Memory impairment with pretreatment but not with posttreatment of quaternary naloxone.
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Animals↗
Biomedical subjects
A V Christensen
Publications and source records attributed to A V Christensen.
Spatial navigation learning in spontaneously hypertensive, renal hypertensive and normotensive Wistar rats.
The relation between blood pressure and cognitive performance was assessed in the spatial navigation task. Spatial learning by rats with spontaneous hypertension (SHR) and Goldblatt renal hypertension (RHR) was compared with that of normotensive Wistar rats (NR). The task required the rats to escape from water by finding a submerged and hidden platform. It was found that SHR rats showed improved learning capacity in the maze task in acquisition compared to the RHR and NR groups already on Day 1 and Day 2. The performances of all tested groups reached almost similar asymptotic level on Day 4 and in the probe trial on Day 5. After a reversal training the SHR rats did not show preference to swim in the new platform position quadrant. The present results confirm earlier reports on different behavioural characteristics associated with hypertension.
Animals↗
Effect of clozapine upon schedule-induced polydipsia (SIP) resembles neither the actions of dopamine D1 nor D2 blockade.
The effects of clozapine (CLOZ) upon acquired schedule-induced polydipsia in rats were compared to the effects of the dopamine (DA) D1 antagonist SCH 23390 (SCH) and the DA D2 antagonist raclopride (RAC). All three compounds suppressed water consumption, but only SCH and RAC decreased drinking efficiency. SCH was the only compound with an effect on panel pressing (PP), causing suppression even at a dose without effect upon water intake. SCH also affected the temporal pattern of licking (TPL) at all doses, while clozapine, 10 mg/kg, only affected the pattern acutely, and raclopride was without effect. In conclusion, PP and the TPL are more sensitive to D1 than D2 blockade. While PP and the TPL are more sensitive than water intake to D1 blockade, the opposite is true for D2 blockade. It is possible to differentiate between DA D1/D2 antagonists and CLOZ in this model, focusing upon reduction in water consumption, with and without reduction in drinking efficiency. Furthermore, it is possible to differentiate between D1 and D2 blockade by analyzing water consumption, PP and the TPL.
Animals↗
Enhanced disruptive spatial learning effect after sufentanil in renal hypertensive rats versus normotensive rats.
The effects of the peripherally administered sufentanil citrate (S), a potent opioid agonist with high affinity for mu receptors on the spatial navigation task, were tested in normotensive Wistar (NR) and renal hypertensive rats (RHR). Rats were injected subcutaneously once daily in doses of 0.25 or 1 microgram/kg S before the water maze training. In NR rats, weak effects of 0.25 micrograms/kg S and impairments after 1 microgram/kg S were seen, whereas in RHR 0.25 and 1 microgram/kg S showed clearcut impairments. These data from the Morris water maze task support previous reports that RHR have an increased sensitivity for opioid agonists.
Animals↗
Differences in performance in three strains of rats in a 5-choice serial reaction time task.
UNLABELLED: Possible discrepancies between an albino stock (Wistar), a mixed strain (pigmented/albino, Brown Norwegian x Lewis) and a pigmented strain (Long Evans) of rats in the acquisition and performance of a visual task for attention were investigated. It was expected that Wistar rats were less accurate in performance of the task, considering the visual deficits genetically linked to albinism in rodents. However, Wistar performed with the same accuracy, speed and impulsivity as Long Evans. The Brown Norwegian/Lewis rats had a decreased responding, speed and impulsivity. During task acquisition they responded with the same accuracy as the other two types of rats. After task acquisition they were also less accurate. IN CONCLUSION: It seems reasonable to use Wistar rats as well as Long Evans for the present task.
Animals↗
The antibacterial effect of some neuroleptics on strains isolated from patients with meningitis.
Eighty-two strains of bacteria (Neisseria meningitidis, Haemophilus influenzae, Enterobacteriaceae, Streptococcus pneumoniae, group B streptococci and Listeria monocytogenes) were examined for their in vitro susceptibility to eight drugs, seven neuroleptics (perphenazine, fluphenazine, cis(Z)-clopenthixol, haloperidol, clozapine, clebopride and SCH 23390), and the neuroleptically inactive trans(E)-clopenthixol. The phenothiazines and the thioxanthenes were, on the whole, the most active drugs when measured, the IC50(50) for each group of bacteria being 7.4 to 84 mg/l (with the exception of the activity against the enterobacteriaceae). The antibacterial potency of clozapine, which has an atypical neuroleptic profile, was between 50 and 140 mg/l. Haloperidol also showed an antibacterial activity in the concentration range 35-140 mg/l. The selective D1 antagonist, SCH 23390 and the selective D2 antagonist, clebopride, inhibited only few of the bacteria in the concentration range investigated.
Antipsychotic Agents↗
The effect of imipramine and lithium on "learned helplessness" and acetylcholinesterase in rat brain.
The effect of short- and long-term treatment with imipramine and lithium on shock stress-induced escape failures in a shuttlebox (the "learned helplessness" model of depression) was investigated in rats. Acetylcholinesterase (AChE) activity was measured in the frontal cortex, hippocampus and striatum after the shuttlebox test. Imipramine was found to normalize escape behavior, whereas lithium further aggravated escape behavior. No correlation was found between escape behavior and AChE activity in the three brain areas investigated. However, a significant decrease in AChE activity in striatum was found in rats exposed either to shock stress and no drug treatment or to drug treatment and no shock stress. In rats exposed to the combination of shock stress and drug (imipramine or lithium), a slight or no decrease of AChE activity occurred. Exposure to shock stress alone produced no changes in AChE activity in the hippocampus and frontal cortex. In conclusion, lithium did not have an antidepressant effect on "learned helplessness" and AChE activity was not correlated to escape behavior. However, both imipramine and lithium normalized the decreased level of AChE activity in striatum in rats exposed to shock stress.
Acetylcholinesterase↗
Effect of imipramine in the "learned helplessness" model of depression in rats is not mimicked by combinations of specific reuptake inhibitors and scopolamine.
Administration of imipramine, which blocks noradrenergic, serotonergic and cholinergic reuptake, to rats for 4 days counteracts the shuttlebox escape failures otherwise seen in rats which have been exposed to inescapable shock (the "learned helplessness" model of depression). The effects of the more selective reuptake inhibitors talsupram (noradrenergic), citalopram (serotonergic) and the anticholinergic compound scopolamine were assessed alone and in combination after acute or 4 days' administration on escape behavior. Their possible synergistic effects when combined with imipramine were also assessed. Talsupram and citalopram were ineffective, whereas scopolamine counteracted the escape failures. Combinations of talsupram, citalopram and a subeffective dose of scopolamine were ineffective. A synergistic effect was only seen when scopolamine was combined with a suboptimal dose of imipramine. Thus, the effect of imipramine on "learned helplessness" might rely partly on its anticholinergic component. However, as an acute high dose of imipramine (25 mg/kg) was ineffective [unlike the acute administration of scopolamine (0.12 mg/kg)], this drug retains a pharmacological effect which is not mimicked by scopolamine alone or by combining the specific reuptake inhibitors with scopolamine.
Animals↗
Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.
A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.
Animals↗
Receptor-binding profiles of neuroleptics.
Dopamine-receptor blockade seems to be a prominent effect of neuroleptics. Blockade of other receptors might, however, contribute to the therapeutic effect. A series of neuroleptics have been tested for affinity to DA D-1 and D-2 receptors, serotonin receptors (S2), alpha-adrenoceptors (alpha 1), histamine receptors (H1), and muscarinic cholinergic receptors. According to the affinity to DA D-1 and D-2 receptors, neuroleptics can be divided into different groups. Thioxanthenes have affinity for both D-1 and D-2 receptors; phenothiazines have affinity for D-2 receptors and considerably lower affinity for D-1 receptors; and butyrophenones, diphenylbutylpiperidines, and benzamides have affinity only for D-2 receptors. Concerning affinity to other receptors the only consistent finding is affinity for S2 receptors. The clinical significance of these findings is speculative. In several behavioral tests the D-1/D-2 classification is also observed, and it is suggested that D-1-receptor activation is responsible for dyskinesia, and that thioxanthenes - due to their D-1 receptor blocking effect-induce less dyskinesia than other neuroleptics.
Antipsychotic Agents↗
Pharmacological differentiation of dopamine D-1 and D-2 antagonists after single and repeated administration.
In single-dose experiments neuroleptics antagonize dopamine (DA)-agonist-induced stereotypies in animals. The antagonistic potency correlates with their clinical antipsychotic effects. In a series of experiments where DA-agonist-induced stereotyped gnawing in mice and rats was inhibited by neuroleptics it was shown that the antagonistic effect of butyrophenones was greatly attenuated by concomitant treatment with anticholinergics. The effect of phenothiazines was slightly attenuated and that of thioxanthenes and SCH 23390 remained unchanged. After repeated administration a differentiation is also seen in the ability of the antagonists to suppress DA-agonist-induced stereotypies. The differentiation in these experiments is similar to that seen in dopamine D-1 and D-2 receptor binding. The compounds can be classified into three pharmacological subgroups: butyrophenones (e.g., haloperidol) with affinity for D-2 receptors; phenothiazines (e.g., fluphenazine and perphenazine) with affinity for both D-2 and D-1 receptors but with preference for the D-2 receptors; and thioxanthenes (e.g., cis(Z)-flupentixol and cis(Z)-clopenthixol) with equal affinity for D-1 and D-2 receptors, and the selective D-1 antagonist SCH 23390. This compound has the same antistereotypic effect as is seen with the neuroleptics. We have also investigated the effect of the above-mentioned neuroleptics and SCH 23390 after 12 days' treatment and 3-5 days withdrawal. They were given either alone or in combination. When they were given alone a clear differentiation was seen between the groups when mice were tested for methylphenidate antagonism. The thioxanthenes and SCH 23390 retain their ability to antagonize the stereotyped gnawing; the phenothiazines show a reduced effect; and the butyrophenones have almost lost their ability to antagonize the stereotyped behavior.
Animals↗
Pharmacology in vivo of the phenylindan derivative, Lu 19-005, a new potent inhibitor of dopamine, noradrenaline and 5-hydroxytryptamine uptake in rat brain.
Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)
5-Hydroxytryptophan↗
3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake.
A series of 3-phenyl-1-indanamines was synthesized and tested for potential antidepressant activity and for inhibition of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) uptake. Trans isomers were generally potent inhibitors of DA, NE, and 5-HT uptake, while cis isomers preferentially inhibited the uptake of 5-HT. The affinity for the DA-uptake site was very dependent on the aromatic substitution pattern where highest potency was found for 3',4'-dichloro substituted compounds (45). This substitution pattern also resulted in high affinity for the NE-and 5-HT-uptake sites, but potent 5-HT-uptake inhibiting activity could also be obtained with other substitution patterns. Only small amines could be accommodated at the 5-HT-uptake site while larger amines such as piperazine could be accommodated both at the DA-and NE-uptake sites. The observed structure-activity relationships were explained from the results of superimpositions of a trans (45) and cis (72) isomer with 5-HT and DA, respectively, in relation to a proposed three-point binding of the uptake inhibitors at the uptake sites. Finally, comparison of the structures of the 3-phenyl-1-indanamines with other newer bicyclic catecholamine- and/or serotonin-uptake inhibitors revealed common structural elements important for potent DA-, NE-, and/or 5-HT-uptake inhibition.
Animals↗
Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics.
Neuroleptics such as thioxanthenes (cis(Z)-flupentixol and cis(Z)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiazepines.
Adrenergic alpha-Antagonists↗
Inhibition of cholera toxin-induced secretion by neuroleptics.
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Animals↗
Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers.
The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
The antinociceptive effect of ketobemidone in comparison with Ketogin.
The antinociceptive effect of ketobemidone, A 29 (N,N-dimethyl-3,3-diphenyl-l-methyl-alkylamine chloride) and Ketogin (combination of ketobemidone and A 29) has been investigated in mice and rats. The hot plate, grid shock, phenylquinone and Randall-Selitto test were used. Ketobemidone caused antinociception whereas A 29 was without effect. Ketogin was in comparison with ketobemidone more potent. The mechanism of the potentiating effect of A 29 remains to be clarified.
Allylamine↗
Neuroleptic classification: implications for tardive dyskinesia.
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Amphetamine↗