Antidopaminergic Activity Research Articles

Reduced haloperidol and haloperidol: Effects on homovanillic acid in caudate and prefrontal cortex

The effects of acute administration of reduced haloperidol (RHAL) on homovanillic acid (HVA) in the caudate and prefrontal cortex were examined in rats. Haloperidol (HAL) was used as a reference compound. Concentrations of HVA and HAL were measured by HPLC/ECD. The maximal HVA response time was 3 hr after the injection, in both caudate and prefrontal cortex, for both RHAL and HAL. The potency of RHAL in the elevations of HVA in the caudate and prefrontal cortex was only about one-third to one-fifth that of HAL. The concentrations of HAL in the prefrontal cortex and caudate after RHAL administration were just about one-third to one-fifth those after HAL administration. These results suggest that less antidopaminergic activity of RHAL in this neuroleptic test might be explained by the lesser conversion of RHAL to HAL.

Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of the rat hippocampus.

The effects of buspirone on hippocampal pyramidal cells of the CA1 region were examined by means of intracellular recordings in in vitro hippocampal brain slices. Bath administration of buspirone elicited a long lasting hyperpolarization which was mediated by an increase in potassium conductance and resembled the hyperpolarizing component of the response to 5-HT (5-hydroxytryptamine). Buspirone, however, failed to mimic the depolarizing action of 5-HT or to reduce the calcium-activated after hyperpolarization. Quantitative comparisons of the hyperpolarizing responses of 5-HT and buspirone revealed that the maximal hyperpolarization induced by buspirone was significantly smaller than that induced by 5-HT. Since the buspirone induced hyperpolarization was also accompanied by a surmountable antagonism of 5-HT responses, these results indicate that buspirone behaves as a partial agonist at a subpopulation of 5-HT receptors in the CA1 region of the hippocampus. Administration of the buspirone congeners gepirone and isapirone also elicited a hyperpolarization and reduced 5-HT responses, although they lack antidopaminergic activity, indicating that the effects observed with buspirone are unlikely to be mediated through dopamine receptors. These results indicated that novel anxiolytics can discriminate between functional 5-HT receptors. In conjunction with previous biochemical and electrophysiological studies, the present results suggest that their administration might alter the balance of serotonergic actions on postsynaptic neurons.

Effects of cisapride on the secretion of pancreatic polypeptide in healthy volunteers.

Plasma human pancreatic polypeptide (hPP) responses to intravenous injections of a new gastric and intestinal motility promoting agent, R51 619 (cisapride), were studied in healthy volunteers. The mean fasting concentrations of plasma hPP (39 +/- 5.4 pg/ml; mean +/- S.E.) were elevated significantly to the peak values of 118 +/- 25.1 pg/ml 30 min after the drug had been given in a dose of 4 mg over 5 min. However, plasma insulin (IRI), glucose and prolactin levels were not elevated. Atropine diminished the cisapride-induced hPP elevation, thereby suggesting that cisapride induced release of acetylcholine but had no antidopaminergic action.

Potential noncataleptic neuroleptic agents; 2,6-Dichloro-, 2,7-dichloro- and 2,8-dichloro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Substitution reactions of 2,6,10-trichloro-, 2,7,10-trichloro- and 2,8,10-trichloro-10,11-dihydrodibenzo[b,f]thiepin (Vabc) with 1-(2-hydroxyethyl)piperazine, 1-methylpiperazine and 1-benzylpiperazine gave the title compounds IIabc, IIIab and IVab. The new chloro compounds Va and Vb were obtained in 6 steps starting from reactions of 2,5-dichloroacetophenone with 2-chlorothiophenol or 3-chlorothiophenol. Compounds IIabc are 6-chloro, 7-chloro and 8-chloro derivatives of the noncataleptic neuroleptic agent docloxythepin (I). They are almost devoid of cataleptic activity and do not inhibit the apomorphine stereotypies in rats. Compounds IIab have a clozapine-like affinity to dopaminergic receptors in the rat brain striatum; the affinity of IIc is much higher. On the other hand only compounds IIb and IIIa prove a significant antidopaminergic activity in vivo (increase significantly the homovanillic acid level in the rat brain striatum).

Noncataleptic neuroleptic agents: 4-Substituted 1-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazines and related compounds

1-(2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine (VI) was used to prepare a new group of potential noncataleptic neuroleptic agents. Addition of acrylonitrile and acrylamide gave the nitrile VII and the amide X. Further transformations of the nitrile VII led to the phenone VIII and the amidoxime IX. Alkylations of compound VI with 2-(2-chloroethyl)-1,3-dioxolane and 2-(2-chloroethyl)-1,3-dioxane resulted in the cyclic acetals XII and XIII. Several improvements of the synthesis of compound VI are reported. Out of the compounds prepared, the amide X (methanesulfonate VňFB-15 496) proved most interesting: it has low acute toxicity, is noncataleptic and has significantly higher antidopaminergic activity than clozapine.

Noncataleptic neuroleptic agents: Synthesis of some esters of 2-chloro-10-(4-(2-hydroxyethyl)piperazino)-10,11-dihydrodibenzo[b,f]thiepin

Reactions of 2-chloro-10-(4-(2-hydroxyethyl)piperazino)-10,11-dihydrodibenzo[b,f]thiepin (I) with phenylacetic, methoxyacetic, methylthioacetic, phenoxyacetic and morpholinoacetic acid in dichloromethane and in the presence of N,N'-carbonyldiimidazole gave the title esters II - VI. Reaction of I with succinic anhydride afforded the hemisuccinate VII. The esters prepared elicited ataxia in low doses, were low-cataleptic, but only II, IV, and VII proved some antidopaminergic activity in the test using the affecting dopamine metabolism in rat brain striatum.

Biochemical and behavioral studies of D1 dopamine receptors utilizing SCH 23390.

Previous research has demonstrated the existence of two distinct dopamine receptor subtypes (Kebabian & Calne, 1979; Creese et al., 1983), possessing unique pharmacologic and biochemical properties. D1 dopamine receptors stimulate adenylate cyclase activity (Hyttel, 1978), while D2 dopamine receptors inhibit this enzyme (Stoof and Kebabian, 1981; Onali et al., 1984; Battaglia et al., 1985). However, both receptor subtypes co-exist in many tissues making the determination of their respective physiological and behavioral roles difficult. All neuroleptics, commonly used drugs in the treatment of schizophrenia, have been shown to be either mixed D1/D2 dopamine receptor antagonists or selective D2 dopamine receptor antagonists. Thus, D2 dopamine receptors have been implicated as the site mediating the antipsychotic and antidopaminergic activity of neuroleptics (Creese et al., 1976; Seeman et al., 1976). By inference, D2 dopamine receptors have been considered to mediate dopaminergic agonists’ behavioral effects as well (Seeman, 1981).

Prolonged antidopaminergic actions of single doses of butyrophenones in the rat

Rats were treated once with doses of haloperidol or of droperidol below and above the acute ID50 vs the dopamine agonist apomorphine; they were later challenged with an acute dose of apomorphine (0.3 mg/kg, SC) and rated for stereotyped behavioral responses. The two neuroleptics were similar in acute anti-apomorphine potency (ID50 = 0.12 and 0.18 mg/kg for haloperidol and droperidol, respectively). The antidopaminergic effects of droperidol persisted for nearly 1 week and those of haloperidol lasted for 20-40 days, depending on the dose given. The computed half-time of disappearance of their antidopaminergic effects was 7.6 +/- 1.0 days and 0.59 +/- 0.17 days for haloperidol and droperidol, respectively, following a dose of 0.3 mg/kg, and these indices of duration of action did not vary significantly at doses between 0.1 and 1.0 mg/kg. Haloperidol reduced the acute entry of 3H-apomorphine into brain by 21.5% 1 week later. Treatment with apomorphine alone just prior to haloperidol (both at 0.3 mg/kg) prevented the prolonged antidopaminergic effects of the neuroleptic evaluated 1 week later. These results indicate that some neuroleptics may have very prolonged activity or retention in tissue at sites of action, even after moderate, single doses. Caution is recommended in the interpretation of studies which assume "neuroleptic-free" conditions of subjects previously exposed to a neuroleptic agent.

Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (DA) receptors in extrapyramidal and limbic preparations of rat brain tissue. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulating adenylate cyclase (D-1 sites) and in competing for high affinity binding of 3H-spiroperidol (D-2 sites) and of 3H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity or higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical and functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

S(+)apomorphines selective inhibition of excitatory effects of dopamine injected into the limbic system of the rat

Dopamine (DA) injected unilaterally into the corpus striatum of the brain of the rat after pretreatment with a monoamine oxidase inhibitor, induced contralateral deviation of the head (ED 50 = 23 μg). Dopamine, administered similarly into the nucleus accumbens septi, induced strong locomotor arousal effects (ED 50 = 32 μg), as reported by others. Systemic administration of the S(+) isomers of apomorphine (APO) and its N- n-propyl analog (NPA) had no significant action on the effects on posture of DA given intrastriatally, even in large doses. In striking contrast, both agents selectively inhibited the locomotor-arousal effects of DA injected into the accumbens, but (+)NPA was seven times more potent (ED 50 = 0.5 mg kg vs 16 μg of DA) and its effects lasted for about 70 min. The dose-effect curves for (+)NPA against two doses of DA demonstrated parallel, lateral displacement, indicating a competitive interaction. These results support the impression that enantiomers and analogs of apomorphine, and especially S(+) N-propylnorapomorphine, have potent antidopaminergic actions that may be selective for limbic areas of the forebrain.

Alteration of dopamine metabolism in different brain regions of the rabbit by estradiol and tamoxifen

Tamoxifen citrate, a mixed estrogen agonist-antagonist, and estradiol 17-β administered separately for 14 days significantly reduced dopamine and dihydroxyphenylacetic acid in the cortex and hypothalamus regions of the brain in immature female rabbits. In addition to these areas, estradiol also reduced dopamine and dihydroxyphenylacetic acid in the striatum but tamoxifen treatment significantly reduced only dihydroxyphenylacetic acid concentration in the striatum. When estradiol and tamoxifen were injected together, dopamine and dihydroxyphenylacetic acid concentrations were reduced only in the cortex. Specific binding of [ 3H]spiperone to dopamine receptors was significantly increased by both estradiol and tamoxifen in the hypothalamus but only tamoxifen increased dopamine binding in the striatum. A low dose of tamoxifen, either alone or in combination with estradiol, increased uterine weight, but a higher dose of tamoxifen was neither an estrogen agonist nor antagonist. These studies indicate that estradiol and tamoxifen alter dopamine metabolism in the various regions of brain differentially. The estrogen agonist activity of tamoxifen does not correspond to antidopaminergic action of estradiol in the striatum.

Effect of propiomazine on plasma prolactin in the rat: counteraction by L-dopa.

A single iv injection of 0.31, 0.62, 1.25, 2.5, 5, 10, or 20 mg/kg body wt of a phenothiazine derivative, propiomazine (PP), into male rats significantly (P less than 0.05) increased plasma prolactin concentrations. The higher doses (5, 10, and 20 mg/kg body wt) produced increases that were greater in both magnitude and duration than those produced by the lower doses. The higher doses of PP, along with the elevations in plasma prolactin, also produced concomitant decreases in plasma luteinizing hormone (LH) levels. Pretreatment with L-dopa (100 mg/kg body wt) completely blocked the PP-induced stimulation of prolactin release, indicating that antidopaminergic action of PP either at the hypothalamic or anterior pituitary level was responsible for its effects on the release of prolactin.

Increased hepatic and reduced prostatic prolactin (PRL) binding in iron deficiency and during neuroleptic treatment: Correlation with changes in serum PRL and testosterone

Iron deficiency (ID) induced in 21 day old male rats for 28 days caused a 7 fold increase in hepatic prolactin (PRL)-specific binding and a parallel 3 fold rise in serum PRL, as expected from both the reported reduction in central dopaminergic (DA) activity and PRL's up-regulating effect on its own liver receptors. Similarly, serum testosterone was increased by 80%. Prostatic PRL binding was slightly reduced (by 27%), possibly because of masking by the raised hormone levels, although more likely by a more generalized reduction in proliferation during ID, as indicated by the 50% prostatic weight loss. Chronic treatment with neuroleptics also increased hepatic PRL binding in accord with their anti DA activity: chlorpromazine (10 mg/kg) or fluphenazine (5 mg/kg) injected daily (i.p.) for 21 days followed by a 3 day drug-free period resulted in 26 and 10 fold increases, respectively. The parallel reductions of serum levels of PRL (by 40%) and of testosterone (by 70%) by both drugs is indicative of the drug withdrawal supersensitivity normally observed in the caudate nucleus DA receptor. A testicular peripheral effect of the neuroleptics probably further accounted for the reduction in testosterone synthesis, reinforcing the induction of liver PRL binding by these drugs and explaining their negative effects on prostate PRL binding and weight. These findings stress the importance of monitoring hormone levels in ID and during treatment with neuroleptics, in order to avoid endocrine side-effects.

GABA receptor agonists: pharmacological spectrum and therapeutic actions.

From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by apomorphine or L-DOPA suggesting that GABAergic stimulation results also in an antidopaminergic action which is exerted beyond the dopamine synapse. These effects of GABA receptor agonists may represent the basis of the antidyskinetic action of these compounds which, however, remains to be fully confirmed. GABA receptor agonists reduce striatal acetylcholine turnover, an effect which occurs at doses much lower than those which affect dopamine neurons. Since hyperactivity of cholinergic neurons plays a determinant role in the pathogenesis of some parkinsonian symptoms, it is conceivable that GABAergic stimulation is effective in ameliorating Parkinson's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Behavior therapy, pimozide treatment and prolactin secretion in anorexia nervosa.

The involvement of the hypothalamic dopaminergic pathway in the treatment of anorexia nervosa (AN) was evaluated by monitoring the serum prolactin (PRL) levels in 10 adolescent anorectic females. 5 patients were treated by behavior therapy program and 5 were treated with pimozide, an antidopaminergic drug. The study was conducted for a period of 20 weeks. Elevation of PRL levels was used as an indicator of antidopaminergic activity. PRL was increased in the 5 patients receiving the antidopaminergic agent, while no elevation was observed in the patients undergoing behavior therapy. All 10 patients were treated successfully as expressed by their gradual gain in weight. It is concluded that antidopaminergic activity does not seem to be a prerequisite for clinical improvement.

Effect of domperidone and dopamine on colonic motor activity in patients with the irritable bowel syndrome.

The effect of domperidone, a peripheral antidopaminergic drug, on sigmoid motor activity in the irritable bowel syndrome, has been evaluated by measuring pressures in 3 opentipped tubes perfused with distilled water at a constant flow rate of 0.636 ml/min and inserted into the sigmoid colon. Domperidone 20 mg i.v. in 10 patients, did not induce any significant change in basal motility, but prevented the increase in motor activity produced by the infusion of dopamine 5 micrograms/kg/min for 10 min. It appears that domperidone had no effect on sigmoid motor activity, although the inhibition of dopamine-induced motility confirms the presence of specific dopaminergic receptors in the colon and the antidopaminergic action of domperidone.

The effects of yohimbine and neuroleptics on apomorphine-induced pecking behaviour in the pigeon

The effects of yohimbine and some neuroleptics were investigated on pecking behaviour, induced by apomorphine. The total pecking counts, recorded for 18 min, elicited by a standard dose of apomorphine (1 mg/kg) were inhibited dose-dependently by yohimbine and the neuroleptics. Haloperidol was found to be the most potent, trifluoperazine, yohimbine, chlorpromazine and the atypical neuroleptics were less effective in decreasing order. Chronic treatment with yohimbine (2.5 mg/kg per day for 20 days) caused an increase in pecking behaviour. These results suggest that apomorphine-induced pecking behaviour in the pigeon could be used as a reliable method for screening neuroleptic drugs and the antidopaminergic activity of yohimbine is verified in this model.

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED 50 for blockade of apomorphine-induced hyperactivity and the ED 50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D 2 receptor antagonist since it displaced [ 3H]spiperone (IC 50 = 1570 nM) but not [ 3H]flupentixol (IC 50 > 100 000 nM) in rat striatum, annd did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC 50 > 100 000 nM). Remoxipride is a potent antagonist of D 2 receptors showing a dose-dependent blockade of [ 3H]spiperone and [ 3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [ 3H]spiperone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D 2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.

Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptor agonist with greater autoreceptor selectivity than 3-PPP enantiomers

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(−)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and α-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.

High dose diazepam treatment and its effect on prolactin secretion in adolescent schizophrenic patients.

Thirteen acute schizophrenic patients aged 14-18 years were treated with gradually increasing doses of diazepam to a maximum of 100-400 mg/day/p.o. with a total duration of treatment of 4 weeks. The clinical antipsychotic effect was evaluated by the Brief Psychiatric Rating Scale (BPRS), while the impact on the hypothalamic hypophyseal pathway was evaluated by monitoring the serum prolactin levels (SPL) determined by a highly sensitive homologous radioimmunoassay (RIA). High diazepam doses (100-400 mg/day) caused sedation but no clinical antipsychotic effect was observed. Diazepam treatment with doses up to 250 mg/day caused no significant rise in SPL, while the treatment with doses of higher than 250 mg/day resulted in a mild but still significant increase in SPL. The clinical and laboratory data suggest that diazepam has no direct antidopaminergic activity. The mild hyperprolactinemia achieved with the extremely high doses of diazepam (greater than 250 mg/day) is possibly due to activation of the GABA system which stimulates prolactin release directly or by inhibiting the dopaminergic neurons or alternatively to activation of the endorphinergic system.