The comparative effect of serotonin agonists on the presynaptic and somatodendritic autoreceptors of serotoninergic neurons

Experimenting on the slices of cortex and dorsal raphe nucleus of midbrain of rats which were incubated with 3H-hydroxytrypta-mine (3H-HT) studies showed the influence of series of serotonin agonists on the spontaneous and electrically stimulated release of 3H-HT from the slices. It was established that the serotonin in concentration of 10(-5) mol/l similarly inhibits the release of 3H-HT from the electrically stimulated slices of the brain cortex (78.6%) and on slices of the dorsal raphe nucleus of the midbrain (81.6%) had no effect on the spontaneous release of serotonin. The serotonin agonists in order of increasing ability to inhibit the electrically stimulated release of 3H-HT from the cortex slices is as follows: ipsapirone (0%), 8-OH-DPAT (23%), kampirone (26.5%), 1.2-PP (28.6%), kaplapirone (35.7%), buspirone (48%) and TFMPP (67%). On the ability to influence the release of 3H-HT from the electrically stimulated slices of the dorsal raphe nucleus of the midbrain of the rats serotonin agonists were in the following order: TEMPP (12.3%), kampirone (40%), 1.2-PP (42.9%), ipsapirone (52%), 8-OH-DPAT (54.1%), kampirone (57.2%) and buspirone (65.3%). It is suggested that the effect of both ipsapirone, kampirone and 8-OH-DPAT is greatly localized on the somato-dendritic synapses P1A-HT receptors, TEMPP is more on the terminal axons of HT-ergic neurones while kampirone, buspirone and active metabolite 1.2-PP act on the presynaptic and somatodendritic autoreceptors of serotonin.     

Effect of antidepressants with different chemical structures on the uptake and release of norepinephrine in sections of the rat cerebral cortex

Experiments with slices of the rat cortex were made to study the interaction between the ability of the antidepressants to inhibit the reverse uptake of 14C-noradrenaline and to inhibit its presynaptic release. The antidepressants studied are distributed into 3 groups according to the ratio of effective concentrations that block the uptake and enhance the release of 14C-noradrenaline from the slices. The first group includes the antidepressants (melipramine, chlorimipramine, Lu 5-003, Lu 3-010, S-394, pyrazidol) that have a ratio close to I and in whose mechanism of aminopotentiating action the main component is unlikely to be distinguished. The second group with a ratio less than I is represented by the substances (nortryptyline, desipramine) whose mechanism of the aminopotentiating action is determined by the inhibitory effect on the neurotransmitter reverse uptake. As to the 3d group antidepressants (thyroliberin, iprindol, noveril, C-356, C-395, amitryptyline), of great importance is their effect on the presynaptic neurotransmitter release from the terminals of the axons of noradrenergic neurons.     

Effect of long-term administration of the antidepressant drug milnacipran on serotonergic and noradrenergic neurotransmission in the rat hippocampus

The effect of a long-term administration of the antidepressant milnacipran on the function of the serotonergic (5-HT) and noradrenergic (NE) systems was studied using single cell recording of CA3 hippocampal pyramidal cells in chloral hydrate-anesthetized male Sprague-Dawley rats, and in vitro [3H]5-HT release measurement from hippocampal slices. The sensitivity of neither the extrasynaptic nor that of the postsynaptic 5-HT1A receptors of the pyramidal neurons was altered, as indicated by their unchanged responsiveness to the microiontophoretic application of 5-HT, and by the unchanged effect of the electrical stimulation at low frequency of the ascending 5-HT bundle, respectively. Increasing the frequency of stimulation (from 1 to 5 Hz) decreased its efficacy in control rats; the milnacipran treatment abolished this phenomenon. This cannot be attributed to a desensitisation of the terminal 5-HT1B autoreceptor, since the suppressive effect of 5-HT agonist 5-carboxyamidotryptamine on [3H]5-HT release was enhanced in milnacipran-treated rats. As for the NE system, the unchanged suppressing effect of microiontophoretic applications of NE and that of the 5 Hz stimulation in the locus coeruleus (LC) on the firing activity of pyramidal neurons indicates that the milnacipran treatment not altered the sensitivity of extrasynaptic alpha2- and postsynaptic alpha1-adrenergic receptors on pyramidal cells, as well as that of the presynaptic alpha2-autoreceptor on NE terminals. The decreased inhibitory effect of NE on the [3H]5-HT release in milnacipran-treated rats revealed that this treatment results in a desensitisation of the presynaptic alpha2-heteroreceptor located on serotonergic terminals. Taken together with the decreased suppressive effect of a low frequency of stimulation of the NE tract, the present results suggest that long-term milnacipran treatment enhances the efficacy of the 5-HT and reduces that of the NE neurotransmission.     

Chronic treatment with zinc and antidepressants induces enhancement of presynaptic/extracellular zinc concentration in the rat prefrontal cortex

Zinc exhibits antidepressant-like activity in preclinical tests/models. Moreover, zinc homeostasis is implicated in the pathophysiology of affective disorders. The aim of the present study was to examine the effect of chronic zinc, citalopram and imipramine intraperitoneal administration on the presynaptic and extracellular zinc concentration in the rat prefrontal cortex and hippocampus. We used two methods: zinc–selenium histochemistry (which images the pool of presynaptic-vesicle zinc) and anodic stripping voltammetry (ASV) for zinc determination in microdialysate (which assays the extracellular zinc concentration). We report that chronic (14×) zinc (hydroaspartate, 10 and 65 mg/kg) and citalopram (20 mg/kg) administration increased the pool of presynaptic zinc (by 34, 50 and 37%, respectively) in the rat prefrontal cortex. The 21% increase induced by imipramine (20 mg/kg) was marginally significant. Likewise, zinc (hydroaspartate, 65 mg/kg), citalopram and imipramine increased the extracellular zinc (although with a different pattern: time point, area under the curve and/or basal level) in this brain region. Furthermore, zinc induced an increase in presynaptic (by 65%) and extracellular zinc (by 90%) in the hippocampus, while both citalopram and imipramine did not. These results indicate that all of the treatments increase presynaptic/extracellular zinc concentrations in the rat prefrontal cortex, which may then contribute to their antidepressant mechanisms. Alterations induced by zinc (but not antidepressants) administration in the hippocampus may be related to specific zinc mechanisms. All the data (previous and present) on the effect of antidepressant treatments on the presynaptic/extracellular zinc concentrations suggest the involvement of this biometal presynaptic/synaptic homeostasis in the antidepressant mechanism(s).     

Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.     

Modification of presynaptic CaM kinase II affinity for ATP in hippocampus after long term blockade of serotonin reuptake

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is markedly enriched at synapses, where it is involved in the control of synaptic transmission, transmitter release and synaptic plasticity. CaMKII has also been found to be involved in the long-term action of antidepressants on post-receptor signaling mechanisms, because monoamine reuptake inhibitors induced an increase in autophosphorylation and activity of the kinase in nerve terminals of hippocampus. To study whether changes in the amount of enzyme or kinetic changes, due to posttranslational modifications, are responsible for kinase activation in nerve terminals, alpha-CaMKII level and kinetic constants of the autophosphorylation reaction as a function of ATP concentration were measured in presynaptic cytosol from hippocampus. Treatment with two serotonin reuptake inhibitors did not change the level of presynaptic kinase or the Vmax of autophosphorylation reaction. Instead the Km of the kinase for ATP was decreased 2.8-fold with fluvoxamine and 3.5-fold with paroxetine, implying an increase in the affinity for ATP. This result represents the first finding of changes in kinetic constants of a major brain enzyme after treatment with antidepressant drugs.     

H3-Receptors Control Histamine Release in Human Brain

The regulation of histamine release was studied on slices prepared from pieces of human cerebral cortex removed during neurosurgery and labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration induced [3H]histamine release, although to a lesser extent than from rat brain slices. Exogenous histamine reduced by up to 60% the K+-evoked release, with an EC50 of 3.5 +/- 0.5 X 10(-8) M. The H3-receptor antagonists impromidine and thioperamide reversed the histamine effect in an apparently competitive manner and enhanced the K+-evoked release, indicating a participation of endogenous histamine in the release control process. The potencies of histamine and the H3-receptor antagonists were similar to those of these agents at presynaptic H3-autoreceptors controlling [3H]histamine release from rat brain slices. It is concluded that H3-receptors control histamine release in the human brain.     

Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats

We have shown recently that cholecystokinin octapeptide (CCK-8s) increases glutamate release from nerve terminals onto neurons of the nucleus tractus solitarius pars centralis (cNTS). The effects of CCK on gastrointestinal-related functions have, however, been attributed almost exclusively to its paracrine action on vagal afferent fibers. Because it has been reported that systemic or perivagal capsaicin pretreatment abolishes the effects of CCK, the aim of the present work was to investigate the response of cNTS neurons to CCK-8s in vagally deafferented rats. In surgically deafferented rats, intraperitoneal administration of 1 or 3 mug/kg CCK-8s increased c-Fos expression in cNTS neurons (139 and 251% of control, respectively), suggesting that CCK-8s' effects are partially independent of vagal afferent fibers. Using whole cell patch-clamp techniques in thin brain stem slices, we observed that CCK-8s increased the frequency of spontaneous and miniature excitatory postsynaptic currents in 43% of the cNTS neurons via a presynaptic mechanism. In slices from deafferented rats, the percentage of cNTS neurons receiving glutamatergic inputs responding to CCK-8s decreased by approximately 50%, further suggesting that central terminals of vagal afferent fibers are not the sole site for the action of CCK-8s in the brain stem. Taken together, our data suggest that the sites of action of CCK-8s include the brain stem, and in cNTS, the actions of CCK-8s are not restricted to vagal central terminals but that nonvagal synapses are also involved.     

Enhancement of Endogenous Release of Glutamate and γ-Aminobutyric Acid from Hippocampus CA1 Slices After In Vivo Long-Term Potentiation

The effect of long-term potentiation (LTP) on endogenous amino acid release from rat hippocampus slices was studied. LTP was induced in vivo by application of a tetanus (200 Hz, 200 ms) to the Schaffer collateral fibers in unanesthetized rats. Endogenous release of glutamate and gamma-aminobutyric acid (GABA) was investigated 60 min after tetanization in CA1 subslices of potentiated and control rats. No significant effects of LTP were observed in basal and K(+)-induced Ca(2+)-independent release components of these amino acids. In contrast, K(+)-induced Ca(2+)-dependent release of both glutamate and GABA increased approximately 100% in slices from potentiated rats. No differences were observed in total content of glutamate and GABA between the subslices from control and LTP animals. These results suggest a persistent increase in the recruitment of the presynaptic vesicular pool of glutamate and GABA during LTP.     

Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system

1. A review of the effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system is presented. 2. The effects of antidepressants on adenylate cyclase activity and on receptor binding in brain tissue are discussed. Effects on a variety of receptor types are considered. 3. The utilization of electrophysiological, behavioral, and neurochemical studies to assess receptor function after chronic antidepressant administration is discussed, as is the use of peripheral receptor estimations in clinical studies. 4. Animal studies on the actions of chronic administration of neuroleptics on pre- and postsynaptic dopamine receptors are reviewed. Effects of these drugs on dopamine receptors in humans are considered from the following perspectives: postmortem and in vivo binding studies in schizophrenia, tardive dyskinesia, and central versus peripheral receptor estimation.     

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.     

Presynaptic modulation of evoked NE release contributes to sympathetic activation after pressure overload

Activation of the sympathetic nervous system is well documented in heart failure. Our previous studies demonstrated an increase in evoked norepinephrine (NE) release from left ventricle (LV) slices at 10 days of pressure overload. The purpose of this study was to test the hypothesis that presynaptic modulation of NE release contributes to sympathetic activation after pressure overload. We examined the functional status of the presynaptic alpha(2)- and beta(2)-receptors and ANG II subtype 1 (AT(1)) receptors in LV slices from 10-day aortic constricted (AC) and sham-operated (SO) rats. Evoked (3)H overflow from LV slices preloaded with [(3)H]NE was increased in AC rats. The alpha(2)-agonist UK-14,304 decreased evoked (3)H overflow with no differences between groups. The beta(2)-agonist salbutamol increased evoked (3)H overflow with greater sensitivity in slices from AC rats. The beta-antagonist propranolol decreased evoked (3)H overflow from LV slices of AC rats but not controls. ANG II increased evoked (3)H overflow with greater sensitivity in slices from AC rats. These data support the hypothesis that aberrant presynaptic modulation of catecholamine release contributes to sympathetic activation after pressure overload.     

Chronic Antidepressant Administration Alters the Subcellular Distribution of Cyclic AMP-Dependent Protein Kinase in Rat Frontal Cortex

The influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by approximately 25%, whereas enzyme activity was increased in the particulate fractions by approximately 20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant drugs, because representatives of several other classes of psychotropic drugs-namely, haloperidol, morphine, and diazepam--failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the clinical actions of these treatments.     

Effect of long-term administration of antidepressants on the lipid composition of brain plasma membranes

The connection between changes in lipid pattern in brain plasma membranes and long-term administration of therapeutically effective doses of antidepressants has not been sufficiently demonstrated so far. Therefore, we analyzed effect of antidepressants that differ in pharmacological selectivity on membrane lipid composition in the rat brain tissue. Laboratory rats were given desipramine, maprotiline, citalopram, moclobemide or lithium for a 4-week period. We observed a significant decrease in phosphatidylethanolamine representation after administration of maprotiline, citalopram and moclobemide when compared with controls. Membrane cholesterol content was decreased after desipramine administration and increased after citalopram or lithium treatment. Electroneutral phospholipids were decreased after the administration of all tested antidepressants except for desipramine. Decrease in phosphatidylserine was found following long-term administration of maprotiline or desipramine; relative representation of phosphatidylinositol was reduced after lithium treatment. Statistically significant negative correlation between cholesterol and electroneutral phospholipids was discovered. Membrane microviscosity evaluated by fluorescence anisotropy of membrane probes was only slightly decreased after desipramine and increased after citalopram administration. Hypothesis was supported that changes in brain neurotransmission produced by antidepressants could be, at least partially, associated with adaptive changes in membrane cholesterol and phospholipids.     

Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs

Depression has been treated pharmacologically for over three decades, but the views regarding the mechanism of action of antidepressant drugs have registered recently a major change. It was increasingly appreciated that adaptive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are connected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphorylation, which represents an obligate step for most pathways, is markedly affected by long-term treatment. Changes were reported to be induced in the function of protein kinase C, cyclic AMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase. For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolated neuronal compartments (microtubules and presynaptic terminals). Antidepressant treatment activates the two kinases and increases the endogenous phosphorylation of selected substrates (microtubule-associated protein 2 and synaptotagmin). These modifications may be partly responsible for the changes induced by antidepressants in neurotransmission. The changes in protein phosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.     

Effect of tianeptine and fluoxetine on the levels of Met-enkephalin and mRNA encoding proenkephalin in the rat.

The purpose of the present study was to evaluate the effects of acute and repeated treatment with two antidepressant drugs (ADs) of opposite pharmacological profile, i.e. tianpetine (TIA, serotonin reuptake enhancer) and fluoxetine (FLU, serotonin reuptake inhibitor) on the levels of Met-Enkephalin, (Met-Enk, a member ofopioid peptide family, which has been suggested to play a role in the mechanism of action ADs) as well as on mRNA coding for proenkephalin (mRNA PENK) in various regions of the rat brain, pituitary, adrenal glands and plasma. Male Wistar rats were treated acutely or repeatedly (10 mg/kg p.o., twice daily for 14 days) with TIA or FLU. Tissue for biochemical experiments was taken 2 h after last dose of appropriate drug. The levels of Met-Enk were estimated by radioimmunoassay, mRNA PENK was measured using in situ hybridization. From the results obtained in the present study it may be concluded that repeated administration of TIA or FLU induced similar changes in the levels of Met-Enk in the rat hippocampus, striatum, hypothalamus and neurointermediate lobe of pituitary. Such an effect is interesting, especially if one takes into account the differences in pharmacological profile between these two antidepressant drugs. It may be suggested that serotonin level might not be crucial for inducing the alterations in the content of Met-Enk. Since we did not observe any changes in the levels of PENK mRNA in the studied rat brain regions after repeated administration of TIA or FLU, it seems that the observed changes in the levels of Met-Enk do not result from effects of these antidepressants on biosynthesis of PENK, but rather from alterations in the peptide release. Another interesting finding of the present study was that in the anterior lobe of pituitary, adrenal glands and plasma, repeated administration of TIA induced alterations in the contents of Met-Enk, while repeated administration of FLU remained without any effect. It is tempting to speculate that such a differentiation between the effects of these two antidepressants might be linked to the well known feature of TIA (but not FLU) which has been shown to reduce both basal and stress-evoked activity of the hypothalamic-pituitary-adrenal (HPA) axis.     

Treatment of C6 Glioma Cells and Rats with Antidepressant Drugs Increases the Detergent Extraction of Gsα from Plasma Membrane

Results from previous studies suggested that chronic treatment of rats or C6 glioma cells with antidepressants augments the coupling between Gs and adenylyl cyclase. As these effects on C6 glioma cells are seen in the absence of presynaptic input, several antidepressant drugs may have a direct "postsynaptic" effect on their target cells. It was hypothesized that the target of antidepressant action was some membrane protein that may regulate coupling between G proteins and adenylyl cyclase. To test this, C6 glioma cells were treated with amitriptyline, desipramine, iprindole, or fluoxetine for 3 days. Chlorpromazine served as a control for these treatments. Membrane proteins were extracted sequentially with Triton X-100 and Triton X-114 from C6 glioma cells. Triton X-100 extracted more G(s alpha) in membranes prepared from antidepressant-treated C6 glioma cells than from control groups. In addition, cell fractionation studies revealed that the amount of G(s alpha) in caveolin-enriched domains was reduced after antidepressant treatment and that adenylyl cyclase comigrated with G(s alpha) in the gradients. These data suggest that some postsynaptic component that increases availability of Gs to activate effector molecules, such as adenylyl cyclase, might be a target of antidepressant treatment.     

Effects of LF-14, THA and physostigmine in rat hippocampus and cerebral cortex

The effects of physostigmine, tetrahydroaminoacridine (THA) and LF-14 [3,3-dimethyl-1(4- amino-3-pyridyl)urea], a 3,4-diaminopyridine derivative, were compared on inhibition of acetyl- cholinesterase (AChE) activity, and release of [³H]acetylcholine (ACh) from rat brain cortical and hippocampal slices. All three compounds caused a concentration dependent inhibition of AChE, with an order of potency physostigmine > THA > LF-14. The electrically stimulated release of ACh from hippocampal and cortical slices was decreased by 10⁻⁵M physostigmine, although the effect was significant only in cortex. THA (5 × 10⁵M) caused a slight, but not significant, decrease in ACh release from both tissues. In contrast, LF-14 (5 × 10⁻⁵ M) caused an approx. 3-fold enhancement of stimulated release. When AChE was inhibited by prior addition of physostigmine, THA caused only a slight enhancement of ACh release, whereas LF-14 greatly increased release. ACh release was also reduced by stimulation of presynaptic muscarinic receptors with oxotremorine. In this case, THA had no effect on ACh release, while LF-14 was able to reverse the inhibition. This study suggests that LF-14 acts to promote ACh release through blocking K⁺ channels, and has a less potent AChE inhibitory effect. It is possible that a compound like LF-14 could be useful in treating diseases of cholinergic dysfunction such as Alzheimer's disease, by both promoting the release of ACh and inhibiting its breakdown.     

Differential presynaptic effects of hexachlorocyclohexane isomers on noradrenaline release in cerebral cortex.

To investigate presynaptic effects of hexachlorocyclohexane (HCH) isomers, the release of noradrenaline (NA) in brain tissue was analyzed using rat cerebral cortical slices preloaded with [3H]-NA. gamma-HCH (lindane) 50 microM significantly enhanced the [3H]-NA release evoked by 15-25 mM K+. alpha- and beta-HCH (50 microM) did not produce any significant effect on K(+)-evoked [3H]-NA release. delta-HCH (50 microM) induced a significant decrease of the 25 mM K(+)-evoked release of [3H]-NA. The effect of the gamma- and delta-HCH isomers on the presynaptic action of the alpha 2-agonist clonidine and the alpha 2-antagonist yohimbine was also studied. The presynaptic inhibitory effect of clonidine and the stimulatory effect of yohimbine on [3H]-NA release was attenuated by lindane and delta-HCH, respectively. These results are consistent with a presynaptic action of the HCH isomers on noradrenergic release processes.     

THE HEXOSE MONOPHOSPHATE PATHWAY IN ETHYLNITROSOUREA INDUCED TUMORS OF THE NERVOUS SYSTEM

Respiration studies in vitro, in which tissue slices were incubated with [1-¹⁴C]glucose or [6-¹⁴C]glucose and ¹⁴CO₂ collected, resulted in C-1/C-6 ¹⁴CO₂ ratios that were higher in slices of tumor and newborn brain than in slices of adult brain. In adult brain, the C-1/C-6 ¹⁴CO₂ ratio averaged close to unity. In slices of tumor and newborn brain however, the mean C-1/C-6 ratio was greater than three. Addition of phenazine methosulfate (PMS) increased conversion of [1-¹⁴C]glucose to ¹⁴CO₂ in slices of normal adult brain 5-fold, and in slices of newborn brain and tumor, approx 12-fold. Injection of animals with 6-aminonicotinamide (6-AN) decreased conversion of [1-¹⁴C]glucose in slices of normal brain 30% but decreased conversion in tumor slices by 80%. Evidence supports the presence of an active hexose monophosphate pathway (HMP) in tumors of the nervous system regulated in part by available NADP⁺ levels. Inhibition by 6-AN was more effective in tumors than in normal adult brain.