Characterization and densification of defect pyrochlore oxide powders ABi2Ta5O16 (A=Na, Tl).

Defect pyrochlore oxide powders ABi2Ta5O16, in the pseudo-binary systems BiTaO4-ATa3O8 (A = Na, Tl), were prepared by solid state method. The structural study showed that all oxides crystallize in a cubic system with the space group Fd3m, the lattice parameter "a" were determined using Rietveld refinement method. For systematic study on densification from powders, the samples were pressed with a uniaxial pressure into pellets; sintering temperature, holding time and heating rate were optimized. Techniques, including X-ray diffraction, IR-Raman, MEB, dilatometry, were employed to investigate the structure and the morphology of the synthesized powders and sintered materials. The dielectric characteristics, relative permittivity and dielectric losses (tgδ), determined at room temperature are comparable to those of other pyrochlores.

Erratum to "Characterization and densification of defect pyrochlore oxide powders ABi2Ta5O16 (A=Na, Tl)" [Heliyon 5 (5) (May 2019) e01628].

[This corrects the article DOI: 10.1016/j.heliyon.2019.e01628.].

The pathophysiological mechanisms of motivational deficits in Parkinson's disease.

Parkinson's disease (PD) is a progressive degenerative disorder that leads to disabling motor symptoms and a wide variety of neuropsychiatric symptoms. Apathy is the most common psychiatric disorder in the early stages of untreated PD and can be defined as a hypodopaminergic syndrome, which also includes anxiety and depression. Apathy is also considered the core feature of the parkinsonian triad (apathy, anxiety and depression) of behavioural non-motor signs, including a motivational deficit. Moreover, apathy is recognised as a distinct chronic neuropsychiatric behavioural disorder based on specific diagnostic criteria. Given the prevalence of apathy in approximately 40% of the general Parkinson's disease population, this appears to be a contributing factor to dementia in PD; also, apathy symptoms are factors that potentially contribute to morbidity, leading to a major impairment of health-related quality of life, thus stressing the importance of understanding the pathophysiology of this disease. Several studies have clearly established a prominent role for DA-mediated signals in PD apathy. However, synergistic interaction between dopaminergic impairment resulting from the neurodegenerative process and deep brain stimulation of the subthalamic nucleus may cause or exacerbate apathy. Furthermore, serotoninergic mechanism signalling is also likely to be of importance in this pathophysiology.

To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABAA receptors modulators?

The relatively common view indicates a possible dissociation between the anxiolytic and sedative/hypnotic properties of benzodiazepines (BZs). Indeed, GABAA receptor (GABAAR) subtypes have specific cerebral distribution in distinct neural circuits. Thus, GABAAR subtype-selective drugs may be expected to perform distinct functions. However, standard behavioral test assays provide limited direction towards highlighting new action mechanisms of ligands targeting GABAARs. Automated behavioral tests, lack sensitivity as some behavioral characteristics or subtle behavioral changes of drug effects or that are not considered in the overall analysis (Ohl et al., 2001) and observation-based analyses are not always performed. In addition, despite the use of genetically engineered mice, any possible dissociation between the anxiolytic and sedative properties of BZs remains controversial. Moreover, the involvement the different subtypes of GABAAR subtypes in the anxious behavior and the mechanism of action of anxiolytic agents remains unclear since there has been little success in the pharmacological investigations so far. This raises the question of the involvement of the different subunits in anxiolytic-like and/or sedative effects; and the actual implication of these subunits, particularly, α-subunits in the modulation of sedation and/or anxiety-related disorders. This present review was prompted by several conflicting studies on the degree of involvement of these subunits in anxiolytic-like and/or sedative effects. To this end, we explored the GABAergic system, particularly, the role of different subunits containing synaptic GABAARs. We report herein the targeting gene encoding the different subunits and their contribution in anxiolytic-like and/or sedative actions, as well as, the mechanism underlying tolerance to BZs.

5-HT2C receptors in psychiatric disorders: A review.

5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.

Enantioselective syntheses of dopaminergic (R)- and (S)-benzyltetrahydroisoquinolines.

Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a,b as the major diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing (R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a) and (1R,S)-12b diastereomers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a-16a) bind to D1 and D2 dopamine receptors with affinities 5-15 times higher than those of the corresponding (1R)-enantiomers (14b-16b). Moreover, (1S)-14a inhibits [3H]dopamine uptake with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very important for the search for new active drugs at dopamine receptors.

Effects of chronic treatments with amineptine and desipramine on motor responses involving dopaminergic systems.

The acute effects of increasing doses of the antidepressant drugs amineptine (5-40 mg/kg, IP) and desipramine (5-20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87-30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1-1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25-20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1-0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Climbing and stereotyped behaviours in mice require the stimulation of D-1 dopamine receptors.

Apomorphine-induced climbing and sniffing behaviours in mice were antagonize by low doses of SCH 23390 and metoclopramide. The selective D-2 dopamine receptor agonists, LY 171555 and RU 24926, and some other dopamine agonists (piribedil, lergotrile, bromocriptine) exerted only inhibitory effects on spontaneous behaviours. The selective D-1 dopamine receptor agonist, SK&F 38393, did not modify the climbing score but increased the sniffing and decreased the gnawing scores compared to the scores of control mice. Typical climbing and stereotyped behaviours were produced by the combination of SK&F 39383 with LY 171555, RU 24926 or with the other dopamine agonists tested. These data suggest that the stimulation of D-1 dopamine receptors is required for the induction of climbing and stereotyped behaviours in mice.

Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents.

S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA (L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg, s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high dose of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.

High-affinity [3H]GBR 12783 binding to a specific site associated with the neuronal dopamine uptake complex in the central nervous system.

We labelled the neuronal dopamine uptake system by using the potent dopamine uptake inhibitor GBR 12783 in its tritiated form (18.3 Ci/mmol). The binding of [3H]GBR 12783 to rat striatal membranes was saturable and specific with a Kd of 1.6 nM and a Bmax of 10.3 pmol X mg protein-1 as determined by Scatchard analysis. [3H]GBR 12783 binding to rat striatal membranes was inhibited by dopamine uptake inhibitors with IC50 highly correlated with their IC50 for inhibiting [3H]dopamine uptake by a rat striatal synaptosomal preparation. The rank order of potency was the following: GBR 12783 greater than amfonelic acid greater than mazindol greater than pyrovalerone greater than nomifensine greater than benztropine greater than amineptine greater than methylphenidate greater than cocaine. Substrates of dopamine uptake competed with [3H]GBR 12783 binding at concentrations higher than those at which they inhibited [3H]dopamine uptake. In rats with a unilateral section of the medial forebrain bundle, the decrease in [3H]GBR 12783 binding to membranes prepared from the ipsilateral striatum was equal to the decrease in [3H]dopamine uptake by a synaptosomal preparation obtained from the same striatum. [3H]GBR 12783 bound in a sodium-dependent manner to membranes prepared from striatum, nucleus accumbens and tuberculum olfactorium. GBR 12783 displayed an approximately 150-fold lower affinity for the cortical norepinephrine uptake system labelled with [3H]desipramine than for the dopamine transport complex labelled with [3H]GBR 12783. [3H]GBR 12783 appears an attractive tool for the selective characterization of the dopamine uptake system in vitro.

The rise of body temperature induced by the stimulation of dopamine D1 receptors is increased in acutely reserpinized mice.

In naive mice, the selective D1 agonist, SK&F 38393 (7.5-30 mg/kg s.c.), induced a significant rise of body temperature (0.5-1 degree C) which was antagonized by SCH 23390 (100 micrograms/kg s.c.) and by flupenthixol (0.4 mg/kg i.p.). In mice treated with reserpine (5 mg/kg s.c.) 18 h before testing, which on its own caused intense hypothermia (10-12 degrees C), SK&F 38393 (1.87-30 mg/kg s.c.) induced a dose-dependent and more marked rise of body temperature (5-7 degrees C). Similarly, SK&F 38393 (30 mg/kg s.c.) partially prevented reserpine-induced hypothermia. The central origin of the SK&F 38393 effects in reserpine-treated mice is indicated by the rise of body temperature induced by the i.c.v. administration of the drug (12.5-50 micrograms per mice). The SK&F 38393-induced rise of body temperature in acutely reserpinized mice was antagonized by SCH 23390 (50-200 micrograms/kg s.c.), clozapine (1.87-30 mg/kg i.p.) or chlorpromazine (2-32 mg/kg i.p.) but not by metoclopramide (25 or 100 mg/kg i.p.) or amisulpride (12.5 or 50 mg/kg). In naive mice, apomorphine (1 mg/kg s.c.) or LY 171555 (0.4 mg/kg s.c.) induced hypothermia which was antagonized by amisulpride (12.5 mg/kg i.p.); a transiently increased body temperature was even measured 30 min after apomorphine injection in amisulpride-treated mice. Apomorphine (1 mg/kg s.c.) induced a rise of body temperature in acutely reserpinized mice which was significantly reduced by SCH 23390 (50 and 200 micrograms/kg s.c.) and significantly increased by amisulpride (12.5 and 50 mg/kg i.p.). These data suggest that pharmacologically different dopamine receptor subtypes mediate different effects on body temperature in mice: D1 dopamine receptors mediate a rise of body temperature which is increased in hypothermic reserpinized animals and dopamine receptors of the D4 subtype mediate the decrease of body temperature in naive mice.

In vivo binding of [3H]GBR 12783, a selective dopamine uptake inhibitor, in mouse striatum.

[3H]GBR 12783 (1,2-(diphenylmethoxy)ethyl-4-(3-phenyl-2-propenyl)-piperazine), a specific dopamine uptake inhibitor, was tested for in vivo central binding in mice. The difference between the striatal and cerebellar levels of radioactivity was maximal 1 hour after the i.v. injection of a tracer dose of [3H]GBR 12783. The additional accumulation of radioactivity in striatum, relatively to cerebellum, was dose-dependently decreased by dopamine uptake inhibitors. It was unaffected by high doses of dopamine receptor agonists or antagonists and of serotonin or norepinephrine uptake blockers. The intrastriatal injection of 6-hydroxydopamine (6-OHDA) resulted in an almost similar decrease in both the synaptosomal [3H]dopamine uptake and the in vivo [3H]GBR 12783 binding. These data suggest that [3H]GBR 12783 injected i.v. labels the dopamine transport complex in the striatum and thus can be used for the in vivo assessment of the density of dopaminergic nerve endings in brain areas.

Interaction of amineptine with agents modifying dopaminergic transmission.

Amineptine, administered at increasing doses (5-40 mg/kg, i.p.) in mice, induces a dose-dependent hyperactivity (measured either in classical activity cages or in a DIGISCAN actimeter) which persists for about 8 h at 20 mg/kg. The increase of locomotor activity induced by 20 mg/kg amineptine is dose-dependently antagonized by metoclopramide (1.25-120 mg/kg i.p.), by SCH 23390 (7.5-8,000 micrograms/kg s.c.) and by amisulpride (1.56-50 mg/kg i.p.). Nevertheless, whereas the increase of locomotor activity induced by amineptine is completely antagonized at a relatively low dose of the discriminant benzamide derivative amisulpride (50 mg/kg i.p.), it is completely antagonized only at high doses of the selective D-2 antagonist metoclopramide (80 mg/kg i.p.) and of the selective D-1 antagonist SCH 23390 (4,000 micrograms/kg s.c.). The increase in locomotor activity induced by amineptine is significantly reduced (a) by low doses of apomorphine (25-300 micrograms/kg s.c.) stimulating dopamine autoreceptors; (b) by a pretreatment with reserpine (4 mg/kg s.c. 24 h prior to testing), which depletes the vesicular stores of monoamines; and (c) by gammabutyrolactone (100 mg/kg i.p. 30 min after amineptine), which inhibits the firing rate of dopaminergic neurons. Similar results are also obtained with the selective dopamine uptake inhibitor GBR 12783 (10 mg/kg i.p.) but not with dexamphetamine (5 mg/kg i.p.), the effects of which persist in reserpine-pretreated mice in gamma-butyrolactone-treated mice. Finally, the study of the interaction of increasing doses of amineptine with dexamphetamine (5 mg/kg i.p.) indicates that a low dose of amineptine (5 mg/kg) potentiates dexamphetamine-induced hyperactivity, whereas a high dose of amineptine (40 mg/kg) reduces dexamphetamine-induced hyperactivity. These data indicate that the stimulation of dopamine receptors induced by amineptine depends to a large degree on the dopamine released from the vesicular stores by the firing rate of dopaminergic neurons. The similarity of the results obtained with amineptine and with the selective dopamine uptake inhibitor GBR 12783 suggests a common mechanism of action that differs from that of dexamphetamine.

Interactions of amineptine with the neuronal dopamine uptake system: neurochemical in vitro and in vivo studies.

The effects of amineptine on 3H-dopamine uptake and 14C-dopamine release have been studied simultaneously in double labelling test performed on rat striatal synaptosomes. 3H-dopamine uptake was completely inhibited at 10 microM amineptine, a concentration which produced only a weak 14C-DA release (13% of the 14C-radioactivity stored). The IC 50 for the inhibition of 3H-DA uptake was not modified by a previous treatment with reserpine whereas the IC 50 of (+) amphetamine and the IC 50 of clomipramine were decreased 9 fold and increased two fold, respectively. In binding studies on rat striatal membranes amineptine displaces in vitro the 3H-GBR 12783, bound specifically to a component of the neuronal DA uptake complex. The apparent affinity of amineptine for this binding site was more than 150 times higher than its affinity for the binding site of 3H-desipramine on rat cortical membranes. In mice, increasing doses of amineptine injected i.p. reduced in a dose dependent manner the specific retention of radioactivity in the striatum after an i.v. injection of a tracer dose of 3H-GBR 12783. These data indicate that amineptine inhibits DA uptake and is virtually devoid of DA releasing effects. It displays a relatively low affinity for the NE uptake system. Its neurochemical profile in the double labelling test clearly differs from that of (+) amphetamine and from that of classical tricyclic anti-depressants.

Preparation of dopaminergic N-alkyl-benzyltetrahydroisoquinolines using a 'one-pot' procedure in acid medium.

The preparation of N-methyl-BTHIQ (4) from N-phenylethyl-phenacetamide (1) by cyclization, reduction and N-alkylation in acid medium has been achieved in good yield in a 'one-pot' procedure. Acylation of imine (2) intermediate afforded the Z and E stereoselectivity in the enamide formation. 6-Hydroxy-BTHIQ (7) shows selectivity for D2 dopamine receptors, while its N-methylated homologue (8) displays higher affinities for both D1 and D2 receptor types, with an unexpected increase in D1 dopamine receptor affinity.