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PubMed1979

Uptake of para-tyramine and meta-tyramine into slices of the caudate nucleus and hypothalamus of the rat.

The kinetics of the uptake of p-tyramine, m-tyramine, and dopamine were investigated in slices of the hypothalamus and striatum of the rat in the presence of nialamide. When uptake was analyzed by a least-squares fit to a Lineweaver-Burk plot, each amine appeared to be concentrated by both a "low"-affinity and a "high"-affinity system in both brain regions. The obtained Km and Vmax values for the "high"-affinity uptake system for each amine in both brain regions were similar. In general terms, the uptake systems in the striatum exhibited larger Km and Vmax values, with the velocity of uptake being in the order dopamine less than m-tyramine less than p-tyramine. 2,4-Dinitrophenol (DNP) and ouabain reduced all uptakes in the caudate, but reduced only the "high"-affinity uptake of m-tyramine and the "low"-affinity uptake of dopamine in the hypothalamus.

Animals↗

PubMed1988

Tricyclic antidepressants, mianserin, and ouabain stimulate inositol phosphate formation in vitro in rat cortical slices.

The ability of tricyclic antidepressants, monoamine oxidase inhibitors, mianserin and ouabain to stimulate hydrolysis of inositol phosphates was examined in rat cerebral cortex slices using a direct assay which involves labelling with [3H]inositol and assaying [3H]inositol phosphates in the presence of lithium. Desimipramine, imipramine, chlorimipramine, mianserin, and ouabain stimulated [3H]inositol phosphate accumulation in a concentration-dependent manner. The monoamine oxidase inhibitors, pargyline and nialamide were without effect. The stimulation of [3H]inositol phosphate accumulation caused by the various substances was not blocked by the antagonists prazosin, ketanserin, atropine, or mepyramine. In contrast, the antagonists prazosin, ketanserin, atropine and mepyramine selectively blocked stimulation of [3H]inositol phosphate accumulation caused by noradrenaline, serotonin, carbachol and histamine respectively. When desimipramine was substituted for lithium in the assay procedure, carbachol was ineffectual in stimulating [3H]inositol phosphate accumulation. In these experiments the control (unstimulated) values were much higher than in the normal (when lithium is present) assay procedure. Desimipramine is quite effective in stimulating [3H]inositol phosphate accumulation either in the presence or absence of lithium in the incubation medium. This is not the case for carbachol where it was essential to have lithium in the incubation medium in order to obtain a stimulation of [3H]inositol phosphate accumulation. Furthermore, in the case of carbachol stimulation, most of the radioactivity was associated with a peak corresponding to inositol monophosphate, while for desimipramine stimulation two clear peaks corresponding to inositol monophosphate and inositol bisphosphate were apparent.

Animals↗

PubMed1979

Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.

The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.

Amino Acids↗

PubMed1979

Hindlimb extensor reflex of spinal rats given tranylcypromine stereoisomers.

The hindlimb extensor reflex of reserpinized, spinal rats was used to determine whether tranylcypromine (dl-TCP) and its stereoisomers (d-TCP and l-TCP) after tryptaminergic neurotransmission. dl-TCP and d-TCP caused an extensor reflex while l-TCP failed to cause a reliable extensor reflex. Neither H 22/54 nor nialamide affected the extensor reflex in rats given dl-TCP, while H 22/54 reduced the reflex in rats given d-TCP. The results suggest that dl-TCP and d-TCP have direct as well as indirect actions on tryptaminergic neurotransmission.

Animals↗

PubMed1994

Additive effects of lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotoninergic system.

In the mouse forced swimming test (FST) pretreatment with a subactive dose of lithium (1 mEq/kg), given IP 45 min before the test, facilitated the antidepressant activity of iprindole, fluoxetine, and moclobemide (given IP 30 min before the test). These antidepressants (ADS) were not active alone in the FST in this study. Moreover, when subactive lithium was combined with a wide range of ADS, each given at subactive doses, those ADS with serotoninergic properties (e.g. imipramine, citalopram, paroxetine, fluoxetine, trazodone, mianserin, and moclobemide) significantly reduced immobility times. ADS acting primarily on noradrenaline (NA) or dopamine (DA) systems (desipramine, maprotiline, viloxazine, and bupropion) did not significantly decrease immobility when given in combination with lithium. This was also the case for RO 16 6491 [a reversible, B specific monoamine oxidase inhibitor (MAOI)], nialamide, and pargyline (both irreversible, mixed MAOIs). The anti-immobility effect of iprindole in combination with lithium suggests either a direct or indirect action on the serotonin (5HT) system by this ADS whose mechanism of action remains obscure. These results, using an animal behavioral model of depression and combining our present knowledge of the acute action of various ADS, support the hypothesis that the potentiation by lithium of ADS is via direct 5HT mechanisms, indirectly via a NA/5HT link, and/or by second messenger systems. Lithium may also facilitate the expression of antidepressant activity of ADS not active by themselves in the FST.

Adrenergic Uptake Inhibitors↗

PubMed1995

The additive effects of quinine on antidepressant drugs in the forced swimming test in mice.

The aim of this study was to investigate if quinine plus antidepressant drugs (ADS) leads to an additive effect in the forced swimming test. Quinine (0.125, 0.5 mg/kg) and ADS (subactive doses) were given IP 45 and 30 min, respectively, before the test. When combined with QUIN, all drugs that act via inhibition of 5-HT uptake (imipramine, amitriptyline, citalopram, paroxetine, fluoxetine and fluvoxamine) significantly increased the swimming time of mice. Among trazodone, mianserin and iprindole (atypical ADS), only iprindole combined with quinine decreased the immobility (increased swimming) of the animals. The specific noradrenaline (NA) uptake inhibitors, desipramine and viloxazine, but not maprotiline, were also found to reduce the immobility time when pretreated with quinine. The mixed monoamine oxidase (MAO) inhibitor (pargyline) and MAO-A inhibitor (moclobemide) also shortened the period of immobility whereas the MAO-B inhibitor (nialamide) and the dopamine (DA) uptake inhibitor (bupropion) did not. Quinine's additive effects on several types of ADS is likely a result of blockade of potassium channels.

Animals↗

PubMed1988

Additive effects of clonidine and antidepressant drugs in the mouse forced-swimming test.

In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8-16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1-4 mg/kg). Pretreatment with alpha-methyl-paratyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antidepressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.

Animals↗

PubMed1996

Reserpine-induced immunocytochemical change of neuropeptide Y in the hypothalamic arcuate nucleus.

The effect of reserpine on neuropeptide Y immunoreactive (NPY-IR) neurons in the rat hypothalamic arcuate nucleus was examined by immunocytochemical techniques. Although only NPY-IR fibers and terminals were distributed in this nucleus in untreated and saline treated rats, single treatment of reserpine (10 mg/kg, i.p.) visualized abundant NPY-IR neuronal cell bodies: the increase began at 12 h of postinjection, reached its maximal level at 48 h, and returned to its normal level at 96 h. Pretreatment of nialamide, a monoamine oxidase inhibitor, prevented these acute reserpine-induced changes, suggesting reserpine acts on NPY neurons through monoaminergic mechanism. Chronic treatment of haloperidol (5 mg/kg, once daily for 5 days) a dopamine receptor antagonist, could induce the similar increase of NPY immunoreactivity. However, interruption of adrenergic and serotonergic neurotransmissions by chronic treatment of propranorol and methysergide, or chemical lesions of ascending noradrenergic and serotonergic pathways by 6-hydroxydopamine and 5,6-dihydroxytryptamine, could not induce any immunoreactive increase of NPY in arcuate neurons. These findings strongly suggest that reserpine-induced NPY increase occurs through dopaminergic afferents in hypothalamic arcuate neurons.

Animals↗

PubMed1997

Supraspinal and segmental signals can be transmitted through separate spinal cord pathways to enhance locomotor activity in extensor muscles in the cat.

The fine control of locomotion results from a complex interaction between descending signals from supraspinal structures and sensory feedback from the limbs. In this report, we studied the interaction between vestibulospinal volleys descending from Deiters' nucleus and group I afferent input from extensor muscles. It has been shown that both pathways can exert powerful control over the amplitude and the timing of muscle bursting activity in the different phases of the step cycle. The effects of stimulating these pathways on the fictive locomotor rhythm were compared in decerebrate, partially spinal cats (ipsilateral ventral quadrant intact) injected with nialamide and L-dopa. As reported before, stimulation of both Deiters' nucleus and group I fibres from ankle extensor muscles, when given during the flexor phase, stopped the flexor activity and initiated activity in extensors. When applied during the extensor phase, the same stimulation prolonged the extensor activity and therefore delayed the onset of flexor activity. This similarity suggests that the two pathways might converge on common spinal interneurones. This possibility was tested with the spatial facilitation technique in lumbosacral motoneurones. Deiters' nucleus and group I fibres from extensor muscles were stimulated with different intensities and with several different coupling intervals. Motoneurones showing clear di- and/or polysynaptic excitation from both pathways were retained for analysis. Surprisingly, in all cases, there were no signs of spatial facilitation, but a simple algebraic sum of the two excitatory postsynaptic potentials. This result indicates that each input acts on the rhythm generator through separate interneuronal pathways.

Animals↗

PubMed1998

Flexor reflex afferents reset the step cycle during fictive locomotion in the cat.

The generation of locomotor-like spinal rhythms has been proposed to involve two neural centres with mutual reciprocal inhibition (Graham Brown's "half-centre" hypothesis). Much later a particular set of segmental flexor reflex pathways were described as being organized in accordance with this half-centre hypothesis. As these pathways became operative following injection of monoaminoxidase inhibitors and L-3,4-dihydroxyphenylalanine (L-dopa), i.e. under the same conditions under which a spontaneous locomotor activity may develop, it was assumed that these particular pathways and spinal rhythm generators involve the same neuronal networks. In order to give further evidence to this hypothesis, we investigated whether short trains to "flexor reflex afferents" (FRA) reset the spinal locomotor rhythm, i.e. shorten or lengthen the stimulated cycle after which the regular rhythm is resumed with step cycles of the original duration. The experiments were performed in anaemically decapitated, high-spinal curarized cats. A steady locomotor rhythm was induced by injection of nialamide and L-dopa and the influence of electrical stimulation (trains of 50-1000 ms) of FRA (joint, cutaneous, and group II and III muscle afferents) onto this rhythm was tested. Stimulation of FRA induced a clear resetting of the locomotor rhythm, which was mainly characterized by a flexion reflex pattern: during the extension phase the extensor activity was interrupted and a flexion phase was initiated; during the late flexion phase mainly a prolongation of that phase with a variable change of the following extension phase was induced. In addition to this prevailing pattern, stimulation of some nerves (in particular nerves to more distal extensors and the sural nerve) could often prolong extension, when stimulated during the late extension, or terminate the flexor burst and initiate a new extension phase, when stimulated during the late flexion phase. This pattern is probably due to the concomitant stimulation of group I afferents in the case of the muscle nerves and to separate non-FRA pathways in the case of the sural nerve. The results demonstrate that the interneurones of the FRA pathways, which are operative during L-dopa-induced locomotion in spinal animals, can be considered as neuronal elements of the rhythm-generating network for locomotion.

Animals↗

PubMed1998

Pharmacologically evoked fictive motor patterns in the acutely spinalized marmoset monkey (Callithrix jacchus).

The existence of a spinal network capable of generating rhythmic alternating activity resembling locomotion still has not been firmly established in primates, including man, although evidence for one is accumulating. The present study investigated whether it is possible to activate such a network by administration of a variety of pharmacological agents to acutely spinalized marmoset monkeys (Callithrix jacchus) in the absence of phasic afferent input to the spinal cord. Fourteen marmoset monkeys were decerebrated, spinalized, and paralyzed. The nerves supplying both hindlimbs were cut and recorded from. In 5 monkeys the effect of electrical stimulation of the brainstem was investigated before spinalization. In 3 of these monkeys, rhythmic activity alternating between extensors and flexor nerves was seen. In the 2 other monkeys only synchronized activity was elicited. In acutely spinalized monkeys, administration of L-3,4-dihydroxyphenylalanine (L-dopa; 3-4 h after treatment with nialamide) failed to evoke any rhythmic alternating activity. In contrast, administration of clonidine elicited alternating activity in all of 8 monkeys tested. In 4 of these monkeys, the activity was restricted to alternation between ipsilateral and contralateral flexor nerves, whereas alternating activity between ipsilateral flexors and extensors was also seen in the other 4 monkeys. Administration of excitatory amino acids (NMDA or NMA) also elicited rhythmic alternating activity in 7 of 10 spinalized monkeys. In 4, rhythmic alternating activity was seen between extensors and flexors on one limb as well as between ipsilateral and contralateral flexors. In 3 monkeys NMDA/NMA produced alternation between extensors and flexors of one limb without alternation between the ipsilateral and contralateral sides. Administration of noradrenaline failed to elicit any rhythmic activity, but rather completely depressed already existing activity. Administration of serotonin (5-HT) was ineffective in facilitating alternating activity in 6 of 8 monkeys and was facilitatory to rhythmic activity in the other 2. We suggest that these data provide further evidence of a network capable of eliciting rhythmic alternating activity resembling locomotion in the primate spinal cord. The network, however, seems to be more difficult to activate pharmacologically in those conditions than in other mammals. This may especially be the case in higher primates, including man.

Animals↗

PubMed2000

Possible mediation of quinolinic acid-induced hippocampal damage by reactive oxygen species.

Several differences exist between quinolinic acid and N-methyl-D-aspartate (NMDA) in the potency and pharmacology of their neurotoxic actions in the brain, suggesting that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors, possibly involving lipid peroxidation. In the present review, studies are considered which have attempted to determine whether free radicals might contribute to the neuronal damage induced by quinolinic acid. Following Injections into the hippocampus of anaesthetised rats, quinolinic acid induced damage is prevented by melatonin, by an action not blocked by the melatonin receptor blocker luzindole. Deprenyl, but not the non-selective monoamine oxidase inhibitor nialamide, also prevent quinolinic acid-induced damage. In vitro, several groups have shown that quinolinic acid can induce lipid peroxidation of brain tissue The results suggest that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Animals↗

PubMed1984

Cellular mode of serotonin action on Cl- transport in the rabbit corneal epithelium.

The present work examines serotonin-induced changes in cell potential difference and barrier resistances in the corneal epithelium in vitro using voltage-measuring microelectrodes and related techniques. Component resistances were determined using voltage and resistance profiles of the epithelium before and during the serotonin response. Serotonin, added to the stromal side of the cornea in the presence of nialamide, markedly reduced transcorneal and apical membrane resistances, while basal barrier resistance increased slightly and shunt resistance was unchanged. The marked drop in apical membrane resistance after serotonin treatment reflects an increase in apical membrane chloride permeability, inasmuch as the serotonin-stimulated short-circuit current is indistinguishable from the increase in net chloride flux. Prolonged (more than 1 h) exposure of corneas to serotonin markedly depolarized the epithelial cells and reduced the voltage divider ratio from 12.3 +/- 2.1 to 1.5 +/- 0.5, while not significantly affecting the stimulated short-circuit current. These later effects suggest changes in epithelial ion distribution during long periods of stimulation by serotonin.

Animals↗

PubMed1979

Innervation of hippocampal explants by central catecholaminergic neurons in co-cultured fetal mouse brain stem explants.

The ability of central catecholaminergic neurons to grow into and establish functional connections with the hippocampus in vitro was studied using organotypic tissue culture. Brain stem explanted from the region of the locus coeruleus and hippocampal explants, from 18-day fetal mice, were maintained as co-cultures and were also grown separately. After 1-4 weeks these tissues were analyzed by glyoxylic acid-induced histofluorescence, by light and electron microscopic radioautography after incubation with [3H]norepinephrine, and by electrophysiology. Brain stem explants exhibited specifically fluorescent catecholaminergic cell bodies and varicose fibers after 2-4 weeks in culture. In contrast, no fluorescent cells or neurites could be seen in isolated hippocampal cultures grown for 2-3 weeks in vitro. When hippocampal explants were grown near brain stem explants, catecholaminergic fibers grew out of the brain stem and entered the hippocampus. In additional experiments, co-cultures of brain stem and hippocampus were incubated with [3H]norepinephrine (0.5 micron) and the monoamine oxidase inhibitor nialamide (100 micron). Radioautographic analyses revealed that brain stem neurites which entered the hippocampus took up norepinephrine, whereas neurites in the isolated hippocampal explants did not. Electron microscopic studies of the hippocampus showed varicose axon terminals within the hippocampus to be preferentially labeled. Although close relationships could be seen between labeled axons and dendrites, junctions exhibiting the membranous modifications associated with synapses were never seen. Electrophysiological studies suggested that the catecholaminergic neurites within the hippocampus were functional. Complex synaptically mediated slow wave discharges could be evoked by electrical stimuli in isolated hippocampal explants. Introduction of the beta adrenergic antagonist propranolol (0.4-4.3 micron) did not alter, or slightly depressed, these hippocampal discharges. On the other hand, in hippocampus-brain stem co-cultures, these concentrations of propranolol enhanced the complex hippocampal responses to brain stem or hippocampal stimuli. Similar enhancement of hippocampal responses by propranolol also occurred in these cocultures after acute surgical extirpation of the brain stem explant. The data suggest, therefore, that the action of propranol was probably to block adrenergic inhibitory connections with hippocampal synaptic networks. These experiments provide morphological and electrophysiological evidence that catecholaminergic neurons from fetal mouse brain stem maintained in organotypic tissue culture can grow into and functionally innervate the hippocampus.

Animals↗

PubMed1982

Modulation of rat brain alpha 2- and beta-adrenergic receptor sensitivity following long-term treatment with antidepressants.

After 7 days of treatment with a variety of antidepressant drugs (desipramine, imipramine, clomipramine, nortriptyline, nialamide), both an increase in alpha 2-receptor density and a decrease in beta-receptor density were observed in the cerebral cortex but not limbic forebrain. However, mianserin caused a marked increase in alpha 2-receptors without any change in beta-receptors. Nisoxetine did not produce any change in these two adrenergic receptors. It is suggested that intrasynaptic norepinephrine is important but that, in addition, other factors may be involved in the increase in alpha 2-receptors induced by antidepressant drugs.

Animals↗

PubMed1982

Does in vivo voltammetry in the hippocampus measure 5-HT release?

In vivo voltammetry enables catecholamine and 5-hydroxytryptamine (5-HT) release to be directly determined in the brains of conscious unrestrained animals. This study concerned the validation of the measurement of 5-HT release using scanning voltammetry at chronically implanted carbon paste/epoxy resin glass microelectrodes in the rat hippocampus. Automated recordings of the current produced by applying a ramp (100 mV/s) potential (0-1 V) to the electrode at 5 min intervals were made over a period of several hours. A current peak at 0.35-0.4 V corresponded to that produced by solutions of 5-HT in vitro. The effect of a number of drug known to affect 5-HT synthesis and release was then studied in vivo. p-Chloroamphetamine (PCA) caused an increase in the peak which correlated with a '5-HT behavioural syndrome'. p-Chlorophenylalanine caused a reduction in the peak and prevented both the increase seen with PCA and the PCA induced behavior. Fluoxetine and L-tryptophan also led to increases in signal; all these results were consistent with the signal reflecting extraneuronal 5-HT. However 5-hydroxyindoleacetic acid (5HIAA) also oxidizes at 0.35-0.4 V in vitro. Probenecid, which blocks 5HIAA egress from the brain caused a large increase in the hippocampal signal. The monoamine oxidase inhibitors pargyline and nialamide, which increases 5-HT and reduce 5HIAA levels, had no significant effect on the signal. These results, together with the greater increase in signal following probenecid than tryptophan and the delayed increase after tryptophan, and interpreted as implying that extraneuronal 5HIAA and 5-HT contribute approximately equally to the hippocampal signal. We conclude that this method gives information distinct from and complementary to biochemical estimations, and offers great scope for the investigation of the role of 5-hydroxyindole release in drug and environmental effects on behaviour.

Animals↗

PubMed1987

Tyrosine hydroxylase-like immunoreactivity and catecholamine fluorescence in ciliary ganglion neurons.

In the ciliary ganglia of monkeys, dogs, cats and rats, some neuronal perikarya exhibited tyrosine hydroxylase-like immunoreactivity; neither dopamine-beta-hydroxylase-like immunoreactivity nor phenylethanolamine-N-methyltransferase-like immunoreactivity was found in perikarya. Some perikarya of ciliary ganglion neurons displayed catecholamine fluorescence; the fluorescent perikarya were significantly increased in number in dogs injected with nialamide. Thus the existence of dopamine-containing ciliary ganglion neurons was suggested.

Animals↗

PubMed1987

Delayed behavioral response to antidepressant drugs following selective damage to the hippocampal noradrenergic innervation in rats.

The present study was undertaken to investigate in rats the role of the noradrenergic innervation of the hippocampus in the reversal by antidepressant drugs of escape failures caused by previous exposure to inescapable shocks (learned helplessness design). Rats were either sham-operated or given a bilateral infusion of 6-hydroxydopamine (6-OHDA, 8.1 micrograms of free base in 0.8 microliter saline containing 0.02% ascorbic acid) into the dorsal hippocampus. Three weeks later, sham and lesioned rats were exposed (experimental rats) or not exposed (control rats) to 60 randomized, inescapable footshocks (0.8 mA, 15 s duration) and, 48 h later, experimental and control rats were subjected to daily consecutive shuttle-box sessions (30 trials/day; intertrial interval = 30 s). Separate groups of experimental animals were given twice daily injection (i.p.) of clomipramine (total daily dose: 16 or 32 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg), nialamide (16 mg/kg) or saline. After behavioral testing, animals were sacrificed and [3H]noradrenaline uptake was assayed in synaptosomal preparations from the hippocampus, the cerebral cortex and the septum, [3H]serotonin uptake being assessed in hippocampal synaptosomes. We found that hippocampal 6-OHDA infusion resulted in a mean 70% reduction in local [3H]noradrenaline uptake and a marked delay in the response to antidepressants (reversal of escape failures over consecutive shuttle-box sessions). The 6-OHDA infusion was found not to alter hippocampal [3H]serotonin uptake but to decrease (30%) [3H]noradrenaline uptake in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗