Effect of morphine on the concentration of monoamines in the emotiogenic zones of the hypothalamus in adult and old rats

The content of monoamines in the emotiogenic hypothalamic zones has been shown to noticeably change with aging of rats. The level of noradrenaline and serotonin increased in the ventromedial nucleus of the hypothalamus, while the concentration of noradrenaline increased in the lateral hypothalamic zone. Single i.p. injections of 10 mg/kg morphine evoked qualitatively different shifts in the monoamine concentrations in the hypothalamic emotiogenic zones of the rats of different ages: the level of dopamine increased in adult animals, while the levels of noradrenaline and serotonin dropped in old rats. It is supposed that in old age the effect of morphine on dopaminergic structures in the emotiogenic hypothalamic zones becomes more moderate, whereas that on the noradrenergic and serotonergic structures is facilitated. The age-related specificities of the morphine effect on the monoaminergic regulation of the emotiogenic hypothalamic zones can determine considerable modifications of a psychotropic effect of the drug in old age.     

Dissociate destruction of noradrenaline and dopamine descending projections in the thoracic spinal cord of the rat

Intracisternal administration of 6-hydroxydopamine to male Wistar rats produced a near complete depletion of noradrenaline levels, as measured by a radioenzymatic assay in micropunches sampled from the dorsal, lateral and ventral horns of the thoracic spinal cord. This drastic effect was reversed by pretreatment with desipramine, a pharmacological inhibitor of noradrenergic neuron uptake. Surprisingly, dopamine content was not significantly reduced. The question as to whether such a lack of concomitant dopamine decrease might be inherent to the dopamine assay itself could be answered by the results obtained with both pharmacological (reserpine) treatments and interference determinations in the dopamine assay. The relative potency of 6-hydroxydopamine to destroy noradrenergic and dopaminergic neurons might account for their differential behavior. Conversely, a large midbrain section performed by knife cut could decrease both dopamine and DOPAC (one of its major acid metabolites) in the thoracic lateral horn and partly in the ventral one. The noradrenaline content was not reduced. Results are discussed in light of recently reported data on dopaminergic descending projections to the spinal cord. The lesion procedures presented here seem to provide valuable tools to dissociate noradrenergic from dopaminergic spinal projections, which is necessary for further anatomical and functional studies on these systems.     

Reduced MPTP toxicity in noradrenaline transporter knockout mice

The noradrenergic neurons of the locus coeruleus (LC) are damaged in Parkinson's disease (PD). Neurotoxin ablation of the LC noradrenergic neurons has been shown to exacerbate the dopaminergic toxicity of MPTP, suggesting that the noradrenergic system protects dopamine neurons. We utilized mice that exhibit elevated synaptic noradrenaline (NA) by genetically deleting the noradrenaline transporter (NET), a key regulator of the noradrenergic system (NET KO mice). NET KO and wild-type littermates were administered MPTP and striatal dopamine terminal integrity was assessed by HPLC of monoamines, immmunoblotting for dopaminergic markers and tyrosine hydroxylase (TH) immunohistochemistry. MPTP significantly reduced striatal dopamine in wild-type mice, but not in the NET KO mice. To confirm that the protection observed in the NET KO mice was due to the lack of NET, we treated wild-type mice with the specific NET inhibitor, nisoxetine, and then challenged them with MPTP. Nisoxetine conferred protection to the dopaminergic system. These data indicate that NA can modulate MPTP toxicity and suggest that manipulation of the noradrenergic system may have therapeutic value in PD.     

Clonidine reverses baclofen-induced increases in noradrenaline turnover in rat brain

The effect of baclofen and clonidine, both individually and in combination, on noradrenaline turnover was examined in several brain regions as well as in the spinal cord using the -methyl-p-tyrosine depletion method. Baclofen (30–50 mg/kg) consistently increased the turnover of noradrenaline in the cortex, hippocampus and spinal cord and this effect was stereoselective for thel-isomer. Clonidine (0.1 mg/kg) decreased noradrenaline turnover in these regions and reversed the effect of baclofen. In the striatum, baclofen (50 mg/kg) decreased the turnover of dopamine in a stereoselective manner. Clonidine (0.1 mg/kg) did not alter dopamine turnover but potentiated the effect of baclofen. These results support behavioural data which suggests that baclofen interacts with central noradrenergic pathways. The nature of such interactions appears to be complex.     

Effects of DSP4 and methylphenidate on spatial memory performance in rats

In this experiment, we have investigated the spatial memory performance of rats following a central noradrenaline depletion induced by three different doses of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and following administration of three different doses of methylphenidate (MPH). The rats were required to find food pellets hidden on a holeboard. The sole administration of DSP4 induced only minor cognitive deficits. However, the treatment with MPH increased the reference memory error, the impulsivity and the motor activity of the DSP4-treated rats. Since the noradrenergic terminals in a DSP4-treated rat are significantly reduced, the administration of MPH has little effect on the noradrenergic system and increases dopaminergic rather than noradrenergic activity, resulting in an imbalance with relatively high dopaminergic and low noradrenergic activities. It is suggested that a reduction of noradrenaline and an increase of dopamine induce ADHD-related deficits and that the depletion of noradrenaline is not sufficient for an appropriate rat model of ADHD.     

Inhibition of Monoamine Oxidase Within Monoaminergic Neurons in the Rat Brain by (E)-β-Fluoromethylene-m-Tyrosine (MDL 72394)

The irreversible inhibition of the monoamine oxidase (MAO) activity within monoaminergic neurons in the rat brain 24 h after single or repeated administration of (E)-beta-fluoromethylene-m-tyrosine (FMMT, MDL 72394) was examined. The enzyme activity was determined by incubating synaptosome-rich homogenates of hypothalamus or striatum with low concentrations of 5-[14C]hydroxytryptamine (5-HT), [14C]noradrenaline (NA), or [14C]dopamine (DA) in the absence and presence of the selective amine uptake inhibitors citalopram (5-HT), maprotiline (NA), and GBR 12909 (DA). After a single subcutaneous injection of FMMT, the inhibition of MAO within the noradrenergic and dopaminergic neurons was significant but only slightly greater than that outside these neurons. The opposite relationship was observed for the serotonergic neurons. After 7 days' treatment of rats with carbidopa, 20 mg/kg p.o., + FMMT once daily, the preference for the inhibition of MAO within the noradrenergic and dopaminergic neurons was accentuated further. The inhibition outside the serotonergic neurons was still greater than within these neurons. The NA uptake inhibitor CPP 199 antagonized the selective inhibition of MAO within the noradrenergic neurons, which indicates that this preference is due to the accumulation of the active metabolite (E)-beta-fluoromethylene-m-tyramine by the NA transporter.     

Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: evidence for serotonin-catecholamine interactions

The present study tested whether administration of the serotonin agonist, quipazine maleate, affects the secretion of luteinizing hormone (LH) and prolactin (PRL) and concomitantly, the activity of central noradrenergic and dopaminergic systems. Quipazine (15 mg/kg, ip) significantly reduced LH and increased PRL when administered to ovariectomized rats. Associated with these changes, the depletion of dopamine seen after synthesis inhibition with alpha-methyl tyrosine was reduced by quipazine in the caudate nucleus and median eminence, suggesting a depression of dopaminergic activity. The depletion of norepinephrine in the median eminence was unaffected. In a second experiment, quipazine (1 microM) diminished the potassium-induced release of both norepinephrine and dopamine from fragments of medial basal hypothalamus, in vitro. Release from preoptic area was unaffected. These results suggest that central serotonergic systems may interact with noradrenergic and dopaminergic systems that regulate LH and PRL secretion, respectively.     

Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson’s Disease

Neurochemical Research - Parkinson’s disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin...     

Pentagastrin modulation of the neuronal sensitivity of the lateral hypothalamus to noradrenaline and dopamine

Experimental study is dedicated to mechanisms of interaction of pentagastrin and monoamines (noradrenaline and dopamine) at the level of single neurones of the rabbits lateral hypothalamus under alimentary motivation and under saturation. It is shown that pentagastrin can modulate the effects of noradrenaline and dopamine on neuronal impulse activity in hungry and fed up animals, and the character of its action depends on the rabbits initial state. It is suggested that pentagastrin is a factor initiating alimentary motivational excitation, while noradrenaline maintains the latter at the definite level up to obtaining useful result by the animal, when dopaminergic mechanisms participating in the process of reinforcement join the noradrenergic ones.     

A and B Forms of Monoamine Oxidase Within the Monoaminergic Neurons of the Rat Brain

The inhibition of the A and B forms of monoamine oxidase (MAO) inside and outside serotonergic, noradrenergic, and dopaminergic synaptosomes in homogenates of rat hypothalamus or striatum by clorgyline, a selective and irreversible MAO-A inhibitor, and selegiline, a selective and irreversible MAO-B inhibitor, was examined. Intrasynaptosomal deamination at low concentrations of the substrates [14C]5-hydroxytryptamine ([14C]5-HT; 0.1 microM), [14C]noradrenaline (0.25 microM), [14C]3,4-dihydroxyphenylethylamine ([14C]dopamine; 0.25 microM), and [14C]tyramine (0.25 microM) was hindered by selective uptake inhibitors (citalopram, maprotiline, and amfonelic acid) in the incubation media. Thus, the difference between the deamination of 14C-amine in the absence and presence of the appropriate selective uptake inhibitor provided a measure of deamination in the specific aminergic synaptosomes. This was verified by determining the loss of MAO activity within noradrenergic and serotonergic systems after degeneration of the nerve terminals by the neurotoxins N-chloroethyl-N-ethyl-2-bromobenzylamine and p-chloroamphetamine. Results with the two inhibitors revealed that the A and B forms were responsible for 80 and 20%, respectively, of the deamination of [14C]5-HT within serotonergic synaptosomes from the hypothalamus. The deamination of [14C]noradrenaline within the noradrenergic synaptosomes from the hypothalamus and that of [14C]dopamine and [14C]tyramine within the striatal dopaminergic synaptosomes were due to MAO-A. About 10% of the deamination of [14C]noradrenaline, [14C]dopamine, and [14C]tyramine outside the noradrenergic or dopaminergic synaptosomes was brought about by the B form, with the remainder being deaminated by MAO-A.     

Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex

Previous results suggest that extracellular dopamine (DA) in the rat cerebral cortex originates from dopaminergic and noradrenergic terminals. To further clarify this issue, dialysate DA, dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) were measured both in the medial prefrontal cortex (mPFC) and in the occipital cortex (OCC), with dense and scarce dopaminergic projections, respectively. Moreover, the effect of the alpha2-adrenoceptor antagonist RS 79948 and the D2-receptor antagonist haloperidol on extracellular DA, DOPAC and NA was investigated. Extracellular DA and DOPAC concentrations in the OCC were 43% and 9%, respectively, those in the mPFC. Haloperidol (0.1 mg/kg i.p.) increased DA and DOPAC (by 35% and 150%, respectively) in the mPFC, but was ineffective in the OCC. In contrast, RS 79948 (1.5 mg/kg i.p.) increased NA, DA and DOPAC, both in the mPFC (by approximately 50%, 60% and 130%, respectively) and the OCC (by approximately 50%, 80% and 200%, respectively). Locally perfused, the DA transporter blocker GBR 12909 (10 micro m) was ineffective in either cortex, whereas desipramine (DMI, 100 micro m) markedly increased extracellular NA and DA in both cortices. The weak haloperidol effect on DA efflux was not enhanced after DA- and NA-transporter blockade, whereas after DMI, RS 79948 markedly increased extracellular NA, and especially DA and DOPAC in both cortices. The results support the hypothesis that most extracellular DA in the cortex is co-released with NA from noradrenergic terminals, such co-release being primarily controlled by alpha2-adrenoceptors.     

Catechol-O-Methyltransferase (COMT) Protein Expression and Activity after Dopaminergic and Noradrenergic Lesions of the Rat Brain

The occurrence of catechol-O-methyltransferase (COMT) in presynaptic neurons remains controversial. This study utilized dopaminergic and noradrenergic toxins to assess the presence of COMT in the presynaptic neurons originating from the substantia nigra, ventral tegmental area or locus coeruleus. Destruction of dopaminergic and noradrenergic neurons was assessed by measuring the dopamine and noradrenaline content in the projection areas of these neurons. Additionally, COMT protein expression and activity were examined in several projection areas to determine whether there are any changes in COMT values. Colocalization studies were done to identify COMT-containing postsynaptic neurons. Despite successful lesioning of dopaminergic and noradrenergic neurons, no changes in COMT protein expression or activity could be noted. These results strongly suggest that COMT is not present in presynaptic dopaminergic and noradrenergic neurons. There was a high colocalization of COMT with the GABAergic marker of short neurons both in the striatum and cortex but only a weak, if any, with the cholinergic marker in the cortex.     

Uptake of [3H]Dopamine into Dopaminergic and Noradrenergic Neurones of the Isolated Neurointermediate Lobe of the Rat Hypophysis. Effects of Desipramine and Nomifensine

Abstract: The isolated neurointermediate lobe (NIL) of the rat hypophysis accumulates [³H]dopamine from the incubation medium. Column chromatographic analysis showed that 92% of the tissue radioactivity was contained in the catecholamine fraction. [³H]Dopamine represented 70% and [³H]noradrenaline 30% of the [³H]catecholamines. Desipramine (1 μM) prevented the formation of [³H]noradrenaline without affecting the storage of [³H]dopamine. Nomifensine (10 μM) blocked the storage of [³H]dopamine and [³H]noradrenaline. Thus, in the NIL, [³H]dopamine is taken up into dopaminergic and noradrenergic neurones. In the latter, [³H]dopamine is converted to [³H]noradrenaline, indicating a significant dopamine β-hydroxylase activity in the NIL tissue. A selective labeling of the dopamine stores with [³H]dopamine can be achieved in the presence of desipramine.     

Differential effect of morphine on dopaminergic neurons in frontal cortex and striatum of the rat

Inhibition of dopamine synthesis by a single injection of α-methyl-para-tyrosine (200 mg/kg, i.p.) was complete from 30 to at least 300 min after administration. When morphine (20 mg/kg) was given intraperitonealy 30 min after α-MpT treatment an enhanced decline of dopamine was observed in frontal parts of the cortex but not in the striatum. These results indicate that morphine affects dopaminergic neurons in frontal parts of the cortex in a way differently from those in the striatum of the rat. This may be caused either by a difference in the properties of dopaminergic nerve endings in both structures or by an effect of morphine on the input to the cortical system which is lacking in the striatum.     

Somatodendritic α2-Adrenoceptors in the Locus Coeruleus Are Involved in the In Vivo Modulation of Cortical Noradrenaline Release by the Antidepressant Desipramine

Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α₂-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α₂-adrenoceptors located in the LC.     

The role of the dopamine and noradrenaline systems in regulating autogenic motor activity in rat pups

In experiments on 3-day rat puppies, studies have been made of the effect of a stimulator of noradrenaline receptors--clonidine, and a stimulator of dopamine receptors--apomorphine on autogenic motor activity. It was shown that clonidine injections result in a significant increase of this activity, whereas apomorphine slightly decreases the latter. The data obtained in the present work together with those described earlier for l-DOPA effects, suggest that double regulation of autogenic activity is realized at early stages of ontogenesis. This regulation includes excitatory noradrenergic mechanisms and inhibitory influences which are mediated presumably by dopaminergic systems of the brain.     

Measurement of Endogenous Noradrenaline Release in the Rat Cerebral Cortex In Vivo by Transcortical Dialysis: Effects of Drugs Affecting Noradrenergic Transmission

The release of endogenous noradrenaline was measured in the cerebral cortex of the halothane-anesthetized rat by using the technique of brain dialysis coupled to a radioenzymatic assay. A thin dialysis tube was inserted transversally in the cerebral cortex (transcortical dialysis) and perfused with Ringer medium (2 microliter min-1). Under basal conditions, the cortical output of noradrenaline was stable over a period of at least 6 h and amounted to 8.7 pg/20 min (not corrected for recovery). Histological control of the perfused area revealed very little damage and normal morphology in the vicinity of the dialysis tube. Omission of calcium from the perfusion medium caused a marked drop in cortical noradrenaline output. Bilateral electrical stimulation (for 10 min) of the ascending noradrenergic pathways in the medial forebrain bundle caused a frequency-dependent increase in cortical noradrenaline output over the range 5-20 Hz. Stimulation at a higher frequency (50 Hz) resulted in a levelling off of the increase in cortical noradrenaline release. Systemic administration of the dopamine-beta-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA 63) (25 mg/kg i.p.) markedly reduced, whereas injection of the monoamine oxidase inhibitor pargyline (75 mg/kg i.p.) resulted in a progressive increase in, cortical noradrenaline output. d-Amphetamine (2 mg/kg i.p.) provoked a sharp increase in cortical noradrenaline release (+450% over basal values within 40 min). Desmethylimipramine (10 mg/kg i.p.) produced a twofold increase of cortical noradrenaline release. Finally, idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.), respectively, increased and decreased the release of noradrenaline from the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.     

The effect of etorphine on dopamine and noradrenaline concentrations in different central nervous system structures in the rat

The effect of etorphine on dopamine and noradrenaline concentrations in different central nervous system structures in the rat. Acta Physiol. Pol., 1977, 28 (6): 529-540. Intramuscular administration of etorphine in immobilizing doses (0.008 mg/kg) was followed by a rise in dopamine concentration in the examined motor structures of the central nervous system (striopallidum, pons, cerebellum, lumbosacral intumescence of the spinal cord). Only in the motor centres of the frontal cortex dropamine concentration was decreased. At the time etorphine decreased the concentration of noradrenaline in striopallidum and raised it in the other examined structures of the central nervous system. A correlation was found between the concentrations of both substances, especially in the frontal motor centres and striopallidum. Post etorphine accumulation of dopamine in the striopallidum (for 6.369 to 11.322 mcg/g of fresh tissue) with simultaneous inhibition of motor activity of the animals suggests that etorphine inhibits the release of dopamine from the presynaptic elements in the motor centres of the central nervous system in rats. This leads to a decreased dopamine action on its receptors. Some post etorphine behavioral changes (rigidity, spastic flexion, muscle tremor) support this hypothesis.     

In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action

In addition to being dopamine antagonists, all antipsychotic drugs are potent antagonists of alpha-1 noradrenergic receptors. Nevertheless, the contribution of alpha blockade to the clinical therapeutic effects of the antipsychotic drugs has never attracted extensive study. In particular, the relative alpha-1 noradrenergic antagonist potency of antipsychotic drugs has rarely been determined in vivo during extended treatment, although such treatment would provide a better model of clinical drug effects than the determination of potencies in in vitro systems, such as assays of competition for binding sites in tissue homogenates, as is most often done. To estimate the physiological efficacy of antipsychotic drugs as dopamine and alpha adrenergic antagonists, we treated rats for four weeks with daily IP injections of the following antipsychotic drugs: Fluphenazine, 1 mg/kg; haloperidol, 1 mg/kg; chlorpromazine, 25 mg/kg; thioridazine, 25 mg/kg; and clozapine, 25 mg/kg. Effective antagonism should lead to an increase in density of the relevant receptors. After two drug-free days, rats were sacrificed and the affinity and density of dopamine D2 and alpha-1 noradrenergic receptors were determined in striatum and brain exclusive of striatum, respectively. Alpha 1 noradrenergic receptor density but not dopamine receptor density was increased after all treatments. Thus, preliminary experiments with this in vivo model suggest that all antipsychotic drugs are effective antagonists at alpha 1 noradrenergic receptors, while not all are effective antagonists at dopamine D2 receptors.