Effect of carbidine on dopamine turnover in the rat corpus striatum

It has been shown that carbidine increases the level of homovanillic acid (HVA) in the corpus striatum of the rat brain. The changes in HVA level allowed forming a judgement on dopamine turnover. By the intensity of this effect, carbidine proved inferior to typical neuroleptics--triphtazine and ftorfenazin. The antidepressant ftoracizin did not alter HVA level. Carbidine ranks between neuroleptics and antidepressants in terms of the effect on dopamine turnover.     

D-2 dopamine receptor synthesis and turnover in rat striatum

Direct injection of phenoxybenzamine into rat striatum inhibited apomorphine-induced stereotyped behavior. This inhibition corresponded well with the inhibition of D-2 dopamine receptor labelling with [3H]spiroperidol. Both the behavioral response and the receptor level were completely restored within 5 days after the injection. The recoveries of both were blocked by cycloheximide. The rate of synthesis and half-life of the D-2 receptor associated with the stereotyped behavior were calculated to be 6.9 fmol/mg protein per h and 28 h, respectively.     

Evidence for selective inhibition of limbic forebrain dopamine synthesis by 8-OH-DPAT in the rat

Summary Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015, 100 mg kg^–1 intraperitoneally. In animals treated with reserpine, 5 mg kg^–1 subcutaneously –18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT_1A receptor agonist 8-OH-DPAT, 0.15–2.4 mol kg^–1, whereas the partial dopamine D₂ receptor agonist (–)3-PPP, 2.5–10.0 mol kg^–1, or the full dopamine D₂ receptor agonist quinpirole, 0.05–0.8 mol kg^–, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mol kg^–1, but not by (–)pindolol, 8 mol kg^–1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (–)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis. This latter effect is probably due to direct stimulation of dopamine autoreceptors, since it was obtained in reserpine-treated rats, and was completely antagonized by raclopride, but not (–)pindolol.Presented in part at the 7th General Meeting of the European Society for Neurochemistry, June 12–17th 1988, Göteborg, Sweden Send offprint requests to S. Ahlenius at the above address     

Chronic treatment with diisopropylfluorophosphate increases dopamine turnover in the striatum of the rat

Following the administration of a single dose of diisopropylfluorophosphate (DFP) there is a rise of acetylcholine (ACh) in the rat striatum and frontal cortex. With chronic treatment, striatal ACh content returns to normal, but frontal cortex ACh remains elevated. In striatum but not frontal cortex, there is a rise of dopamine (DA) content and turnover after chronic DFP treatment. We speculate that DA content and turnover are increased after chronic DFP because the nigrostriatal neuronal feedback loop and local feedback loops are activated to compensate for increased cholinergic tone.     

On the mechanism of mergocryptine-induced suppression of dopamine turnover in the rat striatum

The effect of mergocryptine, a new ergot alkaloid, on the cerebral dopaminergic systems was examined using Wistar rats. The administration of mergocryptine (1 and 10 mg/kg i.p.) induced a significant suppression of striatal dopamine (DA) turnover. In vitro addition of mergocryptine (0.01-100 microM) induced a dose-dependent suppression of the release of [3H]DA from striatal slices. Mergocryptine inhibited [3H]apomorphine binding to a striatal synaptosomal fraction, and its IC50 value was found to be 0.23 microM. Pretreatment with apomorphine (100 micrograms/kg s.c.) showed an additive effect on the mergocryptine (10 mg/kg)-induced suppression of DA turnover. These results suggest that mergocryptine may induce the suppression of striatal DA turnover by reducing DA release via the stimulation of presynaptic dopaminergic autoreceptors.     

Nicotine and epibatidine alter differently nomifensine-elevated dopamine output in the rat dorsal and ventral striatum

We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 microg/kg but not 3.0 microg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 microg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 microg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic dopaminergic pathways.     

Inhibition of histamine turnover by 8-OH-DPAT,buspirone and 5-hydroxytryptophan in the mouse and rat brain

Summary The effects of 5-hydroxytryptamine (5-HT) receptor agonists on histamine turnover in mouse and rat brains were examined. The histamine turnover rate was estimated from the accumulation of tele-methylhistamine 90 min after i.p. injection of pargyline (65 mg/kg). In whole mouse brains, the histamine turnover was significantly inhibited by the 5-HT_1A agonists, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (> 0.5 mg/kg) and buspirone (> 2 mg/kg) injected s. c. 10 min before pargyline treatment. 5-hydroxytryptophan (20 mg/kg) also significantly inhibited histamine turnover. Injections of the 5-HT_1B agonist m-trifluoromethylphenylpiperazine (10 and 20 mg/kg) or the 5-HT₂ agonist (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1, 2 and 5 mg/kg)), however, did not affect histamine turnover. The inhibitory effect of 8-OH-DPAT (1 mg/kg) on histamine turnover was significantly antagonized (by 40%) by pindolol (20 mg/kg) and slightly antagonized (by 29%) by spiperone (10 mg/kg), while methysergide (20 mg/kg) and ketanserin (10 mg/kg) demonstrated no antagonistic effects. 8-OH-DPAT (0.3 and 1 mg/kg) also showed an inhibiting effect on histamine turnover in various regions of rat brains. Although the extent of inhibition was slightly larger in the striatum and cerebral cortex, there was no marked regional difference. These results suggest that histaminergic activity in the brain is regulated by 5-HT_1A receptors. Send offprint requests to R. Oishi at the above address     

Effect of cholecystokinin on acetylcholine turnover and dopamine release in the rat striatum and cortex

The effect of sulfated cholecystokinin (CCK-8S) on acetylcholine turnover (TRACh) and dopamine (DA) release in the rat cerebral cortex and striatum was studied in unanaesthetized animals in vivo. CCK-8S (1 mg/kg s.c.) decreased TRACh in the fronto-parietal cortex but not in the striatum. This effect was prevented by peripheral (10 mg/kg i.p.) but not central (1 microgram i.v.t.) administration of the peripheral CCK receptor antagonist CR 1409. In a separate study, CCK-8S decreased 3-methoxytyramine (3-MT) levels (an index of DA release) in the fronto-parietal cortex and in the striatum. CR 1409 appeared to have a partial agonist action, reducing cortical and striatal 3-MT levels, and only partially reversing the effect of CCK-8S in the striatum. These data indicate that peripheral administration of CCK-8S decrease TRACh in the cortex but not in the striatum and that this action is mediated by peripheral-type CCK receptors possibly located outside the CNS. CCK-8S also reduces DA release in the cortex and in the striatum, and this effect appears to be mediated by a mechanism of action different from that modulating cortical TRACh.     

Increased levels of proneurotensin/neuromedin N mRNA in rat striatum and nucleus accumbens induced by 7-OH-DPAT and nafadotride.

The D3 dopamine receptor has been proposed as a potential antipsychotic site. In this study, the effects of the D3-preferring compounds 7-OH-DPAT and nafadotride on levels of proneurotensin/neuromedin N (proNT/N) were assessed. Adult, male, Sprague-Dawley rats were injected subcutaneously (s.c.) with the agonist 7-OH-DPAT (0.1 mg/kg) or antagonist nafadotride (1 mg/kg) at doses previously shown to produce negligible occupancy of D2 receptors in vivo. As a positive control, an additional group of animals was treated with haloperidol (3 mg/kg, s.c.). ProNT/N mRNA levels were determined by in situ hybridization. 7-OH-DPAT increased proNT/N mRNA in the nucleus accumbens shell. Nafadotride increased proNT/N mRNA levels in the nucleus accumbens shell and dorsomedial caudate nucleus to levels comparable to those produced by haloperidol. Nafadotride also increased proNT/N mRNA in the anterior and dorsal caudate but to a lesser extent than haloperidol. These data indicate that 7-OH-DPAT and nafadotride increase proNT/N mRNA levels in brain areas affected by antipsychotic drugs and suggest that the D3 receptor may regulate proNT/N mRNA expression in the nucleus accumbens shell.     

Effects of acute and chronic systemic administration of some typical antipsychotic drugs on turnover of dopamine and potassium ion-induced release of dopamine in the striatum of the rat in vivo

Chronoamperometry was used to measure the dose dependency of antipsychotic drug (spiperone, haloperidol and chlorpromazine)-induced increases in depolarization-stimulated release of dopamine in the striatum of the rat in vivo. The dose-response curves were found to be at least biphasic (small doses increased release and large doses inhibited release) and different in shape from dose-response curves for increases in the turnover of dopamine, suggesting that the two processes may not be related. The threshold dose to induce increased depolarization-stimulated release of dopamine correlated with the values in the literature for doses required to block stereotype induced by apomorphine and amphetamine and doses sufficient to cause a maximal increase in release correlated with the doses required for the induction of catalepsy. In addition, the ratio of the doses required to obtain half-maximal and maximal increases in stimulated release of dopamine, matched values in the literature of the ratio of doses required to ameliorate psychotic symptoms, whereas the doses required to reverse the increase induced by antipsychotic drugs did not. Chronic administration of haloperidol resulted in alterations in the dose-response curves for both the release and turnover of DA. Chronic administration caused a reversal of the effect of acute administration in the small dose range (inhibition as opposed to enhancement of release), a decrease in the maximum magnitude of release of dopamine obtained and an overall shift to the right of the dose-response curve. Chronic administration of haloperidol decreased turnover, relative to animals receiving the drug acutely and no shift in the position of the dose-response curve was observed.     

Effect of gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum

Gamma-butyrolactone (GBL), a precursor for the naturally occurring central nervous system depressant, gamma-hydroxybutyrate (GHB), administered in anesthetic doses, produces an increase in rat corpus striatum dopamine levels without affecting norepinephrine or serotonin levels. The rise and fall of the dopamine levels coincide with the changes of brain GHB levels and the behavioral effects of the drug. The specific activity of striatal dopamine was found to be greater in rats injected with ³H-tyrosine shortly before or shortly after GBL, as compared with controls, which were not treated with GBL. The specific activity of cortical norepinephrine in GBL-treated rats was not significantly different from that observed in untreated controls. No significant difference was observed in blood or striatal tyrosine specific activity of GBL-treated rats. Levels of dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, also increased in the corpus stratium after GBL, but the increase did not occur until after brain levels of GHB began to fall. These results suggest that the drug either increases dopamine synthesis and or blocks the release of dopamine from a rapidly turning over functional compartment within the neurons, or both. Perhaps as a result of the ability of GHB to block the release of dopamine, this drug also interferes with the metabolism of dopamine for a certain period of time after administration.     

Certain dopamine agonists increase dopamine synthesis in the striatum of rat brain

N,N-Dipropylamino-5,6-dihydroxytetrahydronaphthalene (DP-5,6-ADTN) induced a rapid and dose-related rise in dopamine (DA) levels in the striatum of rat brain. The increase of DA was less pronounced in the tuberculum olfactorium and there was no change in the frontal cortex. DP-5,6-ADTN and DP-6,7-ADTN also caused a rapid increase in striatal DA synthesis (evaluated from the rise of 3,4-dihydroxyphenylalanine after decarboxylase inhibition) which lasted about 20 min and was followed by a decrease. The increase in DA synthesis rate after the DP-ADTNs was restricted to the striatum, only a decrease was observed in mesolimbic areas and frontal cortex. Dose-effect curves showed that the ED 50% for the stimulation of DA synthesis was somewhat higher (approx. 0.2 mumol/kg) than the ED 50% for the decreasing effect (approx. 0.01 mumol/kg). The increase in striatal DA biosynthesis was not seen after the DA agonists piribedil, TL-99 or apomorphine. Pretreatment of rats with gamma-hydroxybutyrolactone or haloperidol prevented the DP-5,6-ADTN-induced increase in DA synthesis.     

Changes in rat striatal dopamine turnover and receptor activity during one years neuroleptic administration

Administration of trifluoperazine (2.5--3.5 mg/kg/day p.o.) or thioridazine (30--40 mg/kg/day) for up to 1 year initially increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in striatum. However, by 1 month and thereafter metabolite levels returned almost to control values. Dopamine concentrations were elevated after 3 months administration of both drugs and also after 12 months administration of trifluoperazine. Trifluoperazine administration for 1 month produced a marked increase in the dissociation constant (KD) for striatal 3H-spiperone binding but a reduction in receptor numbers. Thereafter receptor numbers increased at 6 and 12 months in both trifluoperazine and thioridazine treated animals compared to control values. The KD for both drug treated groups returned to normal at 6 months; however, by 12 months drug treated animals again demonstrated high KD values. Dopamine stimulation of striatal adenylate cyclase was inhibited after administration of trifluoperazine or thioridazine for 1 week or 1 month. However, by 6 and 12 months this effect was replaced by an enhanced stimulation. Administration of lower doses of trifluoperazine (0.7--0.9 mg/kg/day p.o.) or thioridazine (6--9 mg/kg/day p.o.) for up to 1 year produced similar although generally less marked changes in these biochemical indices of dopamine function. This study provides evidence of biochemical changes which parallel the behavioural findings of enhanced dopamine receptor activity that occur during continuous long-term neuroleptic administration to rodents.     

Effects of 8-OH-DPAT on motor activity in the rat

The administration of 8-OH-DPAT to rats produced a dose-dependent suppression of spontaneous locomotor activity in an open field arena. 8-OH-DPAT was administered in the dose range 12.5-1,600 micrograms.kg-1 SC. Vertical activity ("rearing") was more sensitive to the treatment than horizontal activity ("locomotion"), both in terms of potency and efficacy. The activity along the walls of the open field arena ("peripheral activity") was increased, and the rearing activity was decreased, relative to total horizontal activity and total activity, respectively. There were no effects by 8-OH-DPAT on treadmill locomotion. The rectal temperature was decreased by 8-OH-DPAT administration, not only in animals tested in the open field, but also in animals with an increased body temperature, produced by treadmill locomotion.     

Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum

Rationale Acute systemic administration of salvinorin A, a naturally occurring κ-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow. Objectives Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed. Materials and methods Salvinorin A was administered via the dialysis probe (0; 20–200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day × 5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment. Results Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced. Conclusions These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ.