injections of 6-OHDA into the substantia nigra (Experiment 1) or with intraventricular 6-OHDA injections in animals pretreated with desmethylimipramine (Experiment 2). Both treatments, however, produced large depletions of telencephalic DA. 6-Hydroxydopa infusions caused a preferential loss of telencephalic norepinephrine (NE) but also failed to alter taste aversion learning. It is concluded that the effect of intraventricular 6-OHDA on amphetamine-induced aversions was the result of depletion of both NE and DA. In a third experiment the generality of the effect was examined by pairing saccharin consumption with injections of the amphetamine congener fenfluramine. Depletion of both NE and DA failed to alter fenfluramine-induced aversions. Infusion of 6-OHDA into the substantia nigra, however, retarded the extinction of such an aversion. Evidence is discussed for a peripheral site of action for fenfluramine in the conditioned aversion paradigm.

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.

Effect of central catecholamine depletion on the osmotic and nonosmotic stimulation of vasopressin (antidiuretic hormone) in the rat.

The central nervous system (CNS) mechanism(s) for the release of antidiuretic hormone (ADH) by various stimuli is unknown. In this study, the role of CNS catecholamines in effecting ADH release was examined in conscious rats 10-14 d after the cerebroventricular injection of 6-hydroxydopamine (6-OHDA). This dose of 6-OHDA caused a 67% depletion of brain tissue norepinephrine and only 3% depletion of heart norepinephrine, as compared with controls, which were injected with the vehicle buffer alone. Either intravenous 3% saline (osmotic stimulus) or intraperitoneal hyperoncotic dextran (nonosmotic stimulus) was administered to water-diuresing rats through indwelling catheters. Neither of these maneuvers changed arterial pressure, pulse, or inulin clearance in control or 6-OHDA rats. The 3% saline caused similar increases in plasma osmolality (15 mosmol/kg H(2)O) in control and 6-OHDA rats. The control rats, however, increased urinary osmolality (Uosm) to 586 mosmol/kg H(2)O, whereas 6-OHDA rats increased Uosm only to 335 mosmol/kg H(2)O (P < 0.005). These changes in Uosm were accompanied by an increase in plasma ADH to 7.6 muIU/ml in control animals vs. 2.9 muIU/ml in 6-OHDA rats (P < 0.005). All waterdiuresing animals had undetectable plasma ADH levels. Dextran-induced hypovolemia caused similar decrements (- 10%) in blood volume in both control and 6-OHDA animals, neither of which had significant changes in plasma osmolality. This nonosmotic hypovolemic stimulus caused an increase in Uosm to 753 mosmol/kg H(2)O in control rats, whereas Uosm in 6-OHDA rats increased to only 358 mosmol/kg H(2)O (P < 0.001). At the same time, ADH levels also were significantly greater in Cont rats (2.4 muIU/ml) than in the 6-OHDA animals (0.69 muIU/ml; P < 0.05). These results therefore suggest that CNS catecholamines may play an important role in mediating ADH release in response to both osmotic and nonosmotic (hypovolemic) stimuli.