Central Catecholamine Research Articles

Norepinephrine levels in paraventricular nucleus of spontaneously hypertensive rats: role of neuropeptide Y

Recent evidence supports the view that the sympathetic system actively participates in the development of hypertension. Because norepinephrine, contained within central neurons involved in cardiovascular sympathetic regulation, is known to coexist with neuropeptide Y, it is possible that a functional interaction between neuropeptide Y and norepinephrine exists within the brain. In an effort to clarify whether or not central catecholamine systems are modulated by neuropeptide Y in hypertensive situations, the paraventricular nucleus of spontaneously hypertensive rats was exposed to neuropeptide Y (10(-9) M), and levels of norepinephrine were sampled by microdialysis. Norepinephrine levels in spontaneously hypertensive rats were significantly increased and did not change after exposure to neuropeptide Y, in sharp contrast to the decreases seen in Wistar-Kyoto controls. To ascertain whether these alterations in norepinephrine control were specific to the model used, a similar series of experiments was carried out in the paraventricular nucleus of aortic-banded rats. These studies supported the previous findings. Norepinephrine levels in aortic-banded rats were markedly elevated when compared with sham-operated controls and demonstrated no change after exposure to neuropeptide Y, whereas decreases of > 50% were seen in sham-operated controls. These results support the view that mechanisms normally involving neuropeptide Y as a neuromodulator in the paraventricular nucleus are altered in hypertensive situations. It is suggested that hypertension may precipitate changes in mechanisms involving brain neuropeptide Y and increased sympathetic activity.

A partial blockade of catecholaminergic neurotransmission with 6-hydroxydopamine decreases mRNA level of gonadotropin releasing hormone in the male rat hypothalamus.

Central catecholamines (CA) are known to be involved in the regulation of synthesis and secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. However, no attempt has been yet made to determine whether CA affects GnRH gene expression. To this end, the effect of 6-hydroxydopamine (6-OHDA), a catecholaminergic neurotoxin, on GnRH mRNA level was examined. Hypothalamic tissues obtained from adult male rats were incubated with medium containing 6-OHDA. To ensure the effect of 6-OHDA on CA depleting action, CA levels in media and in postincubation tissues were determined. Increasing concentrations of 6-OHDA resulted in decrease in norepinephrine (NE) and dopamine (DA) contents in a dose dependent manner. Treatment with 6-OHDA (5 x 10(-4) M produced a time-dependent decrease in NE but not DA, when CA levels in media were determined at 30 min intervals during the incubation period. To determine changes in GnRH mRNA level in response to 6-OHDA treatment in vitro, for 2.5 h total cytoplasmic RNA fractions were isolated from postincubation hypothalamic tissues and used for RNA-blot hybridization with 32P-labeled GnRH riboprobe. A blockade of CA neurotransmission with 6-OHDA (5 x 10(-4) M) significantly reduced GnRH mRNA level by half over its control and internal control (actin mRNA) groups. Northern blot analysis revealed that addition of NE (1 x 10(-6) M) reversed the decreased GnRH mRNA level by 6-OHDA.(ABSTRACT TRUNCATED AT 250 WORDS)

Central and Endocrine Aspects of Tongue-Flicking and Exploratory Behavior in <i>Anolis carolinensis</i>

Tongue-flicking in reptiles is frequently seen to increase in novel habitats and is presumed to involve the acquisition of chemical information. Like most behavioral patterns, however, tongue-flicking has both multiple causes and multiple functions, only some of which involve chemosensation. This paper describes units of exploratory behavior, including use of the tongue, in a microsmatic lizard, the green anole, Anolis carolinensis. This species employs its tongue in a manner suggestive of chemosensory exploration, but it possesses modest peripheral chemosensory organs and reduced central representation of chemosensory target cell groups. Further, specific elements of exploratory behavior are affected differently by treatments that involve altering levels of stress-sensitive hormones, androgen, and central catecholamines. Such differential responses suggest that exploratory behavior is an ensemble of individual units, some of which are selectively sensitive to specific physiological elements of the stress response and of elevated arousal.

Tryptophanemia and tyrosinemia in adolescents with impulsive behavior.

Tryptophan (TRP) and tyrosine (TYR), respectively the circulating precursors of the central serotonergic (5-HT) and catecholamine systems, were measured in eight adolescents with impulsive behavior regardless of the exact type of disorder. The 6 week study period included weekly blood sampling and clinical evaluation. The ratios of TRP and TYR to large neutral amino acids (LNAA), which indicate the availability for the synthesis of neurotransmitters, were calculated. Comparison of results with eight hospitalized controls of the same age (12.5 to 18 years) revealed lower total TRP levels in four adolescent patients, a lower TRP/LNAA ratio in three adolescents, and a lower free TRP concentration in six adolescents with discretely enhanced albuminemia. A slight increase in TYR and the TYR/LNAA ratio was noted in nearly all of the adolescent patients. Despite the heterogeneity of individual biological results, the impulsive behavior subjects in this study seemed to present abnormalities in neurotransmitter precursors.

Tyrosine pretreatment alleviates suppression of schedule-controlled responding produced by corticotropin releasing factor (CRF) in rats

Disruption of performance observed when animals are exposed to physical Stressors which deplete brain catecholamines can be alleviated by pretreatment with the catecholamine precursor tyrosine. Central administration of the stress hormone corticotropin releasing factor (CRF) has been shown to affect a variety of behaviors and also to potently increase the release of central catecholamines. Since CRF-induced disruption of behavior may involve CRF-induced depletion of brain catecholamines, the present study examined whether tyrosine would alleviate suppression of schedule-controlled responding in rats resulting from ICV administration of CRF. Administration of CRF (1.0 μg–10 μg) produced dose-dependent suppression of response rate and total number of earned reinforcers in rats responding on a multiple fixed-interval 60 s/fixed-ratio 20 schedule for food reinforcement. Pretreatment with 200 mg/kg tyrosine (IP) administered with ICV saline decreased response rate but did not lower total reinforcers, whereas 400 mg/kg of tyrosine decreased both. Injection of 400 mg/kg tyrosine reduced, but did not completely restore, CRF-induced suppression of behavior. The 200 mg/kg tyrosine dose was less effective in alleviating CRF-induced suppression of performance. These data indicate that pretreatment with the catecholamine precursor tyrosine can partially ameliorate performance decrements resulting from CRF administration.

Synergistic and persistent interaction between the D2 agonist, bromocriptine, and the D1 selective agonist, CY 208–243

In mice pretreated with reserpine and α- methyl- dl -p- tyrosin (αMPT) to deplete central catecholamines, the D2 dopamine receptor-selective agonist, bromocriptine, at a dose to 10 mg/kg produced no locomotor activity. The D1-selective agonist, CY 208–243, generated a dose-dependent locomotor response in this animal model for Parkinson's disease; low doses elicited little or no effect while higher doses resulted in a short burst of locomotor activity (2 h). The combination of CY 208–243 and bromocriptine had a dramatic synergistic effect on locomotion. Most importantly, this combination of D1 and D2 agonists converted a brief (2 h) effect on locomotion to one which persisted for up to 6 h. These results suggest that the combination of D1 and D2 dopamine receptor agonists can affect both the intensity and the persistence of a locomotor response.

Central catecholamine, sympathetic nerve and vascular protein in the acute phase of two-kidney, one-clip renovascular hypertension in rats.

Incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries in two-kidney, one-clip hypertensive rats was greater than that in normotensive rats. Splanchnicotomy predominantly over the root of mesenteric arteries or intracranioventricular injection of 6-hydroxydopamine prevented the development of hypertension in 2K-1C rats concomitant with the reduction of incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries. The content of norepinephrine in the hypothalamus in 2K-1C rats was lower than that in normotensive control rats. These findings indicate that increased non-collagenous protein synthesis in mesenteric arteries or low level of hypothalamic norepinephrine has facilitative effects on the development of 2K-1C hypertension.

Catecholamine metabolism in the vas deferens and the adrenal gland with special reference to the central catecholamine-depleted state.

Experiments were carried out to elucidate the role of central catecholamines in regulating catecholamine metabolism in the vas deferens and adrenal gland of the rat. Rats were injected intracerebroventricularly (i.c.v.) with either vehicle or 6-hydroxydopamine (6-OHDA). Groups of animals pretreated with vehicle or 6-OHDA (i.c.v.) were injected intraperitoneally (i.p.) with alpha-methyl-para-tyrosine (AMT), a tyrosine hydroxylase inhibitor. Catecholamine turnover rates were estimated by determining norepinephrine or epinephrine content after administering AMT. Central norepinephrine and dopamine contents decreased significantly (p less than 0.05) after treatment with 6-OHDA and AMT. The norepinephrine content of the vas deferens of rats pretreated with 6-OHDA was markedly reduced (p less than 0.001) after administration of AMT, whereas that of the vehicle-treated rats remained unchanged. Administration of 6-OHDA had no effect on the norepinephrine or epinephrine content of the adrenal gland. The present results indicate that central monoaminergic neurons have an inhibitory effect on the adrenergic neurons of the vas deferens. In contrast, this inhibitory regulation does not appear to be exerted on the adrenal glands.

Central nervous system catecholamine content and norepinephrine release after AV3V ablation

Electrolytic ablation of the periventricular tissue surrounding the anteroventral third cerebral ventricle (AV3V-X) results in immediate increases in norepinephrine release in the paraventricular hypothalamic nucleus/anterior hypothalamus (P/A) and in the dorsomedial medulla (DM) and depletion of norepinephrine and epinephrine throughout the brain. The present study determined whether catecholamine depletion and/or altered norepinephrine release persisted after recovery from the acute effects of AV3V-X. Fourteen to eighteen days after surgery, catecholamine concentrations throughout the brain and norepinephrine release in the P/A and DM during hemorrhage were measured in control-operated and AV3V-X rats. AV3V-X decreased epinephrine content only in the midbrain, increased norepinephrine only in the cortex, and produced no differences in central nervous system dopamine. Hemorrhage-induced norepinephrine release was significantly greater in the P/A of AV3V-X rats than in control animals, whereas norepinephrine release in the DM increased equally in both groups. Thus AV3V-X does not result in chronic global central nervous system catecholamine depletion and enhances norepinephrine release in the P/A during hemorrhage.

Changes in Central Catecholamine in M-SHRSP under Conditions of Enucleating Adrenal Medulla

Changes in Central Catecholamine in M-SHRSP under Conditions of Enucleating Adrenal Medulla

Modulation of sympathetic activity by brain neuropeptide Y in cardiac hypertrophy

Several observations now support the view that the sympathetic system actively participates in the development of cardiac hypertrophy. Since norepinephrine (NE)-containing neurons involved in cardiovascular regulation in the brain are known to coexist with neuropeptide Y (NPY), it is possible that a functional interaction between NPY and NE exists centrally. In an effort to clarify whether or not central catecholamine systems are modulated by NPY soon after imposing an increased pressure overload on the heart, male Sprague-Dawley rats underwent aortic constriction and were examined 14 days later. Rats were anesthetized and subjected to microdialysis sampling by stereotaxically implanting a probe into the caudal ventrolateral medulla (A 1). Perfusate was collected after a 1-hour stabilization period, purified, and analyzed for interstitial concentrations of NE and other catecholamines using high-performance liquid chromatography with an electrochemical detector. Extracellular NE concentrations in the A 1 area were found to be decreased. These results were associated with increased rate of change in the specific activity of NE (NE turnover) in heart, indicating increased sympathetic activity and an increased left ventricular weight. Also, infusion of NPY (10 −9 mol/L) by microdialysis in the A 1 area resulted in the reduction of NE concentration; epinephrine and dopamine levels were also decreased. In contrast, methionine-enkephalin, another neuropeptide, had no effect on the extracellular catecholamine concentrations in the A 1 area. Since neurons of the A 1 group project almost exclusively to forebrain structures inhibiting sympathetic activity, it is concluded that decreases of NE and other catecholamines in afferent pathways regulating the caudal ventrolateral medulla may lead to an enhanced sympathetic activity. It is suggested that cardiac hypertrophy may be precipitated secondary to changes in brain NPY levels.

Stressor-induced alterations of natural killer cell activity and central catecholamines in mice

Natural killer (NK) cell cytotoxicity was determined at various intervals (0.5, 24 or 48 h) following exposure to uncontrollable footshock in 3 strains of mice. Stressor application provoked reductions of NK activity, but the time course of the NK changes varied across strains. Whereas NK cytotoxicity was markedly reduced in C57BL/6J mice 0.5–48 h following stressor exposure, this effect was delayed in C3H/HeJ mice, being evident 24–48 h following stressor application. In BALB/cByJ mice, NK activity was significantly reduced 24 h after footshock, but in contrast to the other strains returned to control levels within 48 h of stressor exposure. Central NE and DA concentrations and activity were influenced by the stressor treatment in a strain-dependent fashion. However, the relationship between the central amine variations and the alterations of NK cytotoxicity associated with the stressor was limited.

Multiple analysis of tyrosine hydroxylase and calmodulin distributions in the forebrain of the rat using a microphotometry system

Immunohistochemical distributions of tyrosine hydroxylase and calmodulin in the rat forebrain were analyzed quantitatively to confirm our previous results that the activities of central catecholamine-synthesizing enzymes are regulated by a calcium-calmodulin-dependent system. The adjacent slices of adult rat brain were stained immunohistochemically for tyrosine hydroxylase and for calmodulin, and the distributions and amounts of these proteins were measured by a fluorescence microphotometry system that was developed in our laboratory. Immunohistochemical fluorescence intensity was measured stepwise at 40 μm intervals through a 6 μmφ (on the slice) pin hole. Each stained brain slice was divided into approximately 100,000 areas, and measured for fluorescence intensity and displayed two- and three-dimensionally. Immunoreactive staining of tyrosine hydroxylase and calmodulin was observed in almost all areas of the brain, but its intensity varied. The relatively high levels of calmodulin could be observed in brain regions with high levels of tyrosine hydroxylase distribution, though high levels of tyrosine hydroxylase could not always be observed in brain regions where high levels of calmodulin were distributed. In the present study, high levels of tyrosine hydroxylase and calmodulin were distributed in the nucleus accumbens septi and the lateral part of the neostriatum regions in which the amount of dopamine was increased by the intraventricular administration of calcium. These findings suggest that the synthesis of central catecholamines is regulated by a calcium-calmodulin-dependent system.

Age-related Changes in Central Catecholamine in M-SHRSP

Age-related Changes in Central Catecholamine in M-SHRSP

Ethanol-induced CTA mediated by acetaldehyde through central catecholamine activity.

The possible involvement of catecholamines (CA) in the mediation of acetaldehyde's conditioned taste aversion (CTA) was examined by testing the effects of alpha-methyl-para-tyrosine (AMPT, a tyrosine hydroxylase inhibitor) on the CTAs produced by acetaldehyde. AMPT blocked the acquisition of the CTA normally produced by a low dose of acetaldehyde (0.2 g/kg), but had no significant effect on CTA produced by a high dose of acetaldehyde (0.3 g/kg). In a second study, acetaldehyde's role in the CTA produced by ethanol was investigated using the pre-exposure conditioned taste aversion paradigm. Pre-exposure to acetaldehyde (both doses) blocked the ethanol CTAs but when pre-exposure with acetaldehyde was coupled with AMPT, only the larger dose of acetaldehyde blocked the ethanol aversion. These results suggest that while the CTA to the low dose of acetaldehyde may be primarily central and catecholamine-mediated, the mechanism underlying the high dose CTA is probably peripheral and emetic in nature. These findings support the conclusion that acetaldehyde may be mediating many of the actions of ethanol.

Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent

Intact male and female spontaneously hypertensive rats showed a progressive increase in blood pressure with growth: males attained systolic blood pressure levels of 244 ± 6 mmHg, and females 205 ± 3 mHg at age 22 weeks. Orchidectomy at age 4 weeks significantly attenuated the systolic blood pressure elevation in the male (195 ± 4 mmHg at age 22 weeks), but ovariectomy at age 4 weeks had no effect on the development of hypertension in the female. The pattern of development of hypertension in orchidectomized males was the same as that in intact and ovariectomized females. Administration of testosterone propionate to gonadectomized rats of both sexes conferred a male pattern of blood pressure development. These results indicate that the sexually dimorphic pattern of hypertension in the spontaneously hypertensive rat is androgen dependent, rather than estrogen dependent. Plasma norepinephrine levels did not differ between the sexes, nor were they altered by gonadectomy or testosterone replacement, suggesting that the higher blood pressures in the intact male and androgen treated male and female SHR are not dependent on increased sympathetic outflow in the established phase of hypertension. Stores of norepinephrine in the posterior hypothalamic region were significantly greater in intact male rats and testosterone treated rats of both sexes than in intact or ovariectomized females, and were higher in the pons of intact female rats than in all other groups. These alterations in central catecholamine stores were not correlated with blood pressure. Further study is needed to assess the functional significance of these androgen mediated alterations in posterior hypothalamic neurons as a determinant of the androgen mediated sexual dimorphism of blood pressure in the spontaneously hypertensive rat.

The Adrenocorticotropin Response to Interleukin-1β Instilled into the Rat Median Eminence Depends on the Local Release of Catecholamines*

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRF but is unable to cross the blood brain barrier. Recently, it was reported that IL-1 beta, instilled directly into the hypothalamic median eminence (ME), rapidly induced ACTH secretion. Thus, due to the lack of a blood brain barrier the ME appears to be a site whereby iv IL-1 beta can access the brain to stimulate CRF and, consequently, ACTH secretion. To evaluate the role of central catecholamines in this process, 250 g male rats were lesioned with 6-hydroxy-dopamine instilled into the lateral ventricle. Ten days later, rats received recombinant h-IL-1 beta (10 or 30 ng) into the ME and blood was sampled via indwelling jugular cannulae. The ACTH response to IL-1 beta, 30 ng, was reduced by approximately 50% in the lesioned rats (P = 0.05), and it was abolished in those receiving IL-1 beta, 10 ng (P less than 0.05). Moreover, in rats given iv IL-1 beta (1 microgram), 6-hydroxy-dopamine significantly reduced the ACTH response by more than 50% (P less than 0.001). To determine the effect of acute epinephrine depletion, 2,3 dichloro-alpha-methylbenzylamine (DCMB, 60 mg/kg BW) and SKF64139 (SKF) (100 mg/kg BW), inhibitors of the enzyme which converts norepinephrine to epinephrine, were administered ip 4 h before intra-ME IL-1 beta (30 ng). DCMB reduced the ACTH response by 80% and SKF reduced it to its own baseline. LY 10853, which acutely depletes both norepinephrine and epinephrine, also reduced the ACTH response by 80%. Because of the reported capacities of DCMB and SKF to block alpha 2 adrenoreceptors in vitro, yohimbine, an alpha 2 receptor antagonist, was studied. Intra-ME yohimbine failed to inhibit the ACTH response to intra-ME IL-1 beta. In contrast, a significant (P less than 0.01) dose-dependent reduction in the ACTH response to intra-ME IL-1 beta (30 ng) was observed in rats pretreated with either a nonselective alpha or beta adrenoreceptor antagonist (phentolamine, 2-40 micrograms or propranolol, 2-20 micrograms, respectively, into the ME). In contrast, intra-ME phentolamine, 20 micrograms, failed to reduce the ACTH response to iv CRF, 1 microgram/kg BW. Thus, the secretion of ACTH stimulated by the action of IL-1 beta at the ME depends, in part, on the local secretion of norepinephrine and epinephrine interacting with both alpha and beta adrenergic receptors.

Catecholamine neurons in fetal brain: effects on breathing movements and electrocorticogram

We investigated the effect of increasing the synaptic concentration of catecholamines released from central pathways on breathing movements and electrocortical (ECoG) activity in fetal sheep in utero. In 11 trials (9 fetuses) intravenous infusion of the noradrenergic uptake inhibitor desipramine (DMI) resulted in an initial increase in the incidence of breathing movements from 47.8 +/- 2.2%/h to a maximum of 77.9 +/- 5.5%/h (P less than 0.05) followed by a subsequent decrease to 18.8 +/- 2.7%/h (P less than 0.05), which was associated with a decrease in the incidence of low-voltage ECoG activity. Mean breath amplitude also increased after DMI infusion from 5.8 +/- 0.2 mmHg to a peak of 8.9 +/- 0.9 mmHg (P less than 0.05). In five fetuses, intravenous injection of the alpha 1-receptor antagonist prazosin 30 min after the start of the DMI infusion blocked the increase of breath amplitude observed when DMI was given alone. Intracisternal infusion of 6-hydroxydopamine (6-OHDA, which causes an initial displacement of transmitter stores followed by a neurotoxic action) in six fetuses caused an increase in mean breath amplitude from 6.6 +/- 0.3 mmHg (control) to 22.3 +/- 5.5 mmHg (P less than 0.05) and a prolonged episode of breathing movements (168.5 +/- 47.2 min). The incidence of low-voltage ECoG activity was also increased significantly. A second infusion of 6-OHDA, 2 days after the first, had no effect on breathing movements or ECoG activities. The two treatments with 6-OHDA also resulted in a significant reduction in the response to intravenous infusion of DMI, indicating that endogenous release of norepinephrine had been reduced by the neurotoxin. These results suggest that 1) there is normally some tonic release of norepinephrine from central pathways, but this release is insufficient to stimulate sustained fetal breathing, and 2) accumulation in the synaptic cleft of catecholamines from central neurons is able to stimulate fetal breathing and promote low-voltage ECoG activity. Possible mechanisms that normally limit the activity of central catecholamine pathways before birth are discussed.

Vasopressor effects of intracerebroventricular injections of PEC-60, a novel porcine 60-residue intestinal peptide, in the awake unrestrained male rat

Intracerebroventricular injections (140–4300 pmol) of a 60-residue polypeptide (now designated PEC-60) isolated from pig intestine produced a dose-dependent increase (peak action 21% ± 2; ED 50 value of 1.7 nmol for the peak effect) in mean arterial blood pressure (MAP) in the awake, unrestrained male rat. The heart rate (HR) was significantly reduced with the highest doses used (1400 and 4300 pmol). The pancreatic secretory trypsin inhibitor (PSTI), with a high degree of sequence similarity to PEC-60, did not significantly change MAP and HR (4300 pmol). These results may indicate a biological role for the putative PEC-60-like peptide demonstrated within central catecholamine cardiovascular neurons.

Some Biological and Behavioral Features Associated with Clinical Personality Types

The author reviews supporting evidence for the existence of two personality prototypes that correspond to two DSM-III-R personality "clusters." These hypothetical personality prototypes are characterized by extreme variations along several interrelated personality trait dimensions and by differences in two biological measures. The possibility that individual differences in central serotonin and/or catecholamine activity may underlie some of the features associated with these prototypes is discussed in light of current data. The usefulness of this conceptualization as a supplemental axis of personality classification is suggested.