Effect of 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)- 2(1H)-quinolinone (OPC-4392), a newly synthesized agonist for presynaptic dopamine D2 receptor, on tyrosine hydroxylation in rat striatal slices

The effects of a newly synthesized compound, 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on tyrosine hydroxylation in situ and in vitro were studied using rat striatal slices and tyrosine hydroxylase (TH) purified from bovine adrenal medulla, respectively. OPC-4392 dose-dependently inhibited L-dihydroxyphenylalanine (DOPA) formation in rat striatal slices with IC50 values of about 10(-6) M. The inhibitory effect of OPC-4392 on in situ DOPA formation was dose-dependently reversed by addition of sulpiride, a dopamine D2 receptor antagonist, whereas no change was observed by addition of nomifensine (5 X 10(-6) M), a blocker of dopamine uptake. From in vitro experiment using purified TH, OPC-4392 affected neither the enzymatic activity nor the Km value for 6-methyl-5,6,7,8-tetrahydropterin (6MPH4). These results suggest that OPC-4392 impairs in situ DOPA formation by stimulating presynaptic dopamine D2 receptor as a dopamine agonist, and not by directly inhibiting the TH activity.     

Presynaptic inhibition of excitatory input from the substantia nigra to caudate nucleus neurons by a substituted quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392)

The effects of a newly synthesized quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl) propoxy]-2(1H)-quinolinone (OPC-4392) on neuronal activities of the caudate nucleus (CN) were investigated in cats anesthetized with alpha-chloralose using a microiontophoretic method. In the CN neurons of which spikes elicited by stimulation of the pars compacta of substantia nigra (SN) were suppressed by iontophoretically applied domperidone, a dopamine D-2 receptor antagonist, application of OPC-4392 (100-200 nA) inhibited the spike generation induced by SN stimulation. Conversely, the CN neurons insensitive to domperidone were unaffected by OPC-4392. Iontophoretic application of CPC-4392 up to 200 nA did not affect glutamate-induced firing of the CN neurons, of which the firing was blocked by dopamine less than 100 nA. In addition, OPC-4392 did not inhibit firing induced by bromocriptine, a dopamine D-2 agonist; while domperidone suppressed the bromocriptine-induced firing without affecting the glutamate-induced firing. These results suggest that OPC-4392 acts on the dopaminergic nerve terminals and inhibits excitatory transmission from the SN to the CN.     

D-2 receptor-mediated inhibition by a substituted quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), of dopaminergic neurons in the ventral tegmental area

A microiontophoretic study was performed to investigate the effects of a newly synthesized quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone (OPC-4392), on neuronal activities of the ventral tegmental area (VTA) of rats anesthetized with chloral hydrate. The VTA neurons, which were identified by antidromic stimulation of the nucleus accumbens (Acc), were classified into type I and type II neurons according to the responses to Acc stimulation: type I neurons had a long spike latency of over 7 msec (9.63 +/- 0.25 msec), and the type II, a short latency of less than 7 msec (2.98 +/- 0.27 msec) upon Acc stimulation. In all of 11 type I neurons, iontophoretically applied OPC-4392 and dopamine inhibited the antidromic spikes elicited by Acc stimulation. This inhibition was antagonized by simultaneous application of domperidone (dopamine D-2 antagonist). However, in 16 out of 19 type II neurons the antidromic spikes were not affected by either OPC-4392 or dopamine. When the effects of iontophoretically applied OPC-4392 and dopamine on spontaneous firings were tested in 32 VTA neurons identified by Acc stimulation (including type I and type II neurons), there was a relationship between the effects of these two drugs. These results suggest that OPC-4392 acts on dopamine D-2 receptors of the dopaminergic neurons in the VTA, thereby inhibiting neuronal activity.     

Interaction of (+)- and (-)-3-PPP with the dopamine receptor in the anterior pituitary gland

The interaction of the enantiomers of the novel dopamine agonist, 3-PPP (3-hydroxyphenyl)-N-n-piperidine) with the dopamine receptor in the anterior pituitary gland was examined. Both (+)- and (-)-3-PPP were effective in suppressing the elevation in serum prolactin (PRL) concentrations in rats treated with alpha-methyl-paratyrosine, an inhibitor of dopamine synthesis. The (+)-enantiomer was slightly more potent than the (-)-enantiomer in this regard. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by both isomers of 3-PPP, with (+)-3-PPP being approximately 10 times more potent than (-)-3-PPP. Both (+)- and (-)-3-PPP displaced 3H-(-)-N-n-propylnorapomorphine (3H-NPA) and 3H-spiperone from bovine anterior pituitary membranes. The Hill coefficients of (+)- and (-)-3-PPP for the displacement of 3H-spiperone were 0.6 and 0.7, respectively. These results are consistent with the view that the (+)- and (-)-enantiomer exhibit dopamine agonist effects at dopamine receptor sites in the anterior pituitary gland. However, (+)-3-PPP demonstrated marked differences in affinity for 3H-NPA- and 3H-spiperone labeled-sites, whereas (-)-)3-PPP showed the same order of affinity for these two sites. In view of these results and the fact that (-)-3-PPP has also been characterized as a dopamine antagonist at postsynaptic receptor sites in the striatum, (-)-3-PPP might be best described as a partial agonist at pituitary dopamine receptors. Moreover, these data are suggestive of a similarity, at least on a pharmacological basis, between dopamine autoreceptors and dopamine receptors in the anterior pituitary gland.     

Effects of the potential neuroleptic peptide des-tyrosine1-γ-endorphin and haloperidol on apomorphine-induced behavioural syndromes in rats and mice

The effects of haloperidol and Des-Tyr¹-γ-endorphin (DTγE) were studied on climbing induced in mice by high doses of apomorphine and on the yawning syndrome induced in rats by low doses of apomorphine. Haloperidol in a dose of 0.0046 mg/kg s.c. potentiated climbing whereas at higher doses climbing was inhibited (ED₅₀=0.03 mg/kg). DTγE had no effect on climbing under normal conditions in doses up to 2 mg/kg s.c.. After three days of handling and saline pre-injections DTγE potentiated climbing in doses from 0.1 to 1 mg/kg.Haloperidol inhibited yawning induced by low doses of apomorphine (ED₅₀=0.01 mg/kg). DTγE, on the other hand, potentiated yawning induced by low apomorphine at doses of 0.02 and 0.04 mg/kg s.c.. From the point of view that low doses of apomorphine predominantly activate presynaptic dopamine autoreceptors while higher doses predominantly activate postsynaptic dopamine receptors the following tentative conclusions are drawn. 1) Haloperidol blocks presynaptic dopamine autoreceptors at low doses and postsynaptic dopamine receptors at higher doses. 2) DTγE sensitizes presynaptic dopamine autoreceptors at low doses, thereby strengthening the local feedback mechanism at the dopaminergic nerve ending, and sensitizes postsynaptic dopamine receptors at higher doses.     

Stress-Induced Enhancement of Suppression of [3H]GABA Release from Striatal Slices by Presynaptic Autoreceptor

The effect of cold and immobilization stress on presynaptic GABAergic autoreceptors was examined using the release of [3H]GABA (gamma-aminobutyric acid) from slices of rat striatum. It was found that in vitro addition of delta-aminolevulinic acid, as well as GABA agonists such as muscimol and imidazoleacetic acid, exhibited a significant suppression of the striatal release of [3H]GABA evoked by the addition of high potassium, whereas delta-aminovaleric acid had no significant effects on the evoked release. These suppressive actions were antagonized invariably by the GABA antagonists, bicuculline and picrotoxin, but not by the glycine antagonist, strychnine. Cholinergic agonists, such as pilocarpine and tetramethylammonium, also attenuated significantly the evoked release of [3H]GABA from striatal slices, while none of its antagonists, including atropine, hexamethonium and d-tubocurarine, affected the release. On the other hand, in vitro addition of dopamine receptor agents such as dopamine, apomorphine, and haloperidol, or the inhibitory amino acids, glycine, beta-alanine, and taurine failed to influence the evoked release of [3H]GABA from striatal slices. Application of a cold and immobilization stress for 3 h was found to induce a significant enhancement of the suppressive effects by muscimol and delta-aminolevulinic acid on the evoked release of [3H]GABA, without affecting that by pilocarpine and tetramethylammonium. These results suggest that the release of GABA from striatal GABA neurons may be regulated by presynaptic autoreceptors for this neuroactive amino acid, and may play a significant functional role in the exhibition of various symptoms induced by stress.     

Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI)

The dopaminergic activity of 4-(2-di-n-propylaminoethyl)indole (DPAI) was investigated. In animal models for postsynaptic dopaminergic activity DPAI showed only very weak or no effects. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal tract, very weak contralateral turning behavior was induced in 4/6 rats. DPAI did not induce stereotyped behavior but caused a pronounced reduction in locomotor activity. In male rats pretreated with reserpine, DPAI lowered serum prolactin levels. Levels of homovanillic acid (HVA) were monitored in the striatum of the chloral hydrate anesthetized rat by means of in vivo voltammetry. DPAI administration reduced the faradaic peak corresponding to HVA. In rats pretreated with the decarboxylase inhibitor, NSD-1015, DPAI blocked the accumulation of dopa in response to gamma-butyrolactone. The results of this study indicate that DPAI possesses a high degree of selectivity for presynaptic dopamine autoreceptors, and little or no effect on postsynaptic dopamine receptors.     

Dopamine Autoreceptor Stimulation Increases Protein Carboxyl Methylation in Striatal Slices

We have investigated the possibility that protein carboxyl methylation is involved in coupling dopamine autoreceptor stimulation to intracellular events such as inhibition of dopamine synthesis or release. The dopamine agonists apomorphine and TL-99 were found to stimulate methyl ester formation in striatal slices preloaded with [3H]methionine. The stimulatory effects of apomorphine were dose-dependent, were not due to changes in [3H]methionine uptake or S-[3H]-adenosylmethionine formation, and were blocked by the stereospecific dopamine antagonist (+)-butaclamol. Stimulation of methyl ester formation by dopamine agonists is readily observed only when slices are prepared from rats pretreated with reserpine to deplete endogenous brain catecholamines. This suggests that in slices prepared from normal rats endogenous dopamine (DA) released during slice preparation and incubation masks the effects produced by exogenously administered dopamine agonists on protein carboxyl methylase (PCM) activity. Additional experiments suggested that the effects of apomorphine were mediated via an interaction with DA autoreceptors rather than with postsynaptic DA receptors. Destruction of monoamine neurons and their associated autoreceptors by injecting 6-hydroxydopamine into the area of the medial forebrain bundle abolished the stimulatory effects of apomorphine on methyl ester formation in striatal slices. Furthermore the putative selective DA autoreceptor agonist EMD 23 448 was also found to stimulate methyl ester formation in striatal slices. These findings, discussed in terms of calcium-dependent functions, support the hypothesis that PCM may be a key component in the biochemical transduction of DA autoreceptor stimulation.     

The effect of chronic L-DOPA administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the ³H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in ³H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.     

[3H]8-Hydroxy-2-(Di-n-Propylamino)Tetralin Binding to Pre- and Postsynaptic 5-Hydroxytryptamine Sites in Various Regions of the Rat Brain

The specific binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([ 3H]8-OH-DPAT) to 5-hydroxytryptamine (5-HT)-related sites was investigated in several regions of the rat brain. Marked differences were observed in the characteristics of binding to membranes from hippocampus, striatum, and cerebral cortex. Hippocampal sites exhibited the highest affinity (KD approximately 2 nM) followed by the cerebral cortex (KD approximately 6 nM) and the striatum (KD approximately 10 nM). Ascorbic acid inhibited specific [3H]8-OH-DPAT binding in all three regions but millimolar concentrations of Ca2+, Mg2+, and Mn2+ enhanced specific binding to hippocampal membranes, whereas only Mn2+ increased it in the cerebral cortex and all three cations inhibited specific binding to striatal membranes. Guanine nucleotides (0.1 mM GDP, GTP) inhibited binding to hippocampal and cortical membranes only. As intracerebral 5,7-dihydroxytryptamine markedly decreased [3H]8-OH-DPAT binding sites in the striatum, but not in the hippocampus, the striatal sites appear to be on serotoninergic afferent fibers. In contrast, in the hippocampus the sites appear to be on postsynaptic 5-HT target cells, as local injection of kainic acid decreased their density. Both types of sites appear to be present in the cerebral cortex. The postsynaptic hippocampal [3H]8-OH-DPAT binding sites are probably identical to the 5-HT1A subsites, but the relationship between the presynaptic binding sites and the presynaptic autoreceptors controlling 5-HT release deserves further investigation.     

Effect of 3-PPP,a putative dopamine autoreceptor agonist,on rat serum prolactin levels

3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) has been reported to be a relatively selective agonist for dopamine (DA) auto-receptors in the striatal and limbic region. We have examined the effect of 3-PPP on rat plasma or serum prolactin levels. 3-PPP produced a non-significant decrease in baseline plasma prolactin levels. It produced a dose-dependent inhibition of the increase in serum prolactin levels produced by gamma-butyrolactone. Both doses of 3-PPP tested completely reversed the increase in serum prolactin levels.produced by reserpine and alpha-methylparatyrosine. These results strongly indicate that 3-PPP directly stimulated DA receptors on pituitary lactotrophes. 3-PPP only weakly inhibited the ability of ³H-spiroperidol to bind to pituitary or striatal membranes, suggesting that it may act at a different DA receptor than classical DA receptor blocking drugs. This DA receptor could have properties in common with the autoreceptors of the mesolimbic and nigrostriatal DA neurons.     

Neurotensin interacts with dopaminergic neurons in rat brain

Neurotensin (NT) injected intracerebroventricularly in rat increases dopamine (DA) turnover in the corpus striatum and nucleus accumbens. Significant increases in 3,4-dihydroxyphenylacetic acid (DOPAC) levels occurred within 15 minutes after injection with peak levels at 60 minutes. The effect on NT on DOPAC and homovanillic acid (HVA) accumulation was dose-dependent at 3–100 μg. NT, like haloperidol, stimulated 3,4-dihydroxyphenylalanine (DOPA) accumulation in striatal neurons, in the presence of DOPA decarboxylase inhibitor, after injection of gamma-butyrolactone (GBL). NT had a similar stimulatory effect on DOPA levels in the accumbens while haloperidol (0.25 mg·kg^?1) had no significant effect in this brain region. NT did not block the inhibitory effect of apomorphine on DOPA accumulation in both the striatum and accumbens, while haloperidol inhibited apomorphine effect in both regions. NT also failed to displace ³H-spiperone from DA receptors and the presence of NT in the binding assay did not alter the ability of DA to displace ³H-spiperone in either brain region. These experiments demonstrate that NT increases DA turnover in both the nigrostriatal and mesolimbic pathways.     

Presynaptic Dopamine Autoreceptors Control Tyrosine Hydroxylase Activation in Depolarized Striatal Dopaminergic Terminals

The possible control of tyrosine hydroxylase (TH) activity by dopaminergic receptor-dependent mechanisms was investigated using rat striatal slices or synaptosomes incubated in the presence of various 3,4-dihydroxyphenylethylamine (dopamine or DA) agonists and antagonists. Under "normal" conditions (4.8 mM K+ in the incubating medium), the DA agonists apomorphine, 6,7-dihydroxy-N,N-dimethyl-2-aminotetralin (TL-99), 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), Trans-(-)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo-3,4- quinoline, and 3-(3-hydroxyphenyl)-N-n-propylpiperidine decreased TH activity in soluble extracts of incubated tissues. In the case of the catechol-containing drugs apomorphine and TL-99, this effect was partly due to a direct inhibition of the enzyme, but in all other cases it appeared to depend on the stimulation of presynaptic DA autoreceptors. No effect of DA antagonists was detected on TH activity under "normal" conditions. In contrast, when tissues were incubated in a K+ -enriched (60 mM) medium, (-)-sulpiride and other DA antagonists enhanced TH activation due to depolarization whereas DA agonists were ineffective. Because (-)-sulpiride also increased the enzyme activity in striatal slices exposed to drugs inducing release of DA, such as veratridine and d-amphetamine, it is concluded that the stimulating effect of the DA antagonist resulted in fact from the blockade of the negative control of TH normally triggered by endogenous DA acting on presynaptic autoreceptors. In contrast to TH activation due to K+ -induced depolarization, the activation evoked by tissue incubation with dibutyryl cyclic AMP was unaffected by the typical agonist 7-OH-DPAT or the antagonist (-)-sulpiride. This would suggest that TH control via presynaptic DA autoreceptors normally concerns possible modulations of the cyclic AMP-dependent phosphorylation of the enzyme.     

Reproduction of a memory trace in amnesia and forgetting following alteration in the activity of pre- and postsynaptic dopamine receptors

The paper deals with analysis of the action of enantiomers 3-PPP on memory trace reproduction disturbed by amnestic effects and spontaneous forgetting in mice. A considerable antiamnestic effect is shown of (+)3-PPP and (-)3-PPP in 10 mg/kg doze changing the activity of postsynaptic dopamine receptors. The influence of drugs in 2 mg/kg doze changing the activity of presynaptic receptors consisted in recovery of conditioned habit only in situation of a weak amnestic effect and at forgetting, when the level of reproduction was like a weak amnesia. The range of enantiomers 3-PPP action on reproduction processes disturbed by amnesia or forgetting is determined by the possibility of specific activation of pre- and postsynaptic receptors at different depth of disturbances of memory trace reproduction causing differentiation of 3-PPP effects.     

(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] but not (-)-3-PPP produces (+)-N-allylnormetazocine-like (SKF 10,047) discriminative stimuli

In rats trained to discriminate the prototypic sigma receptor agonist, (+)-N-Allylnormetazocine [(+)-N-Allylnormetazocine [(+)-NANM/SKF 10,047], from saline, the (+)- but not the (-)-isomer of 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) produced (+)-NANM-like discriminative stimuli. (+)-3-PPP binds stereo selectively to the (+)-NANM binding site, but not to the phencyclidine binding site. Additionally, phencyclidine was found to produce (+)-NANM-like discriminative stimuli. Although the 3-PPP isomers were shown to produce changes in central dopaminergic activity (Hjorth et al. Life Sci 37, 673, 1985), the discriminative stimulus properties of (+)-3-PPP are apparently not mediated via the dopaminergic system. This hypothesis is supported by the fact that apomorphine did not produce (+)-NANM-like discriminative stimuli. These stimuli are thus non-dopaminergic and may be due to the (+)-3-PPP actions at the sigma binding site. However, it is possible that (+)-NANM, PCP, and (+)-3-PPP may have common non-sigma pharmacologic properties that account for the similar discriminative stimulus properties of these compounds.     

Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter

The dopamine transporter (DAT) regulates the temporal and spatial actions of dopamine by reuptaking this neurotransmitter into the presynaptic neurons. We recently generated transgenic mice overexpressing DAT (DAT-tg) that have a 3-fold increase in DAT protein levels which results in a 40% reduction of the extracellular DA concentration in the striatum. The aim of this study was to examine the effect of this reduction in dopaminergic tone on postsynaptic responses mediated by dopamine receptors. We report here that DAT-tg mice have increased levels of striatal D1 (30%) and D2 (approximately 60%) dopamine receptors with D1 receptor signaling components not significantly altered, as evidenced by unaffected basal or stimulated levels of phospho-GluR1 (Ser845) and phospho-ERK2. However, the novel D2 mediated Akt signaling is markedly altered in DAT-tg animals. In particular, there is a 300% increase in the basal levels of phospho-Akt in the striatum of DAT-tg, reflecting the reduced extracellular dopamine tone in these animals. This increase in basal pAkt levels can be pharmacologically recapitulated by partial dopamine depletion in WT mice treated with the selective tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MPT). Behaviorally, DAT-tg animals demonstrate an augmented synergistic interaction between up-regulated D1 and D2 receptors, which results in increased climbing behavior in transgenic mice after stimulation with either apomorphine or a co-administration of selective D1 and D2 receptor agonists. In sum, our study reveals that hypodopaminegia caused by up-regulation of DAT results in significant alterations at postsynaptic receptor function with most notable dysregulation at the level of D2 receptor signaling.     

Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: discrepancies between in vitro and in vivo observations

In vitro radioligand binding and autoradiographic distribution studies have suggested the possible involvement of central sigma-opiate sites in the effects of several purportedly dopaminergic agents. Specifically, Largent et al. (Proc. Nat. Acad. Sci. 81, 4983, 1984) proposed that "actions of 3-PPP at sigma receptors may account for the effect of the drug on behavior and dopaminergic nerve function". Using the sigma-opiate- and dopamine (DA)-preferring (-)- and (+)-enantiomer, respectively, of butaclamol, and the two enantiomers of 3-PPP, the present study was undertaken to address the in vivo functional significance of this proposal. To this end we investigated various biological responses considered to reflect drug interactions with DA cell body and terminal autoreceptors and with presumed non-synaptic and postsynaptic DA receptors in the rat CNS. (+)- but not (-)-butaclamol antagonized the 3-PPP (either enantiomer)-induced DA synthesis and prolactin decreases in GBL-treated rats, the (+)-3-PPP-induced inhibition of substantia nigra DA cell firing and the (+)-3-PPP-induced reversal of reserpine akinesia. Taken together with previous findings available data suggest that DA rather than sigma-opiate receptors mediate the neurochemical, electrophysiological, behavioral and other physiological (prolactin, body temperature) effects of 3-PPP and its enantiomers. The in vivo pharmacological relevance of the claimed non-dopaminergic, proposedly sigma-opiatergic, radioligand binding demonstrated in vitro (with e.g. (+)-3-PPP) thus remains to be established.     

The role of the dopaminergic system and GABA-benzodiazepine- ionophore complex in the regulation of memory retrieval

The spontaneous forgetting model has been used to demonstrate the possibility of the memory forgetten trace extraction under the dopamine reuptake blockade by nomifensine and bupropion, increase of its quantity by amfonelic acid, activation of the postsynaptic dopaminergic receptors by (+)3-PPP, blockade of the latter by (-)3-PPP, and under the blockade of separate links of the GABA-benzodiazepine-ionophore complex by bicuculline, picrotoxin, flumazepil and R015-3505. Effectiveness of the neuropharmacological actions improving the memory forgotten trace retrieval is shown to depend upon the duration of the spontaneous forgetting process. The presynaptic receptors are involved in the retrieval process control--improvement of the conditioned habit performance after forgetting due to the activation of presynaptic dopaminergic receptors by specific agonist (-)3-PPP is clearly correlated with the initial retrieval level. The above facts underlie a hypothesis about the neurochemical forgetting mechanisms.     

In vitro and in vivo pharmacological profile of 4-(4-fluorobenzylidene)-1-[2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl] ethyl] piperidine (NRA0161)

Atypical antipsychotic properties of 4-(4-fluorobenzylidene)-1-[2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl] piperidine (NRA0161) were investigated by in vitro receptor affinities, in vivo receptor occupancies and findings were compared with those of risperidone and haloperidol in rodent behavioral studies. In in vitro receptor binding studies, NRA0161 has a high affinity for human cloned dopamine D(4) and 5-HT(2A) receptor with Ki values of 1.00 and 2.52 nM, respectively. NRA0161 had a relatively high affinity for the alpha(1) adrenoceptor (Ki; 10.44 nM) and a low affinity for the dopamine D(2) receptor (Ki; 95.80 nM). In in vivo receptor binding studies, NRA0161 highly occupied the 5-HT(2A) receptor in rat frontal cortex. In contrast, NRA0161 did not occupy the striatal D(2) receptor. In behavioral studies, NRA0161, risperidone and haloperidol antagonized the locomotor hyperactivity in mice, as induced by methamphetamine (MAP). At a higher dosage, NRA0161, risperidone and haloperidol dose-dependently antagonized the MAP-induced stereotyped behavior in mice and NRA0161 dose-dependently and significantly induced catalepsy in rats. The ED(50) value in inhibiting the MAP-induced locomotor hyperactivity was 30 times lower than that inhibiting the MAP-induced stereotyped behavior and 50 times lower than that which induced catalepsy.These findings suggest that NRA0161 may have atypical antipsychotic activities yet without producing extrapyramidal side effects.     

Dopaminergic modulation of footshock induced aggression in paired rats.

Footshock induced aggression (FIA) was induced in weight matched paired rats and three paradigms of aggressive behaviour was recorded, namely, the latency to fight (LF), total period of physical contact (TPP) and cumulative aggression scores (CAS). Dopamine (DA), administered centrally, and peripherally administered L-dopa (with benserazide, a peripheral decarboxylase inhibitor), a DA precursor, and the postsynaptic D2 receptor agonists, apomorphine, N-n-propyl-norapomorphine (PNA), bromocriptine, lisuride and pergolide, induced a dose-related facilitation of FIA characterized by decrease in LF and increase in TPP and CAS. However, the DA presynaptic receptor agonist, BHT-920, induced a biphasic effect with inhibition of FIA being induced by a lower dose and facilitation of the aggressive behaviour produced by a higher dose. The postsynaptic D2 receptor antagonists, haloperidol, spiperone and pimozide, induced a dose-related attenuation of FIA, an effect not seen with domperidone, a peripheral DA receptor antagonist. The results indicate that central dopaminergic postsynaptic D2 receptors have a modulatory facilitative effect on FIA, while the presynaptic DA autoreceptors mitigate aggressive behaviour. However, the presynaptic DA receptor agonist, BHT-920, appears to lose its receptor specificity on dose increment. Long term administration of haloperidol, followed by withdrawal, or desipramine, induced per se augmentation of FIA and potentiated the aggression-facilitative effects of L-dopa, apomorphine and PNA. Since both these treatments are known to induce supersensitivity of central postsynaptic dopamine D2 receptors, the effects are likely to be related to augmented function of dopamine neurones. The findings, in conjunction with a recent report from this laboratory indicating an increase in rat brain DA levels in FIA, support the contention that the central DA system has a facilitative effect on FIA.