Biomedical subjects
Publications and source records attributed to A Reches.
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Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.
Electroconvulsive treatment (ECT) has a transitory beneficial effect on patients with Parkinson's disease (PD). The possibility that this effect is mediated by dopamine (DA) receptors was investigated in the rat brain. Repeated ECT or chronic haloperidol treatment induced supersensitivity of putative autoreceptors in the nigrostrital and mesolimbic DA pathways as reflected by enhanced apomorphine-induced inhibition of DA synthesis. Effect of simultaneous administration of ECT plus haloperidol on DA receptor sensitivity were not additive. Chronic haloperidol treatment induced significant elevations in the density of 3[H]-spiperone striatal binding sites. Concurrent administration of ECT had no effect on the neuroleptic-induced supersensitivity. ECT alone was also without effect on 3[H]-spiperone binding. Thus, ECT-induced increases in the sensitivity of presynaptic autoinhibition of DA release was not reflected by changes in the striatal 3[H]-spiperone binding sites. This suggests that effects of ECT on the DA system are not mediated by dopamine D2 receptors.
Levels of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the CSF of rats at various times after repeated electroshock treatment (EST) or chronic administration of haloperidol. The acidic metabolites were analyzed in 25 microliter CSF using HPLC with an electrochemical detector. A significant decrease in the CSF levels of DOPAC and HVA was found 4 days after the last administration of chronic haloperidol, EST, or both. The decrease in the level of the dopamine metabolites indicated a slower dopamine turnover, which might have resulted from hypersensitivity of presynaptic dopamine receptors after these treatments. Rats treated with haloperidol also showed an increase in 5-HIAA levels, possibly due to enhanced serotonin turnover. The 5-HIAA increase following haloperidol was prevented by a concurrent administration of EST, suggesting attenuation by EST of the haloperidol-induced enhancement of serotonin turnover.
The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (0.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses. Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility. Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolide-induced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide. On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.
The selective decreases in both basal and analgesic pain thresholds following systemic administration of parachlorophenylalanine (PCPA) has been attributed to the inhibition of tryptophan hydroxylase and subsequent depletion of brain serotonin. These effects only occur at high systemic doses which have other general debilitating effects. The present study examined the relationship between PCPA's nociceptive and serotonin-depleting effects following intracerebroventricular (ICV) administration. The first experiment determined that an ICV dose of 3 mg, but not 1 mg, of PCPA significantly decreased jump thresholds at 0.5, 48 and 120 hr after injection. These effects were not due to osmolarity shifts since hypertonic saline injections failed to alter thresholds. The second experiment demonstrated a time-dependent reduction of morphine (5 mg/kg) analgesia as a function of the interval between ICV PCPA and the systemic morphine injection. PCPA reduced morphine analgesia if it was administered 24 hr prior to the opiate and eliminated morphine analgesia if it was administered 48 hr prior to the opiate. Pretreatment with ICV PCPA either 0.5 or 72 hr prior to the opiate failed to alter morphine analgesia. The third and fourth experiments indicated that hippocampal and spinal levels of either serotonin or 5-hydroxyindoleacetic acid were not significantly affected by ICV PCPA pretreatment. These data indicate that the hyperalgesia and morphine analgesia impairments noted following ICV PCPA do not correspond with changes in serotonin from hippocampal or spinal tissue and such effects are discussed in terms of alternative modes of action.
Refractory response to dopamine (DA) agonists is a common problem in the treatment of Parkinson's disease. In rats with unilateral lesions of the substantia nigra, denervation induced significant increases in striatal 3(H)-spiperone binding sites ipsilateral to the lesion. Chronic treatment with levodopa or with pergolide mesylate significantly decreased the number of 3(H)-spiperone striatal binding sites. Agonist-induced decreases were approximately equivalent in intact and denervated striata and did not appear to be affected by lesions. These results suggest that the poor response to DA agonist in certain parkinsonian patients with chronic drug exposure may be mediated by drug-induced DA receptor down-regulation.
OMD inhibits L-DOPA utilization in rat corpus striatum. This effect is probably mediated through competition with L-DOPA for brain uptake mechanism. Such competition may explain the inhibition exerted by OMD on L-DOPA-induced rotation in rats with unilateral destruction of the nigrostriatal pathway. U-0521, a potent COMT inhibitor, was shown, after i.p. injection, to effectively block the accumulation of OMD in the plasma and to enhance L-DOPA metabolism in rat brain. This drug, however, was not active when given orally to rats and to a single patient with Parkinson's disease. It is suggested that the combined use of L-DOPA plus an orally active COMT inhibitor may be useful in future treatment of Parkinson's disease.
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We studied the effect of prolactin on the dopamine (DA) receptor density and DA turnover of the rat corpus striatum. Chronic hyperprolactinemia was produced in female rats by implanting prolactin-secreting pituitary tumors. Even in the presence of circulating prolactin concentrations that were two to three orders of magnitude greater than normal, there was no apparent change in the affinity or maximal site numbers of DA receptors in the corpus striatum. In concert with this observation, prolactin also failed to alter DA turnover in the corpus striatum as reflected in the DA/DOPAC ratio. Under the conditions of our experiments, there was no evidence to confirm previous observations of increased density of DA receptors of the corpus striatum in the hyperprolactinemic state.
Concurrent administration of lithium (Li) significantly attenuates the dopamine (DA) depleting effects of reserpine and tetrabenazine, but does not change alpha-methyl-p-tyrosine (AMPT) induced DA depletion in rat brain. This effect of Li is probably mediated, in part, by inhibiting the magnesium-dependent binding of both reserpine and tetrabenazine to their specific receptor sites. Such interaction between these drugs may attenuate the beneficial effects of tetrabenazine and reserpine on patients with tardive dyskinesia or tardive dystonia who are treated concurrently with lithium for their psychiatric disorder.
Noradrenergic (alpha 1 and beta) and serotonergic (5HT1 and 5HT2) receptors were assayed in the brains of ovariectomized female rats treated for 2 weeks with estrogen, progesterone or a combination of both hormones. Estrogen treatment resulted in a decrease in the number of 5HT1 and beta adrenergic receptors, with a concomitant increase in 5HT2 receptors. Progesterone alone caused a smaller increase in 5HT2 receptors, a similar decrease in 5HT1 and had no significant effect on noradrenergic receptors. When given with estrogen, progesterone blocked the estrogen effect on 5HT2 receptors but did not inhibit the estrogen-mediated decrease in 5HT1 and beta adrenergic receptors. alpha 1 adrenergic receptors were not affected by any of the hormone treatment paradigms. beta adrenergic and 5HT2 receptors are often implicated in antidepressant action, and the modulation of these two receptor types by ovarian hormones might be relevant to hormone-linked affective changes such as premenstrual tension and post-partum depression.
Long-term lithium treatment attenuated the hypokinetic effect of reserpine in a patient with tardive dyskinesia. In rats, prophylactic lithium administration inhibits reserpine-induced dopamine depletion in the brain. These data indicate that lithium may limit the therapeutic efficacy of reserpine in tardive dyskinesia.
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We measured the kinetic constants for the unidirectional influx of L-DOPA into red blood cells of patients with Parkinson's disease (seven patients), Huntington's disease (seven patients), and other extrapyramidal diseases (11 patients), and in five controls. Influx consisted of two components with low affinity and high exchange capacity. In individual subjects, the L-DOPA concentration giving half-maximal influx (Km) varied between 0.04 and 2.19 mM, and the maximum velocity (Vmax) of the saturable transport component was between 20 and 578 mumol/l cell water/h, which is compatible with the neutral amino acids of low affinity for the transport system. The range of Kd (the first-order rate constant for the unsaturable component) was between 0.11 and 0.36 hour-1. There was no gross deficit of the L-DOPA uptake process in patients with Parkinson's disease, Huntington's disease, dystonia, or other extrapyramidal diseases.
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Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. We studied other possible mechanisms of action of this drug. TBZ decreased DA concentration in rat striatum and nucleus accumbens in a dose-dependent manner with an IC50 of approximately 1.2 mg.kg-1. Maximal depletion was obtained within 30 min with only partial recovery at 8 hr. TBZ induced (at 40 mg . kg-1) 5- to 8-fold increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in both brain regions. Unlike reserpine, TBZ completely abolished the apomorphine-induced inhibition of DA synthesis under conditions in which this effect is mediated by presynaptic DA receptors. Both TBZ (5 mg . kg-1) and reserpine (5 mg . kg-1) depleted, at 1 hr, striatal DA content by approximately 90%. However, TBZ, but not reserpine, significantly stimulated in vivo tyrosine hydroxylase activity. TBZ also inhibited [3H]spiperone binding in the striatum with Ki = 2.1 X 10(-6) M. In rats, with unilateral destruction of the nigrostriatal pathway with 6-hydroxydopamine, pretreatment with TBZ significantly reduced the number of rotations induced by apomorphine. Finally, in rats treated with either TBZ (5 mg . kg-1) or reserpine (5 mg . kg-1), prolactin levels significantly increased as compared to control values. TBZ, but not reserpine, blocked apomorphine inhibition of prolactin secretion. We conclude that, in addition to depleting monoamines, TBZ also blocks both presynaptic and postsynaptic DA receptors in rat brain.
The effects of the catechol-O-methyltransferase (COMT) inhibitor 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) were studied in red blood cells (RBC) and corpus striatum in the rat. In vitro U-0521 inhibited RBC COMT activity in a dose-dependent manner with an IC50 of 6 x 10(-6)M. In vivo maximum inhibition (90%) of enzyme activity in RBC was obtained with 250 mg/kg with a peak effect at 5 min and enzyme recovery within 90 min. In U-0521-pretreated rats L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation in RBC and corpus striatum, after injection of L-DOPA, was significantly higher than in nonpretreated rats. The use of COMT inhibitor along with L-DOPA may be of benefit in the treatment of Parkinson's disease.