Modulation of motor functions involving central dopaminergic system by L-histidine

There exists a possibility of interactions of histaminergic system with other neurotransmitters and their receptors in the central nervous system. Experimental evidences suggest a possible inhibitory influence of histaminergic system on the dopaminergic system. To elucidate the possible interaction between the histaminergic and dopaminergic pathways, we devised a strategy to study their effects on locomotor function and stereotypy behaviour. We investigated the effect of L-histidine, the precursor of histamine, on apomorphine-induced stereotypy and perphenazine-induced catalepsy. Histidine antagonised apomorphine-induced stereotypy. This inhibitory effect of histidine was abolished by both H1- and H2-receptor antagonists, chlorpheniramine and cimetidine, respectively. Perphenazine-induced catalepsy was potentiated by histidine and this effect was inhibited by chlorpheniramine alone but not by cimetidine. These results confirm a possible histamine-dopamine interaction in the modulation of motor functions by the central nervous system.     

The effect of frontal cortex lesion on the activity of the dopaminergic system in rat striatum

The experiment was carried out on male Wistar rats weighing 180-220 g with lesion in the cortex of the frontal lobe. The activity of the dopaminergic system was studied by means of behavioural tests such as determination of spontaneous motor activity, apomorphine-induced stereotypy, haloperidol-induced catalepsy. Increased intensity of stereotypy was observed reaching a maximum 14 days after frontal lobe damage. Moreover, a slight tendency was observed for inhibition of haloperidol-induced catalepsy without changes in the spontaneous motor activity of the animals. Biochemical investigations demonstrated reduced dopamine content in the striatum on the side of the lesion.     

The effect of collagen degradation products (CDP) on the central dopaminergic system

The effect of collagen degradation products (CDP I--molecular weight circa 3000 D and CDP II--molecular weight circa 1200 D) on the central dopaminergic system was studied. Differences in the action of both these fractions in the apomorphine stereotypy test were noted; CDP I administered to rats in a dose of 5 micrograms just before application of the drug inducing the stereotypy enhanced the stereotypic behaviour of the animals whereas a dose of 40 micrograms significantly inhibited such behaviour. CDP II, on the other hand, had no effect on this type of stereotypy. Both fractions given in doses of 15 and 40 micrograms enhanced the stereotypy induced by amphetamine. CDP I and CDP II (15 and 40 micrograms) administered 30 min before observation of the animals intensified the cataleptic action of haloperidol, whereas both fractions (CDP I and CDP II) when administered 45 min before observation reduced the catalepsy.     

Effect of intranasal administration of dopamine on anxiety and locomotor activity of two lines of mice

Intranasal administration of dopamine (0.3; 3 and 30 microg/kg) on anxious behaviour of mice was studied using elevated plus-maze and open fields tests and the pinch-induced catalepsy on parallel bars test. Dopamine was introduced as nose drops or inhalation of nanoparticles of the compound solution in C57B1/6J and CBA/Lac mice with differences of dopaminergic function features. In our experiment, dopamine had anxiolytic and elevated motor activity effects in C57B1/6J, but not in the CBA/Lac mice. Nose drops were more effective than inhalation; perhaps, it was a more stressful manipulation. Apparently dopamine increased the number of CBA/Lac mice who demonstrated catalepsy and the reflex duration. Indeed, the neurotransmitter is active in different psycho-emotional phenomena.     

Partial reversal of behavioral action of the agonist D-Trp-6-LH-RH by naloxone in mice

The effects of the superactive agonist analog D-Trp-6-LH-RH were investigated in several neuropharmacological tests: inhibition of picrotoxin-induced seizures, open-field behavior, hot-plate and tail-flick tests, assessment of catalepsy and apomorphine-induced cage-climbing. In most tests, D-Trp-6-LH-RH was administered subcutaneously (sc.) at the dose of 100 micrograms/kg. The opiate involvement in the peptide action was checked by using naloxone HCl (NX) in a dose of 1 mg/kg intraperitoneally (ip.), with the exception of the analgesic tests where the dose was 0.5 mg/kg. The analog significantly suppressed the open-field parameters of ambulation, rearing and grooming; except for grooming, these actions were fully antagonized by NX. Similarly, NX pretreatment restored to the control levels the latencies of seizure parameters increased by D-Trp-6-LH-RH. The hot-plate latencies did not change after pretreatment with NX but the opiate antagonist was fully able to antagonize the analgesic effect of the peptide in the tail-flick test. The cataleptogenic effect and the inhibition of apomorphine-induced cage-climbing demonstrated after D-Trp-LH-RH were not antagonized by NX.     

Pro-Leu-Gly-NH2 and pareptide inhibit development of tolerance to haloperidol catalepsy in the mouse

Single doses of MIF-1 (0.03-2.0 mg/kg, SC) and chronic pretreatments with MIF-1 (0.03-2.0 mg/kg, SC, BID, 3 1/2 days) or pareptide (0.25 mg/kg, SC, BID, 3 1/2 days) did not affect the acute cataleptic response to haloperidol in the mouse. Chronic pretreatment with haloperidol (8.0 mg/kg, IP, BID, 3 days) decreased the duration of catalepsy in mice given smaller challenge dose of haloperidol (2.0 or 3.0 mg/kg, IP) 15 hours after the last pretreatment injections. Administration of either MIF-1 or pareptide to mice also chronically pretreated with haloperidol antagonized the development of tolerance.     

Behavioral and radioligand binding evidence for irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible alpha adrenergic antagonist, also acts as a potent and longlasting in vivo antagonist of D-2 dopamine receptors. Rats given EEDQ 3-10 mg/kg i.p. exhibit catalepsy and greatly reduced apomorphine-induced stereotypy, behavioral effects associated with D-2 dopamine receptor blockade. These effects are apparent up to 4 days after drug administration, with scores returning to control level by day 7. In vitro receptor binding assays of striatal membrane preparations from these animals using the radioligand 3H-spiroperidol directly demonstrate that EEDQ is a potent D-2 dopamine receptor antagonist, revealing the apparent basis of the behavioral effects of EEDQ. This antagonism proceeds via a reduction in D-2 receptor Bmax, with no change in the observed KD for 3H-spiroperidol, and is resistant to extensive washing of the membrane preparation after in vivo EEDQ exposure. These observations suggest that EEDQ inhibition of D-2 receptors is irreversible. Administration of behaviorally active doses of EEDQ effect a reduction of 50-85% in D-2 receptor number. Recovery of this loss roughly parallels recovery of normal catalepsy and apomorphine stereotypy scores. These doses of EEDQ also reduce binding of 3H-flupentixol to D-1 and 3H-dopamine to D-3 type dopaminergic binding sites, putative dopamine receptors with no known behavioral correlates. Recovery of D-1 and D-3 binding also occurs with a similar timecourse. Because of the apparent covalent nature of its interaction with dopamine receptors and because of its activity after peripheral administration, EEDQ may prove useful in the study of the function and turnover of dopamine receptors.     

Psychoactive-drug response is affected by acute low-level microwave irradiation

The effects of various psychoactive drugs were studied in rats exposed for 45 min in a circularly polarized, pulsed microwave field (2450 MHz; SAR 0.6 W/kg; 2-microseconds pulses, 500 pps). Apomorphine-induced hypothermia and stereotypy were enhanced by irradiation. Amphetamine-induced hyperthermia was attenuated while stereotypy was unaffected. Morphine-induced catalepsy and lethality were enhanced by irradiation at certain dosages of the drug. Since these drugs have different modes of action on central neural mechanisms and the effects of microwaves depend on the particular drug studied, these results show the complex nature of the effect of microwave irradiation on brain functions.     

Effects of dextromethorphan on dopamine dependent behaviours in rats

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.     

MIF-1 fails to modify agonist-induced oral activity in neonatal 6-OHDA-treated rats

-Prolyl- -leucyl-glycinamide (MIF-1) is known to attenuate apomorphine-induced stereotypies in adult rats that are lesioned as neonates with 6-hydroxydopamine (6-OHDA). To test whether MIF-1 would affect dopamine (DA) agonist-induced and serotonin (5-HT) agonist-induced oral activity, both intact and neonatal 6-OHDA-treated rats were studied. Rats at 3 days from birth were injected with desipramine (20 mg/kg, IP), 1 h before 6-OHDA HBr (100 μg, salt form, in each lateral ventricle) or its vehicle, saline-ascorbic acid (0.1%). At approximately 6 months rats were treated with MIF-1 (0.1, 1.0, or 10.0 mg/kg, IP), 10 min before SKF 39393 HCl (1.0 mg/kg, IP) or m-chlorophenylpiperazine 2HCl (m-CPP 2HCl; 0.5 mg/kg, IP), DA D₁ and 5-HT_1C,2 receptor agonists, respectively. Although both agonists increased oral activity in control and neonatal 6-OHDA-treated rats, MIF-1 did not modify the response. In rats that received either of the three doses of MIF-1 for 21 consecutive days, there was still no observed effect of MIF-1 on the oral response of control and 6-OHDA-lesioned rats to SKF 38393 and m-CPP. These findings indicate that MIF-1 does not modify the oral activity response of supersensitized D₁ and 5-HT_1C receptors in adult rats that are lesioned neonatally with 6-OHDA.     

An experimental study of the antidepressive properties of captopril]

Captopril, as well as amitriptyline, was shown to enhance apomorphine-induced stereotype in mice. At doses, which failed to modify the effect of apomorphine, both substances reversed the inhibitory action of sulpiride and haloperidol on stereotypical behaviour. Treatment with captopril (25 mg/kg) did not modify the open-field behaviour, but significantly reduced the immobility in the forced swim test (20 mg/kg) Dopaminergic link was suggested to be involved in the CNS effect of captopril.     

Dual action on central dopamine function of transdihydrolisuride,a 9, 10-dihydrogenated analogue of the ergot dopamine agonist lisuride

Transdihydrolisuride (TDHL), a 9, 10-dihydrogenated analogue of the ergot dopamine (DA) agonist lisuride (LIS), was investigated for its influence on central dopaminergic functions in rats and mice after single i.p. administration. TDHL (0.39–25 mg/kg) unexpectedly induced catalepsy and antagonized apomorphine-induced stereotypes in rats; it was approx. 3–5 times less potent than the DA antagonist haloperidol. TDHL (0.025–6.25 mg/kg) caused hypokinesia and antagonized the apomorphine-induced hyperactivity in rats. Pre-treatment with TDHL (0.78–12.5 mg/kg) which per se did not alter thermoregulation at room temperature, antagonized the hypothermia induced by the DA agonist apomorphine (5 mg/kg i.p.) in mice. These DA antagonistic properties contrasted with the prolactin (PRL) lowering effect of TDHL (0.01–10 mg/kg p.o.) in reserpinized female rats thus indicating DA agonist function. PRL inhibition tended to be longer lasting (>8h) than after LIS (0.01–1 mg/kg p.o.) with comparable potency. In healthy volunteers TDHL (0.2–1 mg p.o.) effectively lowered PRL levels with similar potency but with a markedly longer duration of action than LIS (>24h after 0.5 mg TDHL). In contrast to the side effects after acute LIS treatment, no comparable adverse reactions such as nausea, emesis or postural hypotension typical for DA agonists could be observed with effective PRL lowering doses of TDHL. The unique profile of TDHL on DA functions suggests its usefulness as a potent, longlasting PRL inhibitor with less unwanted effects. The behavioural findings indicate the potential usefulness of TDHL as a neuroleptic, which due to its partial DA agonistic action, should lack typical extrapyramidal or neuroendocrine side effects of classic DA receptor blocking agents. Possible implications of the dual function of TDHL upon central DA receptors are discussed with regard to the incidence of side effects or selectivity of action for other conceivable therapeutic indications.     

Central nervous system actions of 2, 5-bis (3,4-dimethoxybenzyl) cyclopentyl amine,a peripheral dopamine blocking agent

The behavioral and brain catecholamine effects of 2,5-bis (3,4-dimethoxybenzyl) cyclopentyl amine were investigated in mice. It rapidly depleted norepinephrine. Chronic dosing also depleted dopamine, but to a lesser degree. As indicated by a lack of effect on amphetamine induced stereotypy and apomorphine induced emesis and failure to induce catalepsy, the compound does not block brain dopamine receptors. It has no effect on brain catecholamine synthesis or dopamine-β-hydroxylase activity.     

Simultaneous catalepsy and apomorphine-induced stereotypic behavior in mice

Intraventricular administration of haloperidol or chlorpromazine produces catalepsy and blocks apomorphine-induced stereotypic behavior. Low intraventricular doses of domperidone, sulpiride and spiperone, equally cataleptogenic as haloperidol or chlorpromazine, augment rather than diminish stereotypic behavior produced by subsequent apomorphine treatment. The resultant stereotypic behavior continues even while the animal is in a rigid cataleptic posture and is marked by persistent gnawing and licking. Prior to the induction of catalepsy and after recovery from it, mice display the entire range of typical apomorphine-induced behavior including sniffing, climbing, gnawing, and licking. This animal model may be related to the clinical observation of the coexistence of tardive dyskinesia and drug-induced Parkinsonism in individual patients.     

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.     

Hereditary catalepsy: genetic and molecular mechanisms of catalepsy in mice

The results of experiments on the inheritance and neurobiological mechanism of high predisposition to tonic immobility (catalepsy) in CBA mice are discussed. Genetic analysis has demonstrated a monogenic inheritance of the predisposition to catalepsy. A set of polymorphic microsatellite markers has been used to demonstrate that the predisposition to catalepsy is linked to the distal fragment of mouse chromosome 13, which contains the gene of the 5-HT1A-serotonin receptor. Pharmacological and biochemical evidence for the association between hereditary catalepsy and 5-HT1A-receptor dysfunction are presented. The use of CBA mice for studying the mechanisms of depression and the effects of antidepressants is discussed.     

Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans

Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D(2)DAR (dopamine receptor) and compound 4/D(2)DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.     

Psychopharmacological profile of hydro-alcoholic extract of Euphorbia neriifolia leaves in mice and rats

The leaf extract of E. neriifolia significantly reduced apomorphine-induced stereotypy in mice at all doses (100, 200, 400 mg/kg body weight) in mice and rats and was devoid of catalepsic effect thereby, suggesting specific dopaminergic receptor modulating activity. The extract (400 mg/kg) potentiated pentobarbitone-induced hypnosis. It showed protection against maximal electro-shock-induced convulsion at 400 mg/kg. E. neriifolia leaf extract had anxiolytic action at 400 mg/kg by increasing the percentage of time spent in open arm in elevated plus-maze. The extract did not reverse scopolamine-induced amnesia on elevated plus-maze. It increased transfer latency at 200 and 400 mg/kg and also in combination with scopolamine. These results indicated anti-anxiety, anti-psychotic and anti-convulsant activity of E. neriifolia leaf extract in mice and rats. Phytochemical study showed the presence of steroidal saponin, reducing sugar, tannins, flavonoids in the crude leaf extract     

Clonazepam and dopamine-related stereotyped behavior

The effect of clonazepam on behavioral stereotypy induced by a number of dopaminergic agonists was investigated. Clonazepam inhibited levodopa- and amphetamine-induced behavior in guinea pigs but did not alter lergotrile- or apomorphine-induced stereotypy. The results suggest that clonazepam influences the central dopaminergic system through a direct effect of dopaminergic presynaptic mechanisms.     

Choline chloride in methylphenidate- and apomorphine-induced stereotypy

The effect of choline chloride on apomorphine- and methylphenidate-induced stereotypy in rats was tested. Subcutaneous administration of a single dose of choline chloride significantly reduced apomorphine-induced stereotypy. These results could not be attributed to a nonspecific obtunding effect of choline chloride, and indicate that choline chloride may increase central cholinergic activity. However, neither acute nor chronic oral administration of choline chloride reversed apomorphine- or methylphenidate-induced stereotypy.