(-)Epigallocatechin-3-gallate prevents the reserpine-induced impairment of short-term social memory in rats.

Reserpine has been confirmed to induce cognitive dysfunction and increase brain neural oxidative stress. Green tea catechins, particularly (-)epigallocatechin-3-gallate (EGCG), have strong antioxidative properties and can protect against numerous oxidative damages. In this study, we examined the possible protective effects of EGCG on reserpine-induced impairment of short-term memory in rats. Reserpine (1 mg/kg, intraperitoneal)-induced memory impairment was assessed using the social recognition task method; locomotor activity and the olfactory discrimination ability were not altered as measured by an open-field test and an olfactory discrimination test, respectively. EGCG treatment (100 and 300 mg/kg, intraperitoneal, for 7 days, starting 6 days before the reserpine injection) could improve the worsened social memory of reserpine-treated rats. Also, EGCG treatment reduced reserpine-induced lipid peroxidation and enhanced the antioxidation power in the hippocampi of reserpine-treated rats. These results suggest a protective effect of EGCG in treating reserpine-induced impairment of memory, most probably through its powerful antioxidative activities. Accordingly, EGCG may hold a clinically relevant value in preventing reserpine-induced cognitive dysfunction.

Involvement of the central monoaminergic system in the antidepressant-like effect of catalpol in mice.

Catalpol is a natural iridoid glycoside with diverse bioactivities that is found in abundance in Rehmannia glutinosa Libosch. (Scrophulariaceae). The present study assessed whether catalpol treatment (5, 10, or 20 mg/kg for 14 days by intragastric administration (i.g.)) has an antidepressant-like effect on mice performing the forced swim test (FST), tail suspension test (TST), open field test (OFT), and tests for reversal of reserpine-induced ptosis, akinesia, and hypothermia. This study also examined the potential role that catalpol plays in the cerebral monoaminergic system. Results indicated that catalpol administration produced an antidepressant-like effect in mice, as indicated by the reduced duration of immobility in the FST and TST, but it had no effect on locomotor activity in the OFT. Catalpol treatment significantly counteracted the decrease in rectal temperature, akinesia, and eyelid ptosis induced by reserpine. Moreover, catalpol increased levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brains of mice, but it did not affect levels of norepinephrine (NE) or dopamine (DA). These antidepressant-like effects of catalpol are essentially similar to the effects of the clinical antidepressant fluoxetine hydrochloride (FH). This is the first study to indicate that catalpol has an antidepressant-like effect and that its action may be mediated by the central serotonergic system, and not by noradrenergic or dopaminergic systems.

Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.

Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.

Effect of Hibiscus rosa sinensis on reserpine-induced neurobehavioral and biochemical alterations in rats.

Effect of methanolic extract of Hibiscus rosa sinensis (100-300 mg/kg) was studied on reserpine-induced orofacial dyskinesia and neurochemical alterations. The rats were treated with intraperitoneal reserpine (1 mg/kg, ip) for 3 days every other day. On day 5, vacuous chewing movements and tongue protrusions were counted for 5 min. Reserpine treated rats significantly developed vacuous chewing movements and tongue protrusions however, coadministration of Hibiscus rosa sinensis roots extract (100, 200 and 300 mg/kg, per orally) attenuated the effects. Biochemical analysis of brain revealed that the reserpine treatment significantly increased lipid peroxidation and decreased levels of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH), an index of oxidative stress process. Coadministration of extract significantly reduced the lipid peroxidation and reversed the decrease in brain SOD, CAT and GSH levels. The results of the present study suggested that Hibiscus rosa sinensis had a protective role against reserpine-induced orofacial dyskinesia and oxidative stress.

Green tea modulates reserpine toxicity in animal models.

Reserpine, a natural product extracted from Rauwolfia serpintina or Rauwolfia vomitoria, is a known dopamine depleter that inhibits several neurotransmitters. Reserpine has been used clinically to control hypertension, schizophrenia, insomnia and insanity. The use of this drug, however, has been limited because of its side effects which include oxidative damage to organs, including the liver. Green tea catechins are potent antioxidants that have the potential to counteract reserpine induced oxidative stress. This study investigated the merits of administering green tea concurrently with reserpine to prevent oxidative hepatic damage in Sprague-Dawely (SD) rats. Reserpine was found to cause hepatic damage, with elevated levels of oxidative stress markers, such as Thiobarbituric Acid Reactive Substances (TBARS), transaminases and cholesterol. Reserpine also induced hepatic ultra-structural damage in the cytoplasmic membrane, nuclear envelope, endoplasmic reticulum (rER), ribosomal stripping and mitochondria. Electron microscopy examination showed revival of liver cells as a result of green tea extract administration to experimental rats.

Antidepressant activity of curcumin: involvement of serotonin and dopamine system.

RATIONALE: Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions. OBJECTIVE: The present study was designed to investigate the involvement of monoaminergic system(s) in the antidepressant activity of curcumin and the effect of piperine, a bioavailability enhancer, on the bioavailability and biological effects of curcumin. METHODS AND OBSERVATIONS: Behavioral (forced swim test), biochemical (monoamine oxidase (MAO) enzyme inhibitory activity), and neurochemical (neurotransmitter levels estimation) tests were carried out. Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. Curcumin (20 mg/kg, i.p.) enhanced the anti-immobility effect of subthreshold doses of various antidepressant drugs like fluoxetine, venlafaxine, or bupropion. However, no significant change in the anti-immobility effect of imipramine and desipramine was observed. Furthermore, combination of subthreshold dose of curcumin and various antidepressant drugs resulted in synergistic increase in serotonin (5-HT) levels as compared to their effect per se. There was no change in the norepinephrine levels. The coadministration of piperine (2.5 mg/kg, i.p.), a bioavailability enhancing agent, with curcumin (20 and 40 mg/kg, i.p.) resulted in potentiation of pharmacological, biochemical, and neurochemical activities. CONCLUSION: The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression.

Thioridazine reduces resistance of methicillin-resistant staphylococcus aureus by inhibiting a reserpine-sensitive efflux pump.

Previous studies suggested that the phenothiazine chlorpromazine (CPZ) could reverse or reduce the antibiotic resistance of bacteria. In some areas of the world, the majority of Staphylococcus aureus isolates are now resistant to methicillin, prompting this study to see whether such resistance can be altered by phenothiazine thioridazine (TZ), an agent with equal antibacterial activity, which is free of the severe side-effects associated with chronic administration of CPZ. The results indicated that, whereas methicillin-sensitive strains of Staphylococcus aureus (MSSA) were not rendered more susceptible to oxacillin, resistance to oxacillin by highly-resistant strains (MRSA) could be significantly reduced by sub-inhibitory concentrations of TZ. Reserpine, an inhibitor of efflux pumps, was also shown to reduce the resistance of MRSA strains to oxacillin in a concentration-dependent manner. The phenothiazines have been shown, by others, to inhibit the efflux pumps of bacteria and the mechanism by which MRSA are rendered more susceptible to oxacillin in the presence of TZ is believed to be due to a similar efflux pump.

Effects of baclofen on reserpine-induced vacuous chewing movements in mice.

We have described that GABA mimetic drugs present the ability to inhibit the expression of reserpine-induced oral movements. In this respect, oral movements is associated with important neuropathologies. This study investigates the effects of an acute or a repeated treatment of different doses of the GABA(B) agonist baclofen, as well as withdrawal from these treatments, on the development and/or expression of reserpine-induced vacuous chewing movements (VCM). Male mice received two injections of vehicle or of 1mg/kg reserpine separated by 48 h. In the first experiment, 24h later, animals were acutely treated with vehicle or baclofen (1, 2 or 4 mg/kg). In the second experiment, animals were treated with vehicle or baclofen (1 or 4 mg/kg) for four consecutive days receiving a concomitant injection of 1mg/kg reserpine (or vehicle) on Days 2 and 4. Twenty-four hours later, animals received vehicle or baclofen. Thirty minutes after the last injection, they were observed for quantification of VCM and open-field general activity. The acute administration of all the doses of baclofen abolished the manifestation of reserpine-induced VCM. Repeated treatment with 1mg/kg baclofen induced tolerance to the ability of an acute injection of this dose to reduce VCM. Treatment with baclofen (4 mg/kg) did not modify spontaneous VCM. Acute administration of the highest dose induced a decrease in general motor activity and a potentiation of the reserpine-induced decrease in general activity. These results reinforce the involvement of GABAergic hypofunction in the expression of oral movements and suggest that a repeated treatment with baclofen induces compensatory changes in GABAergic transmission that can attenuate its acute property to decrease VCM.

Biphasic effects of losartan potassium on immobility in mice.

The effects of losartan potassium, an angiotensin AT(1) receptor blocker on immobility in forced swim test have been studied. Effect of losartan potassium, nortriptyline HCl, fluoxetine HCl and reserpine per se and in combination on forced swimming-induced immobility in mice have also been studied. In mice, losartan potassium elicits biphasic responses i.e. positive responses at lower doses (0.1, 1.0 and 5 mg/kg, i.p.) in the forced swim test, a test of potential antidepressant activity and vice versa at higher dose (20 and 100 mg/kg, i.p.). In chronic studies, enhancement in immobility was observed for losartan potassium (3 and 30 mg/kg, p.o., 21 days). In acute combination studies, losartan potassium (1 and 5 mg/kg) significantly reversed the reserpine-induced immobility, but vice versa at 100 mg/kg. Losartan potassium (0.1 and 5 mg/kg) potentiate antidepressant activity of nortriptyline (30 mg/kg, i.p.) in mice, but vice versa at 100 mg/kg. Likewise, Losartan potassium (100 mg/kg), significantly reversed antidepressant activity of fluoxetine HCl, but at 0.1 and 5 mg/kg, failed to modify fluoxetine HCl induced immobility. The obtained biphasic effect of losartan potassium on immobility in mice might be due to inhibitory effect on AT(1) receptor at lower dose and pronounced effect on AT(2) receptor at higher dose (large concentrations of losartan potassium can displace Angiotensin II (Ang II) from its AT(1) receptor to AT(2) receptor.

Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat.

1. This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg(-1) s.c.). 18 h later, behavioural effects of the group III mGlu receptor agonists L-serine-O-phosphate (L-SOP) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) were examined. 3. In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 microl) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83+/-21 rotations 120 min(-1) (n=8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 microl) inhibited the response to L-SOP (2000 nmol) by 77%. Unilateral injection of L-SOP (250-1000 nmol in 2.5 microl) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 47+/-6 rotations 30 min(-1) (n=6). M-SOP (50 nmol in 2.5 microl) inhibited the response to L-SOP (500 nmol) by 78%. 4. Following i.c.v. injection, L-SOP (2000-2500 nmol in 2.5 microl) or L-AP4 (0.5-100 nmol in 2 microl) produced a dose-dependent reversal of akinesia, attaining a maximum of 45+/-17 (n=8) and 72+/-3 (n=9) arbitrary locomotor units 30 min(-1), respectively. 6. These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.

Reversal of reserpine-induced orofacial dyskinesia and cognitive dysfunction by quercetin.

Tardive dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells or may be due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. Repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. Chronic treatment with quercetin for a period of 4 weeks to reserpine-treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced VCMs and TPs. Reserpine-treated animals also showed poor retention of memory in elevated plus-maze task paradigm. Chronic quercetin administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine-treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of quercetin dose dependently (50-100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The results of the present study clearly indicated that quercetin has a protective role against reserpine-induced orofacial dyskinesia and memory impairment. Consequently, the use of quercetin as a therapeutic agent for the treatment of TD should be considered.

[Psychotropic effects of alkaloid lappaconitine and its various derivatives]. / Psikhotropnye svoistva alkaloida lappakonitina i ego nekotorykh proizvodnykh.

The psychotropic activity of (I, base), its N-oxide, and a complex of the base with 18-alpha-H-glycyrrhizic acid (1:2) was studied. It was established that I and its N-oxide exhibit dopaminopositive effect whereas the complex produces a serotoninopositive effect. Toxicities of the lipophilic I is half that of the hydrophilic; toxicity of N-oxide and the complex are 60 and 100 times lower than the activity of lappaconitine (base).

Lipopolysaccharide-mediated immobility in mice: reversal by cyclooxygenase enzyme inhibitors.

Endotoxin (lipopolysaccharide, LPS) is known to activate the hypothalamo-pituitary adrenocortical axis, as well as norepinephrine and indolamine metabolism. In the present study we examined the effects of systemically administered LPS on forced swimming-induced despair behavior in mice. LPS (50 micrograms/mouse i.p.) time-dependently enhanced the forced swimming-induced immobility period. The increase in immobility time was highest after 2 h of LPS administration. Desipramine (10 mg/kg), a tricycle antidepressant, or fluoxetine (10 mg/kg), a serotonin reuptake inhibitor, significantly reversed the LPS-induced increase in immobility time. Cyclooxygenase inhibitors nimesulide (1, 2 and 5 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) did not alter the despair behavior per se. Nimesulide (10 mg/kg) did reverse reserpine-induced immobility. Nimesulide (2 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) significantly reversed LPS-mediated despair behavior. The present study demonstrated that LPS-induced inflammatory responses in the brain may cause despair behavior. Reversal with a cyclooxygenase inhibitor indicates the role of prostaglandins in despair behavior.

The group II metabotropic glutamate receptor agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat.

1. This study examined whether activation of group II metabotropic glutamate (mGlu) receptors in the substantia nigra pars reticulata (SNr) could reverse akinesia in a rodent model of Parkinson's disease (PD). 2. Male Sprague Dawley rats, stereotaxically cannulated above either the SNr or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg-1 s.c.). Eighteen hours later, the rotational behaviour induced by unilateral injection of the group II mGlu receptor agonist, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), was examined. 3. Following intranigral injection, DCG-IV (0.125-0.75 nmol in 0.1 microliter) produced a dose-dependent increase in net contraversive rotations (n = 6-8 animals per dose), reaching a maximum of 395 +/- 51 rotations 60 min-1 after 0.75 nmol. The effects of DCG-IV (0.5 nmol) were inhibited by 63.0 +/- 9.0% following 30 min pre-treatment with the group II mGlu receptor antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 100 nmol in 0.2 microliter; n = 6). 4. Following intraventricular injection, DCG-IV (0.125-1.5 nmol in 2 microliters) produced a dose-dependent increase in bilateral locomotor activity (n = 6-7 animals per dose), reaching a maximum of 180 +/- 21 locomotor units 30 min-1 after 0.5 nmol. Pre-treatment with EGLU (200 nmol in 2 microliters) inhibited the effects of DCG-IV (0.5 nmol) by 68.2 +/- 12.3% (n = 5). 5. These data show that activation of group II mGlu receptors in the SNr provides relief of akinesia in the reserpinized rat model of PD. The reversal seen following intraventricular administration supports the likely therapeutic benefit of systemically-active group II mGlu receptor agonists in PD.

Pharmacological profile of milnacipran, a new antidepressant, given acutely.

Pharmacological effects of acute treatment with milnacipran (MIL), a clinically active antidepressant (a noradrenaline [NA] and 5-hydroxytryptamine [5-HT] reuptake inhibitor without any affinity for neurotransmitter receptors) were studied in mice and rats. MIL inhibited the reserpine- or apomorphine-induced hypothermia in mice and enhanced the L-5-hydroxytryptophan-induced head twitches in rats. It reduced the immobility time in Porsolt's test in mice and rats, but either did not change the locomotor activity (mice) or decreased it (rats). MIL changed neither the clonidine-induced aggressiveness in mice nor the behavioral syndrome induced by oxotremorine in rats. The obtained results indicate that MIL, given acutely, shows a pharmacological profile similar to that of tricyclic NA and 5-HT reuptake inhibitors. In contrast to the antidepressants mentioned above, MIL does not exhibit an alpha1-adrenolytic or cholinolytic activity (in vivo tests).

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. OBJECTIVES: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson's disease. METHODS: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

Pharmacology of the new reversible inhibitor of monoamine oxidase A, RS-8359.

RS-8359 is a new reversible inhibitor of monoamine oxidase A (RIMA). With a selectivity ratio of about 2200 for the A:B enzyme types, it is one of the most specific of this class of compounds. As a result, it shows relatively little effect upon blood pressure when administered together with tyramine, thus effectively eliminating the 'cheese' effect which has contributed to the limited clinical use of the classical monoamine oxidase inhibitors (MAOIs). RS-8359 shows little affinity for the common central nervous system receptors and little anticholinergic effect. These characteristics suggest a relatively benign adverse event profile, which may be particularly advantageous in the elderly and may generally contribute to patient acceptance and compliance. In terms of its effects upon serotonin (5-hydroxytryptamine), RS-8359 gives increases similar to those of other MAOIs with activity sustained for about 9 h. In behavioural investigations, the compound gives results similar to those found with several antidepressants widely used in the clinic. Overall, the pharmacology of RS-8359 indicates that it should have antidepressant activity in man.

[Synthesis and pharmacological action of TRH analog peptide (Taltirelin)].

Taltirelin hydrate[1-methyl-(S)-4,5-dihydroorotyl-L-histidyl-L-prolineamide tetrahydrate] is a new orally active thyrotropin releasing hormone (TRH) peptide analog synthetized from aspartic acid. From preclinical studies with mice and rats, Taltirelin hydrate was found to be highly stable in the blood and brain as compared with TRH. Furthermore, the CNS stimulating actions of Taltirelin hydrate such as antagonistic actions against pentobarbital-induced anesthesia and reserpine- induced hypothermia were found to be about 100 times stronger and about 8 times longer-lasting as compared with those of TRH. Meanwhile, the affinity of Taltirelin hydrate for TRH-receptors was about 10 times lower, and the endocrine action was about 5 times less potent than those of TRH. Therefore, high CNS-selectivity and long-lasting action of Taltirelin hydrate would be attributed to its high stability in the body and low affinity for TRH-receptors. Oral administrations of Taltirelin hydrate ameliorated consiousness impairment, memory impairment and motor dysfunction in several models. The clinical studies for patients with spinocerebellar degeneration are in progress.

Effects of dopaminergic agents on reversal of reserpine-induced impairment in conditioned avoidance response in rats.

Male Slc:Wistar, Std:Wistar, and Slc:F344/N rats had good acquisition of the conditioned avoidance response (CAR), while that of the male Slc:Wistar/ST, Jcl:Wistar, and Crj:Wistar rats was bad. Reserpine-induced impairment (RII) in CAR was observed 2-72 h after administration of dopaminergic (DAergic) agents in male Slc:Wistar rats. Amitriptyline (5-80 mg/kg, P.O.), imipramine, desipramine, cis-dosulepine, and trans-dosulepine at dose of 40 mg/kg, P.O. showed no antagonism against RII in CAR 20-23 h after reserpine injection (1 mg/kg, S.C.). However, the atypical antidepressive agents sibutramine (5-10 mg/kg, P.O.), bupropion (40 mg/kg, P.O.), and nomifensine (10-40 mg/kg, P.O.) exhibited antagonism against RII in CAR. The calcium channel antagonists flunarizine, nimodipine, and KP-840 at dose of 10 and 100 mg/kg, P.O., the cerebral improving agent indeloxazine (20-80 mg/kg, P.O.), the anticholinergic agent atropine (5-40 mg/kg, P.O.), 5-hydroxy-L-tryptophan (5-HTP) (40 mg/kg, I.P.), a precursor of 5-hydroxytryptamine (5-HT), and (+/-)-threo-dihydroxyphenylserine [(+/-)-threo-DOPS] (20-200 mg/kg P.O.), a norepinephrine (NE) precursor, showed no antagonism against RII in CAR. The DAergic agents methamphetamine (5 mg/kg, P.O.) and amantadine (50-250 mg/kg, P.O.), L-DOPA (200 mg/kg, P.O.), and the DAergic D1/D2 receptor agonist apomorphine (0.1-1 mg/kg, S.C.) showed marked antagonism against RII in CAR. Although the DAergic D1-receptor agonist KF-38393 (0.3-30 mg/kg, I.P.) and the DAergic D2-receptor agonist quinpirole (0.3-10 mg/kg, I.P.) induced only a weak recovery of RII in CAR when they were administered alone, in contrast to a potent synergistic recovery of RII in CAR, which was observed when SKF-38393 (1 mg/kg, I.P.) and quinpirole (1 mg/kg, I.P.) were administered together. These results suggest that the DAergic nervous system rather than the adrenergic or 5-HT nervous system is involved in RII in CAR, and that both the DAergic D1- and D2-mediated nervous systems play important roles in this process.