Cholinergic system, rearing environment and trajectory learning during aging in mice.

Three, 12- and 20-month-old C57BL6/J mice, reared in standard conditions or in enriched environments, were administered subcutaneously either scopolamine hydrobromide, 0.6 or 1.2 mg kg(-1), or physiological saline (control mice) 15 min before testing their abilities to find an invisible platform in a modified version of the Morris water maze, the starting point being kept unchanged throughout the experiment to allow the aged animals to solve the task. The results demonstrated that: 1) All control mice, whatever their age, were able to learn the platform location, but the number of trials needed to reach the learning criterion (3 consecutive trials in less than 8 s) increased with age; 2) All the scopolamine-treated mice, whatever their age, were also able to learn the platform location. However, compared to age-matched controls, the number of trials needed to reach the learning criterion was greater; 3) Rearing the animals in an enriched environment antagonized the effect of scopolamine, but only in the youngest (3 month-old) mice. All control and scopolamine-treated mice, whatever their age and their rearing environment, remembered, 7 days later, the platform location.

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.

Influence of cholinergic system on motor learning during aging in mice.

Three, 12- and 20-month-old C57Bl6 mice, reared in standard conditions or in an enriched environment, were administered subcutaneously either scopolamine hydrobromide (SIGMA), 0.6 and 1.2 mg kg(-1), or physiological saline 15 min before testing their motor skills (muscular strength, dynamic equilibrium and motor coordination) and motor learning abilities (number of trials needed to reach a learning criterion on a rotorod rotating at 27 revolutions per min). The results demonstrated a lack of correlation between motor skill scores and between motor skill and motor learning scores, suggesting that the rotorod training procedure measures motor learning and not motor skills or is insensitive to changes in motor skills. They also demonstrated that motor skills decreased with age but were insensitive to environmental rearing and to scopolamine. In contrast, the learning scores, which also decreased with age, were very sensitive to scopolamine, particularly in the oldest mice. These results are discussed according to the role of cholinergic system in motor learning during aging.

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.

Chronic stress in pregnant rats: effects on growth rate, anxiety and memory capabilities of the offspring.

Female rats were repeatedly stressed for 10 periods of 15 min by the presence of a cat, at the 10th (S10) or the 19th (S19) gestational day. The litter from stressed females often contained a majority of males or a majority of females, especially in the S19 group. The death of pups was dramatically high in the S19 group and, compared with controls, growth of the surviving animals was slower. When adult, their long-term memory was altered and they exhibited an aversive behavior relative to wide areas. Moreover, cognitive alterations were revealed by the low level of exploration and the inability to rapidly process the relevant environmental cues. These deficits resemble those of psychiatric patients who had been submitted to pre-natal stress.

Halogenated boldine derivatives with enhanced monoamine receptor selectivity.

(S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. Initial halogenation occurs at C-3, followed (in the cases of chlorine and bromine) by the less reactive C-8, to afford 3-haloboldines- and 3,8-dihaloboldines (2-5). Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo derivative 6 was obtained. Radioligand binding studies of these products showed that halogenation of boldine at C-3 favors affinity for D(1)- (vs D(2)-) dopaminergic receptors, attaining a low nanomolar IC(50) value in the case of 3-iodoboldine (6).

Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission.

The dopaminergic and antioxidant properties of pukateine [(R)-11-hydroxy-1,2-methylenedioxyaporphine, PUK], a natural aporphine derivative, were analyzed in the rat central nervous system. At dopamine (DA) D1 ([3H]-SCH 23390) and D2 ([3H]-raclopride) binding sites, PUK showed IC50 values in the submicromolar range (0.4 and 0.6 microM, respectively). When the uptake of tritiated dopamine was assayed by using a synaptosomal preparation, PUK showed an IC50 = 46 microM. In 6-hydroxydopamine unilaterally denervated rats, PUK (8 mg/kg but not 4 mg/kg) elicited a significant contralateral circling, a behavior classically associated with a dopaminergic agonist action. When perfused through a microdialysis probe inserted into the striatum, PUK (340 microM) induced a significant increase in dopamine levels. In vitro experiments with a crude rat brain mitochondrial suspension showed that PUK did not affect monoamine oxidase activities, at concentrations as high as 100 microM. PUK potently (IC50 = 15 microM) and dose-dependently inhibited the basal lipid peroxidation of a rat brain membrane preparation. As a whole, PUK showed a unique profile of action, comprising an increase in extracellular DA, an agonist-like interaction with DA receptors, and antioxidant activity. Thus, PUK may be taken as a lead compound for the development of novel therapeutic strategies for Parkinson disease.

Biochemical and behavioral effects of boldine and glaucine on dopamine systems.

The aporphine alkaloids boldine and glaucine have been reported to show "neuroleptic-like" actions in mice, suggesting that they may act as dopamine antagonists. We have found that in vitro boldine displaces specific striatal [3H]-SCH 23390 binding with IC50 = 0.4 microM and [3H]-raclopride binding with IC50 = 0.5 microM, while the affinities of glaucine at the same sites are an order of magnitude lower. In vivo, however, 40 mg/kg boldine (i.p.) did not modify specific striatal [3H]-raclopride binding and only decreased [3H]-SCH 23390 binding by 25%. On the other hand, 40 mg/kg glaucine (i.p.) displaced both radioligands by about 50%. Behaviors (climbing, sniffing, grooming) elicited in mice by apomorphine (0.75 mg/kg s.c.) were not modified by boldine at doses up to 40 mg/kg (i.p.) but were almost completely abolished by 40 mg/kg glaucine (i.p.). In the apomorphine-induced (0.1 mg/kg s.c.) rat yawning and penile erection model, boldine and glaucine appeared to be similarly effective, inhibiting both behaviors by more than 50% at 40 mg/kg (i.p.). Boldine and glaucine, injected i.p. at doses up to 40 mg/kg, were poor modifiers of dopamine metabolism in mouse and rat striatum. These data suggest that boldine does not display effective central dopaminergic antagonist activities in vivo in spite of its good binding affinity at D1- and D2-like receptors, and that glaucine, although less effective in vitro, does appear to exhibit some antidopaminergic properties in vivo.

Similar pharmacological properties of 8-OH-DPAT and alnespirone (S 20499) at dopamine receptors: comparison with buspirone.

Alnespirone (S 20499) has previously been described as a potential anxiolytic drug that acts by stimulation of 5-HT1A receptors. Some data suggest that alnespirone might also be a weak dopamine D2 receptor agonist: it displays moderate affinity for dopamine D2 receptors in vitro and it inhibits prolactin release and induces yawning in rats. In order to test for possible interactions of alnespirone with dopamine receptors in vivo, we studied the changes of in vivo striatal [3H]SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine) and [3H]raclopride binding following the injection of a tracer dose of either tritiated ligand (4 microCi) in mice treated with increasing doses of alnespirone (5, 10, 20 and 40 mg/kg, i.p.) and, in the same animals, the changes in the levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). These changes were compared with those produced by increasing doses of the reference 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin, 0.25, 1 and 4 mg/kg, i.p.) or buspirone (5 and 20 mg/kg, i.p.). Decreased in vivo striatal [3H]SCH 23390 specific binding was observed in mice treated with 5, 10 and 40 mg/kg alnespirone. In contrast, increased in vivo striatal [3H]raclopride specific binding was observed in mice treated with 5 and 20 mg/kg alnespirone. In these animals, the striatal 5-HIAA/5-HT ratio was decreased by 5 to 40 mg/kg alnespirone, whereas the striatal HVA/DA ratio was unaffected at all tested doses of alnespirone. Similarly, 8-OH-DPAT decreased specific in vivo striatal [3H]SCH 23390 binding at 0.25, 1 and 4 mg/kg, and increased in vivo specific striatal [3H]raclopride binding at 1 and 4 mg/kg. In the same animals, all tested doses of 8-OH-DPAT decreased the striatal 5-HIAA/5-HT ratio but did not modify the striatal HVA/dopamine ratio. Buspirone (5 and 20 mg/kg) completely inhibited in vivo specific striatal [3H]raclopride binding and increased the striatal HVA/DA ratio but did not modify the striatal 5-HIAA/5-HT ratio, whereas apomorphine (3 mg/kg) decreased both in vivo specific striatal [3H]SCH 23390 and [3H]raclopride binding as well as the striatal HVA/DA and 5-HIAA/5-HT ratios. Finally, increasing doses of alnespirone or 8-OH-DPAT weakly increased sniffing induced by apomorphine (0.75 mg/kg, s.c.) in mice and decreased grooming induced by the dopamine D1 receptor agonist SK&F 39393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, 1.87 mg/kg, s.c.), whereas buspirone decreased both apomorphine-induced sniffing and SK&F 39393-induced grooming. These results indicate that alnespirone and 8-OH-DPAT have a similar profile and do not seem to interact directly with dopamine receptors. The results also suggest that the stimulation of 5-HT1A receptors by either alnespirone or 8-OH-DPAT modulates the availability of striatal [3H]SCH 23390 and [3H]raclopride binding sites and possibly the functioning of striatal dopamine D1 and D2 receptors in opposite directions.

Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(+)-nor-roefractine.

(R)-(+)-nor-Roefractine (1) was synthesized by the Bischler-Napieralski route, using asymmetric reduction of the 1, 2-didehydro precursor imine with sodium (S)-N-CBZ-prolinyloxyborohydride. Compound 1 was able to displace [3H]-raclopride (a D2 dopamine receptor-selective ligand) from its specific binding sites in rat striatum with selectivity vs [3H]-SCH23390 (D1 dopamine receptor-selective ligand).

Acute stress in pregnant rats: effects on growth rate, learning, and memory capabilities of the offspring.

Growth rate of the offspring of female rats stressed by the presence of a cat at the 10th or the 19th gestational day was lower than that of controls whereas footshocks administered at the same periods did not significantly influence growth rate of the young. Whatever the nature of the stress and the time when it was administered to the mother, the death rate of the young rats was much greater than that in controls. When adult, the offspring of stressed mothers exhibited learning and memory impairments in a delayed alternation task as well as in passive avoidance conditioning. Alteration of these cognitive functions is interpreted in terms of subtle dysfunctions in the development of the nervous system through modifications of the hormonal components of the mothers, particularly eventual alterations of the nervous system biochemistry of the offspring.

Effects of various isoquinoline alkaloids on in vitro 3H-dopamine uptake by rat striatal synaptosomes.

Various alkaloids having an isoquinoline skeleton from different species of the Annonaceae, Fumariacae, and Aristolochiacae (aporphine, cularine, benzylisoquinoline, and bisbenzylisoquinoline derivatives) were tested for their ability to inhibit in vitro 3H-dopamine uptake by rat striatal dopamine D1 3H-SCH 23390 AND D2 3H-raclopride binding sites. Except for some aporphine derivatives (anonaine [1], norstephalagine [2], isopiline [3]) and some bisbenzylisoquinoline alkaloids (dimethylgrisabine [27], antioquine [28], obaberine [29], isotetrandrine [30]) that displayed affinities of the same order as the reference compounds (nomifensine [38], amineptine [39], dexamphetamine [40]), the other tested products had low, or no, affinity on the 3H-dopamine uptake since, in comparison, its affinity at dopamine D1 3H-SCH 23390 and D2 3H-raclopride binding sites was low. These data suggest that it could be possible to synthesize anonaine-like products displaying intense dopamine-uptake inhibitory properties, which could lead to a potential antidepressant activity.

Post-synaptic 5-HT1A receptor involvement in yawning and penile erections induced by apomorphine, physostigmine and mCPP in rats.

Apomorphine and mCPP induced yawning associated with penile erections in rats, whereas physostigmine induced only yawns. Apomorphine-induced yawning and penile erections were antagonized by low doses of raclopride, whereas physostigmine-induced yawning and mCPP-induced effects were only partly inhibited at high doses of raclopride. Scopolamine as well as clozapine antagonized yawning and penile erections induced by apomorphine, mCPP and physostigmine. Similarly, the 5-HT1A agonists 8-OH-DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine, mCPP and physostigmine, and at similar doses induced lower lip retraction and hyperreactivity to handling. The beta/5-HT1A antagonist tertatolol reversed the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections and increased apomorphine- and physostigmine-induced yawn frequency but not penile erection frequency. Like tertatolol, propranolol increased apomorphine- and physostigmine-induced yawn frequency, whereas ICI 118551 increased only physostigmine-induced yawning. 8-OH-DPAT- and S 14506-induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol. Finally, p-chlorophenylalanine pretreatment produced about 95% depletion in 5-HT in hypothalamus, hippocampus, striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Displacement activity of bisbenzylisoquinoline alkaloids at striatal 3H-SCH 23390 and 3H-raclopride binding sites.

Fifteen bisbenzylisoquinoline alkaloids (BBIQ) with one ether bridge (thaligrisine [1], berbamunine [2], dimethylgrisabine [3], pampulhamine [4], and methyl-dauricine [5]), with two ether bridges (homoaromoline, isotetrandrine, and obaberine), with one ether bridge and one biphenyl bridge (oxandrine, dimethylpseudoxandrine, pseudoxandrine, and antioquine) or secoderivatives (secoobaberine, secoantioquine, and secolucidine), were tested for their ability to displace 3H-raclopride or 3H-SCH 23390 from their specific dopaminergic binding sites to rat striatal membranes. The most active compounds were found in the group of BBIQs with one ether bridge. Inactive or weakly active compounds were found in this group of BBIQs with one ether bridge and in the other groups. Analysis of tridimensional representations indicates that the differnt activities among the BBIQs with one ether bridge could be related to strong differences between the spatial occupancy of these compounds according to their stereochemistry.

Noradrenergic system: effect of DSP4 and FLA-57 on ethanol intake in ethanol preferring rats.

Ethanol preferring rats (male Long-Evans; n = 6) were selected as drinking rats (DR) and treated with DSP4 (50 mg.kg-1 IP) at the end of the preference selection. Two more groups received DSP4 (50 mg.kg-1 IP) + the inhibitor of dopamine beta-hydroxylase FLA-57 (1 mg.kg-1.d-1 during two weeks), IP (n = 5) or FLA-57 alone (1 mg.kg-1.d-1 during two weeks IP) (n = 5). The control DR group (n = 6) received NaCl 0.9%. 3H-Noradrenaline uptake was studied at the 17th day of treatment in DR, treated or not with DSP4, and in ethanol naive rats treated (n = 6) or not (n = 6) with DSP4 (50 mg.kg-1, IP) DSP4 does not modify ethanol intake in DR, and both treated groups (DR or ethanol naive rats). 3H-Noradrenaline uptake was decreased (about 60%), both in cortex and hippocampus. But the association of FLA-57 and DSP4 decreases both ethanol and fluid intakes. It was suggested 1) that the 40% of intact neurons was able to compensate the DSP4-induced noradrenergic neurons destruction, 2) that the destruction of noradrenergic pathways (FLA-57 + DSP4) is associated with a decrease in ethanol intake but also in fluid intakes, suggesting finally 3) that the modulation of ethanol intake by the noradrenergic system was partial or indirect.

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.

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)

Potentiation of apomorphine-induced stereotyped behaviour by acute treatment with dopamine depleting agents: a potential role for an increased stimulation of D1 dopamine receptors.

Treatment of mice with reserpine (10 mg/kg, s.c.) and alpha-methylparatyrosine (400 mg/kg) led to the potentiation of stereotyped behaviour, induced by apomorphine (0.37-1.5 mg/kg, s.c.), i.e. to the appearance of licking and gnawing in addition to climbing and sniffing occurring in control mice. Similar results were obtained by combined treatment with SK&F 38393 (30 mg/kg, s.c.) and RU 24926 (15 mg/kg, i.p.). In mice treated with dopamine depleting agents, SCH 23390 (1.25-20 micrograms/kg, s.c.) and metoclopramide (0.62-20 mg/kg, i.p.) antagonized gnawing induced by 0.75 mg/kg (s.c.) apomorphine, at doses significantly larger than those required for the antagonism of climbing and sniffing. The same treatment with reserpine and alpha-methylparatyrosine produced an increased formation of cyclic AMP, induced by SK&F 38393 (10(-8)-10(-4) M), from homogenates of the striatum of the rat. Potentiation of apomorphine-induced stereotyped behaviour and increased SK&F 38393-induced formation of cyclic AMP had similar time-courses with a maximum 18 hr after treatment. These data suggest that the potentiation of apomorphine-induced stereotyped behaviour produced by acute treatment with dopamine depleting agents is at least partly due to an increased activity of the adenylate cyclase linked to D1 dopamine receptors. Finally, a small dose of amisulpride (a discriminant benzamide derivative) potentiated the stereotyped behaviour induced by the combined treatment with SK&F 38393 and RU 24926 in naive mice and, in a more marked manner, in mice treated with dopamine depleting agents; amisulpride did not produce stereotyped behaviour when combined with SK&F 38393 or RU 24926 administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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.