Availability Of Catecholamines Research Articles

Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity

ObjectiveSympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects. MethodsTo address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2LyzM−/− mice). ResultsThese animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2LyzM−/− mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation. ConclusionsOur studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.

A Catecholamine Precursor Does Not Influence Exercise Performance in Warm Conditions.

Acute doses of Sinemet® (L-DOPA combined with carbidopa) previously failed to influence prolonged exercise performance in a temperate environment, but it is not known whether acute doses of L-DOPA timed to reach maximum plasma concentrations (Cmax) during exercise will improve prolonged cycling performance in warm conditions (30.2°C ± 0.2°C, 50% ± 1%). Ten physically active men (age, 26 ± 4 yr; height, 1.76 ± 0.08 m; body mass, 76.3 ± 10.6 kg; V˙O2peak, 57 ± 8 mL·kg(-1)·min(-1)) were recruited for this study. Participants cycled for 1 h at 60% V˙O2peak followed by a 30-min exercise test, during which they were instructed to complete as much work as possible. Heart rate, skin and core temperatures, as well as RPE and thermal stress were recorded throughout the exercise, and blood samples were collected at rest, at 15-min intervals during the first hour of exercise, and at the end of the exercise test. Finger tapping tests at the beginning and end of the exercise were conducted to examine fine motor control. There was no significant difference in the work done on the placebo (314 ± 43 kJ) and L-DOPA trials (326 ± 48 kJ, P = 0.276). Prolactin concentrations were increased at the end of the exercise in all trials (P < 0.001), but this response was attenuated at the end of the exercise for the L-DOPA trial (11.4 ± 5.5 ng·mL(-1)) and placebo trials (20.8 ± 3.3 ng·mL(-1), P = 0.003). No differences between trials were found for any other measure. The results suggest that increasing central catecholamine availability inhibits the normal prolactin response to exercise in the heat but does not alter performance, thermoregulation, or sympathetic outflow.

Inhibition of catecholamine degradation ameliorates while chemical sympathectomy aggravates the severity of acute Friend retrovirus infection in mice

Several lines of evidence indicate that the sympathetic nervous system (SNS) might be involved in the pathogenesis and progression of retroviral infections. However, experimental data are scarce and findings inconsistent. Here, we investigated the role of the SNS during acute infection with Friend virus (FV), a pathogenic murine retrovirus that causes polyclonal proliferation of erythroid precursor cells and splenomegaly in adult mice. Experimental animals were infected with FV complex, and viral load, spleen weight, and splenic noradrenaline (NA) concentration was analyzed until 25days post infection. Results show that FV infection caused a massive but transient depletion in splenic NA during the acute phase of the disease. At the peak of the virus-induced splenomegaly, splenic NA concentration was reduced by about 90% compared to naïve uninfected mice. Concurrently, expression of the catecholamine degrading enzymes monoamine oxidase A (MAO-A) and catechol-O-methyltransferase (COMT) was significantly upregulated in immune cells of the spleen. Pharmacological inhibition of MAO-A and COMT by the selective inhibitors clorgyline and 3,5-dinitrocatechol, respectively, efficiently blocked NA degradation and significantly reduced viral load and virus-induced splenomegaly. In contrast, chemical sympathectomy prior to FV inoculation aggravated the acute infection and extended the duration of the disease. Together these findings demonstrate that catecholamine availability at the site of viral replication is an important factor affecting the course of retroviral infections.

The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease

IntroductionMany of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis. MethodsWe investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme. ResultsPD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81M TH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co-substrate BH4. ConclusionThe data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG.

Ingestive and locomotor behaviours induced by pharmacological manipulation of -adrenoceptors into the median raphe nucleus

The present study evaluated the involvement of α-adrenoceptors of the median raphe nucleus (MRN) in satiated rats, in food and water intake and motor behaviour. Control groups were treated with saline (SAL) or adrenaline (ADR), injected into the MRN seven minutes after injection of the vehicle used to solubilize the antagonists, propylene glycol (PLG) or SAL. Experimental groups were treated with an α-adrenoceptor antagonist, prazosin (α1, 20 or 40 nmol) or yohimbine (α2, 20 or 40 nmol) or phentolamine (non-selective α, 20 or 40 nmol), followed (later) by injection of ADR or SAL. Behaviour was recorded for 30 min. The injection of ADR and the blockade of α1 receptors resulted in hyperphagia whereas blocking α2 or α1 and α2 simultaneously did not change feeding behaviour. Pre-treatment with prazosin, followed by injection of ADR was not able to cause an increase in the amount of food ingested, while the higher dose of the α1 antagonist reduced the latency to start feeding. Pre-treatment with prazosin also caused hyperactivity. However, pre-treatment with phentolamine or yohimbine was able to block ADR-induced feeding. The present study supports the hypothesis that there is a tonic activation of α1-adrenoceptors in the MRN in satiated rats, which activates an inhibitory influence in areas that control food intake. Injection of ADR seems to activate α2 receptors, resulting in a decrease in the availability of endogenous catecholamines, which reduces the release of the signal that inhibits food intake, leading to hyperphagia.

Antidepressants: From MAOIs to SSRIs and more

Byline: Chaitra. Ramachandraih, Narayana. Subramanyam, Kral. Bar, Glen. Baker, Vikram. Yeragani The era of antidepressants started with isoniazid, an antitubercular agent, which was accidentally found to have euphoric effects in patients with tuberculosis who were receiving this drug. The mood elevating property of the drug, considered to be a side effect, became the primary effect in depression and heralded the synthesis of generations of newer antidepressants. It also shifted the focus of psychiatrists from psychodynamic processes to a biological basis of the illness. [sup][1] Isoniazid belongs to a group of hydrazine compounds, which were synthesized by Fischer in the 1870's. Isonicotinyl hydrazine (isoniazid) was synthesized by Meyer and Malley at Prague from these hydrazine compounds. Forty years later it was re-synthesized by another group of scientists. By chance, it was found to be an effective antitubercular agent. In 1952, Zeller discovered that iproniazid, another hydrazine derivative, inhibited monoamine oxidase (MAO) enzyme, so named by a group of scientists led by Blaschko and Richter in 1937. The enzyme caused the oxidation of adrenaline, a monoamine and was inhibited by ephedrine. However, Mary Hare had observed similar results in 1928 with an enzyme, tyramine oxidase, which later was found to be MAO. The MAO enzyme acts on a number of endogenous and exogenous amines (serotonin, catecholamines, tyramine, beta-phenylethylamine, benzylamine). In the year 1952, Selikoff and Robidzek observed that iproniazid had greater psychostimulatory effects than isoniazid in patients with and without tuberculosis. Subsequent studies by Smith, Kamman, and del Pino found similar stimulatory effects. The effects were described as mood elevating. The patients showed increased vigor and appetite, weight gain, improved sleep, and sociability. In some cases, it caused psychomotor agitation, hypersexuality and psychoses, behavior described as "dancing in the hall". Lurie, a private psychiatrist, coined the term "antidepressant" for the psychostimulatory effects of isoniazid in depressed patients. Until then various terms such as "thymeretics" and "psychic energizers" were used to describe these effects. Kline, Loomer, and Saunders found a correlation between the effects of the antitubercular agents and their inhibitory action on MAO and used iproniazid for the first time on a group of patients with depression. They recorded significant improvement in 70% of the patients. Later studies showed that its MAO-inhibiting property increased serotonin levels in the brain similar to the effects seen with 5-hydroxytrytophan, a precursor of serotonin, which crosses the blood-brain barrier. This was also substantiated by the reversal of reserpine-induced depression by iproniazid, as reserpine depletes biogenic amines. These studies showed promising results in depression through clinical and biochemical observations, Iproniazid was launched as an antitubercular agent because of disagreements among psychiatrists and also due to its hepato and nephrotoxicity. The drug and some other hydrazine derivatives were later taken off of the market. [sup][2],[3] The above findings paved the way to the develolpment of the first class of exclusive MAO inhibitors such as isocarboxazid, tranylcypramine, phenelzine, mebanazine, nialamide, pheniprazine, and etryptamine (an indole derivative). In the meantime, the enzyme MAO was reported by Johnston, in 1968, to exist in two isomeric forms. MAO-A was found in the small intestine and MAO-B was extracted from rat brain. MAO-A deaminated adrenaline, noradrenaline, and serotonin, whereas MAO-B acted on benzylamine and [sz]-phenylethylamine. Dopamine and tyramine were the substrates for both of the isomeric forms. The classical MAO inhibitors such as tranylcypramine and phenelzine inhibited both the isoenzymes. Tranylcypramine, a derivative of cyclopropylamine, was first used in 1959 as an antidepressant, and soon MAO inhibitors became frequently prescribed antidepressants. …

Antidepressant response to electroconvulsive therapy is sustained after catecholamine depletion

Although the antidepressant mechanism of ECT is unknown, there are data to support noradrenergic involvement. Patients who had been recently successfully treated with ECT for major depression were studied in a randomized double-blind cross-over design comparing catecholamine depletion using α-methyl-para-tyrosine to a placebo procedure. Mean MADRS scores at baseline (4.2 SD 2.7) and following depletion (4.6 SD 1.1) were similar, despite a 57.7% decrease in serum homovanillic acid (HVA) and a 61.5% decrease in 3-methoxy-4-hydroxyenylethyleneglycol (MHPG). These data suggest that catecholamine availability may not be necessary for acutely maintaining an antidepressant response to ECT.

Brain monoamines and early visual information-processing speed

Visual inspection time (IT) is a measure of information-processing speed, which correlates reliably with psychometric intelligence. Pharmacological research into IT indicates that manipulation of the cholinergic system modulates performance on the IT task, however the contribution of other neurotransmitters to this modality remains unclear. This study was designed to examine the effects of low brain serotonin and catecholamine availability on IT using the established method of amino-acid precursor depletion. Female participants (n=13) completed three experimental sessions; tryptophan depletion (TD); tyrosine/phenylalanine depletion (TPD); and a balanced control condition (B) in a randomized, double-blind cross-over design. IT assessments were performed at baseline and approx. 5 h post-mixture administration. IT scores were unaffected by either of the treatment conditions. These findings suggest that monoamines, whilst implicated in various forms of cognition are not central to IT, which measures the efficiency of perceptual intake and information-processing speed.

ACUTE CHANGES IN 3H-PAC AND 125I-PYY BINDING IN THE NUCLEUS TRACTUS SOLITARII AND HYPOTHALAMUS AFTER A HYPERTENSIVE STIMULUS

Activation of alpha-2-adrenergic and neuropeptide Y (NPY) receptors in the nucleus tractus solitarii (NTS) induces hypotension and bradycardia. On the contrary, activation of angiotensin II (Ang II) receptors leads to hypertension. Acute changes in binding parameters of alpha-2-adrenergic, NPY and Ang II receptors were evaluated in the NTS and paraventricular hypothalamic nucleus (PVN) of rats after a hypertensive stimulus employing quantitative receptor autoradiography. Saturation experiments showed a decrease in the number (Bmax) of alpha-2-adrenergic binding sites in the NTS 6 hours after coarctation-induced hypertension. Furthermore, the affinity of NPY receptors was diminished as seen by the increase in the KD value of 125 I-PYY. Tyrosine hydroxylase and NPY immunoreactivities were increased in the NTS and ventral medulla. Binding of 125 I-Ang II was not changed in the NTS. Binding of all ligands analyzed was not altered in the PVN. The results suggest an acute down-regulation of alpha-2-adrenergic and NPY receptors involved with hypotension in response to hypertensive stimulus, which might be related to an increased availability of catecholamines and NPY in the NTS.

A brain Na +, K +-ATPase inhibitor (endobain E) enhances norepinephrine release in rat hypothalamus

We have shown that synaptosomal membrane Na +, K +-ATPase activity is stimulated or inhibited by norepinephrine according to the presence or absence of a brain soluble fraction. Gel filtration of such soluble fraction has allowed the separation of two fractions, peaks I and II, able to stimulate and inhibit Na +, K +-ATPase activity, respectively. Peak II behaves much like ouabain, which has suggested the term endobain. From peak II, a subfraction termed II-E (endobain E), which highly inhibits Na +, K +-ATPase, has been separated by anionic exchange chromatography in a Synchropack AX-300 column. We determined the in vitro effect of endobain E obtained from rat cerebral cortex on neuronal norepinephrine release by incubating rat hypothalamic tissue in the presence of [ 3H]norepinephrine. Neuronal norepinephrine release was quantified as the factor above basal [ 3H]norepinephrine released to the medium at experimental and three post-experimental periods. Endobain E was found to increase norepinephrine release in a concentration-dependent fashion, reaching 200%, equivalent to the effect achieved with 400 μM ouabain. Ouabain effect persisted along three post-experimental periods whereas that of endobain E remained only during the first post-experimental period. These results led us to conclude that endobain increases norepinephrine release in hypothalamic neurons at the presynaptic nerve ending level, an effect resembling that of ouabain. It is postulated that endobain E may enhance catecholamine availability in the synaptic gap, leading to an increase in noradrenergic activity.

The effects of hydergine on the MAO activity of the aged and adult rat brain

Despite the fact that hydergine has been used in the treatment of dementia for many years, its mechanism of action is still not clear. Current studies imply that the major effect of hydergine may be the modulation of synaptic neurotransmission rather than solely increasing blood flow as was once thought. A prominent feature that accompanies aging is an increase in monoamine oxidase (MAO) levels which results in decreased availability of catecholamines in the synaptic cleft. The aim of this study was to determine the effects of hydergine on the MAO activity in different brain regions (cortex, olfactory bulb, hypothalamus, hippocampus, striatum, cerebellum) of old (30 months) and adult (12 months) male Sprague-Dawley rats. In cortex and olfactory bulb MAO levels were higher in the aged group. In hippocampus and hypothalamus hydergine treatment caused significant decreases in MAO levels. An interaction between age and hydergine treatment was observed in the hypothalamus, hippocampus and cerebellum. The hydergine effect was more pronounced in the aged group in the hypothalamus and cerebellum, and more pronounced in the adult in the hippocampus. Our findings imply that increased brain MAO activity in aging can be modified by hydergine treatment in some brain regions.

Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart

S(+)-Ketamine is judged to produce more potent anesthesia than either the racemate or the R(-) ketamine isomer because of differential activation of specific cerebral receptors. Other than central nervous system effects, the most important side effects of ketamine occur in the cardiovascular system. We examined the direct cardiac effects of the isomers and the racemate of ketamine in the isolated perfused guinea pig heart. Twenty-three guinea pig hearts were perfused by the Langendorff technique with modified 37 degrees C Krebs-Ringer's solution (97% oxygen and 3% carbon dioxide) at a constant perfusion pressure. Eight animals were pretreated with reserpine to deplete hearts of catecholamines. These pretreated hearts were also perfused with Krebs-Ringer's solution containing propranolol, phenoxybenzamine, and atropine to block any remaining effects of catecholamines and of acetylcholine. Five additional hearts were perfused with naloxone to block cardiac opioid receptors. Ten hearts were not treated. All 23 hearts were then exposed to four increasing equimolar concentrations of each isomer and the racemate of ketamine for 10 min. Heart rate, atrioventricular conduction time (AVCT), left ventricular pressure, coronary flow, and inflow and outflow oxygen tensions were measured. Percentage oxygen extraction, oxygen delivery, and oxygen consumption were calculated. Both isomers and the racemate caused a concentration-dependent depression of systolic left ventricular pressure and an increase in AVCT. In the untreated hearts, S(+)-ketamine decreased heart rate and left ventricular pressure and, at higher concentrations, oxygen consumption and percentage oxygen extraction significantly less than R(-)-ketamine independent of blocked or unblocked opioid receptors. Racemic ketamine depressed cardiac function to a degree intermediate to that produced by the isomers. Coronary flow and AVCT were equally affected by the isomers and by the racemic mixture. In the catecholamine-depleted hearts both isomers and the racemate caused equipotent depression of all variables. In these hearts cardiac depression was greater, and AVCT, coronary flow, and oxygen delivery were significantly greater than in untreated and opioid receptor-blocked hearts. Lesser cardiac depression by the S(+) isomer is attributable to an increased availability of catecholamines, because previous depletion of catecholamine stores and autonomic blockade completely inhibited these differences. The inability of cardiac tissue to reuptake released catecholamines into neuronal or extraneuronal sites during exposure to ketamine is stereoselective and caused predominantly by the S(+) isomer. Cardiac opioid receptors are apparently not involved in this phenomenon.

Blockade of α-and β-adrenergic receptors can prevent stimulation of liver ornithine decarboxylase activity by glucocorticoid or laparatomy

Rat liver ornithine decarboxylase induction by dexamethasone or laparatomy, which is dramatically impaired by catecholamine depletion, is not affected by α-and β-adrenergic blockers administered simultaneously 1 h prior to steroid injection or operation. However, if blockade is maintained for 24 h, an effect comparable to that of catecholamine depletion is obtained. Reciprocally, the response of the decarboxylase to catecholamines is severely compromised in adrenalectomized rats. Under the same conditions, induction of tyrosine aminotransferase by dexamethasone is not significantly affected by catecholamine availability, which altogether demonstrates that rat liver ornithine decarboxylase activity is specifically governed by the interaction between glucocorticoids and catecholamines.

Electrophysiological effects of a chemical defibrillatory agent, dibenzepin

The aim was to study the cellular cardiac electrophysiological effects of the antifibrillatory drug, dibenzepin. Standard microelectrode techniques were used to measure the effects of dibenzepin (3 microM, 9 microM) on conduction time, Vmax and input resistance in canine papillary muscles, in vitro, at three paced cycle lengths (1000, 400, 200 ms). Results were compared when adrenaline (0.5-5 microM) or propranolol (0.2 microM) were present. Papillary muscles (n = 25) from hearts of adult mongrel dogs, weight 13-18 kg, were used. Dibenzepin, at 3 microM, caused significant reduction of Vmax at cycle lengths less than or equal to 400 ms. Paradoxically, the conduction time decreased at all three cycle lengths when measured along the longitudinal axis of the fibre between two microelectrodes spaced 2 mm apart. Superfusion of dibenzepin (3 microM) and propranolol (0.2 microM) significantly reduced Vmax and lengthened conduction time at all cycle lengths. Dibenzepin reduced input resistance from 1.45 to 0.76 M omega, thereby suggesting that improved coupling may occur between cells to account for the shortening of conduction time. Propranolol blocked these results. The defibrillatory action of dibenzepin may be related to a decreased intercellular resistance caused by increased catecholamine availability during fibrillation. This would result in improved conduction and, thereby, a decrease of the critical number of asynchronous re-entrant circuits necessary to maintain fibrillation.

Catecholamine training effects from exercise programs: A bridge to exercise-temperament relationships

Three studies were conducted to test whether a catecholamine training effect results from a long-term aerobic exercise program. Study I showed significant increases in urinary adrenaline and noradrenaline following moderate mental stress/challenge for male aerobics subjects after a semester of training. Control groups of nonexercisers and continuously in-condition marathoners showed no comparable pre- to post semester catecholamine increases. Male and female Aerobics subjects were contrasted with nonexercisers across a semester in Study 2; the hypothesis was confirmed that postsemester increases in catecholamines occurred only following an episode of mental challenges/stress, and not following base-rate-rest conditions. Under conditions of more active challenge than in Studies 1 and 2, women subjects in Study 3 provided directional but nonsignificant support for the Study 2 findings. The results are discussed in the context of literature on the relationship of catecholamine availability during challenge/stress to temperament and on the relationship of aerobic training to temperament. At a theoretical level, the question is discussed of increased catecholamine availability being a likely mediator in the exercise program to temperament relationship.

Strain-specific differences in levels of the mRNA for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase

The activity of the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) is 3- to 8-fold greater in rats of the Fischer 344 and Buffalo strains. The biochemical basis for the strain difference has been analyzed at the level of PNMT protein and messenger RNA production. Fischer rat adrenals possess approximately 5-fold more PNMT protein than those of the Buffalo rat as established by Western blotting and immunoprecipitation of adrenal gland homogenates. Poly(A)+ RNAs purified from adrenal glands of each strain were translated in a reticulocyte lysate system, immunoprecipitated with antibody to PNMT and fractionated by SDS-PAGE. A 35S-labelled protein of Mr = 34,000 was immunoprecipitated from adrenals of Fischer and Buffalo rats, indicating that the molecular weights of PNMT do not differ in these strains prior to post-translational processing. Hybridization of a 740 base pair (bp) cDNA for PNMT indicated that the mRNAs for PNMT are the same size in the adrenals of both strains. However, the adrenals of Fischer rats contain 2- to 4-fold more PNMT mRNA than Buffalo rats, as established by quantitative dot blot hybridization and Northern blot analysis. The medulla oblongata, the site of cell bodies of central adrenergic neurons, also contains approximately 2-fold more PNMT mRNA in Fischer rats. The strain specificity in the production of PNMT reflects differences in the expression of the gene for PNMT. Thus, an inherited capacity for PNMT expression may in fact provide the intrinsic determinants responsible for neurotransmitter production. These data provide a direct link between regulation of catecholamine enzyme biosynthesis at the genomic level and the availability of specific catecholamines for neurotransmitter and hormonal functions.

Potentiation of cold-water swim analgesia by acute, but not chronic desipramine administration

Like other stress responses, cold-water swim (CWS) analgesia can be altered by changes in norepinephrine (NE) availability. While clonidine pretreatment potentiates CWS analgesia, lesions placed in the noradrenergic locus coeruleus reduce this response. Desipramine (DMI) can alter both the availability and receptor function of catecholamines, particularly NE: while both acute and chronic DMI treatments decrease NE reuptake, subsensitivity of beta-adrenergic receptors occurs only after chronic DMI treatment. The present study examined whether acute and chronic DMI treatments differentially alter CWS analgesia as measured by the jump test. CWS hypothermia and basal jump thresholds. The first experiment determined that pretreatment at either 24, 5 and 1 hr or only at 1 hr with DMI doses of 20 and 5 but not 1 mg/kg potentiated CWS analgesia. The second experiment found that chronic DMI pretreatment at a dose of 10 mg/kg administered twice daily over seven days failed to alter CWS analgesia at 1, 24, 48 or 72 hr thereafter. Neither CWS hypothermia nor basal jump thresholds were affected by the acute or chronic DMI injection regimens. The selective potentiation of CWS analgesia by acute DMI pretreatment is discussed in terms of the differential actions of acute and chronic injection regimens upon NE availability, receptor function, and adaptation processes.

Effects of carbamazepine and anti-depressant drugs on endogenous catecholamine levels in the cerebroventricular compartment of the rat.

Concentrations of endogenous norepinephrine, dopamine and epinephrine in cerebroventricular perfusates were used to evaluate the effects of drugs on the availability of extracellular catecholamines in the intact rat brain. Administration of the antidepressant drugs imipramine, desmethylimipramine or tranylcypromine resulted in marked increases of both norepinephrine and dopamine concentrations while epinephrine levels were not affected. Treatment with a similar dose of carbamazepine - an anticonvulsant drug with antidepressant activity - resulted in a significant increase in dopamine concentrations without apparent effect on either norepinephrine or epinephrine. It is suggested that at the applied dose, carbamazepine may act to modify the uptake, release or metabolism of dopamine in brain areas adjacent to the cerebroventricular space without affecting the other catecholamines.

Ascorbic acid and the prevention of the early action of cadmium on scrotal and cryptorchid testes in the rat.

An injection of cadmium chloride at a dose level of 0.45 mg/100 g bw, exerts a differential deleterious influence on cryptorchid and contralateral scrotal testes of the same rat. A considerable damage of the cryptorchid testis is caused, with degenerative changes, after 72h following cadmium administration. However, a concomitant regimen of ascorbic acid, a potent antitoxic agent as well as a blocker of nonspecific stresses, prevents those testicular lesions quite appreciably. On the basis of our experimental documentation we believe that the adverse influence of cadmium at the testicular level might be a mediation of the metabolic alteration due to an augmented availability of endogenous catecholamines.

Reversal of stress-induced analgesia by apomorphine, but not by amphetamine

Acute exposure to severe stressors induce profound analgesia as well as depleting catecholamine levels. The present study examined whether d-amphetamine and apomorphine, agents which increase catecholamine availability, would alter the analgesic effectiveness of cold-water swims (CWS) and 2-deoxy-D-glucose (2-DG) as measured by an operant liminal escape procedure. Two groups of 10 rats each were tested to determine alterations in liminal escape threshold functions following amphetamine at doses of 0.25, 0.5, 1,2 mg/kg and following apomorphine at doses of 0.025, 0.05, 0.1, 0.2 mg/kg. Half of the amphetamine and half of the apomorphine groups were tested across their respective dose ranges for the drug effects upon CWS analgesia. The remaining animals in each group received 2-DG (600 mg/kg IP) alone followed by 2-DG paired with each stimulant dose. No dose of amphetamine or apomorphine alone altered escape thresholds. While amphetamine produced slight potentiations of 2-DG analgesia at the two low doses, apomorphine at the 0.05 and 0.1 mg/kg doses returned CWS and 2-DG analgesia to within normal placebo values. These results provide indirect evidence for a role for brain norepinephrine and dopamine in stress-induced analgesia, and these data are discussed with respect to catecholamine involvement in pain-inhibitory processes.