Sven Ove Ögren

Role of serotonin in memory: facilitation by alaproclate and zimeldine

The effects of alaproclate and zimeldine on memory retrieval were examined in male Swiss Webster mice using a one-trial inhibitory avoidance task. All drugs were administered IP prior to the retention test 24 h after training. Both drugs were found to facilitate memory retrieval significantly in a dose-and time-dependent fashion that could not be explained in terms of non-specific effects of the drug (illness, lack of motility, etc.) at the time of the test. The temporal effects of alaproclate and zimeldine on memory closely followed their course of concentration of the drug within the blood stream. The facilitation of retrieval induced by alaproclate and zimeldine was blocked by the putative serotonergic receptor agonist quipazine but not blocked by the antagonist cyproheptadine. Pretreatment with quipazine alone in a group of animals trained to a shock level which normally results in high levels of suppression was not sufficient to produce memory impairment, suggesting that quipazine was probably antagonizing the facilitative effects of alaproclate and zimeldine directly, rather than overriding the facilitation through an indirect action on retrieval in general. The present results lend further support to the suggestion that serotonin plays a significant role in memory.

D1- and D2-receptor antagonist induce catalepsy via different efferent. Striatal pathways

The D1- and D2-receptor antagonists SCH 23390 and raclopride produced a dose-dependent catalepsy as studied by a vertical grid test in the male rat. The benzodiazepine antagonist Ro 15-1788 antagonized catalepsy induced by the D2-receptor antagonist raclopride while it failed to block the action of SCH 23390. The antimuscarinic drug scopolamine reduced and the γ-aminobutyric acid (GABA) agonist muscimol enhanced catalepsy induced by both SCH 23390 and raclopride. The results suggest that D2-antagonist-induced catalepsy is mainly mediated via activation of the strio-pallidal GABA pathways whereas D1-receptor antagonist induced catalepsy is mainly mediated via increased activity in the nigrothalamic GABA pathways.

Evidence for a possible functional interaction between serotonergic and cholinergic mechanisms in memory retrieval

A total of three experiments were conducted. In Experiment 1, the dose-dependent effects of the pretest administration of the serotonergic agonist alaproclate and the selective muscarinic cholinergic agonist oxotremorine, alone and in combination, were assessed in a one-trial inhibitory avoidance task. A clear dose-dependent enhancement of performance was demonstrated as a result of all three treatment conditions, which could not be explained in terms of nonspecific effects of the drugs on behavior in general. In addition, the facilitation of retrieval performance produced by the combined treatment of alaproclate and oxotremorine was observed at dose levels well below those observed following administration of either compound alone. In Experiment 2 attempts were made to block the enhancements of retention resulting from the different treatment conditions (alaproclate, oxotremorine, or the combination of alaproclate and oxotremorine) by pretreating the mice with either scopolamine (a muscarinic cholinergic antagonist) or quipazine (a serotonergic agonist). The results of these experiments indicate that (a) quipazine completely blocked the enhancement of retrieval resulting from alaproclate but not that following oxotremorine or oxotremorine in combination with alaproclate, while (b) scopolamine blocked the enhancement of retrieval resulting from oxotremorine alone as well as that resulting from alaproclate plus oxotremorine but failed to block the memory enhancement resulting from alaproclate. The present results lend further support to the view that both serotonin and acetylcholine play important roles in memory retrieval. More importantly, the results of the present series of experiments provide additional support for a functional interaction between the serotonergic and cholinergic nervous systems in the mediation of behavior.

Effects of typical and atypical antipsychotic drugs on two-way active avoidance. Relationship to DA receptor blocking profile.

The dose-dependent and time-dependent effects of the novel antipsychotic compound remoxipride, as well as the reference compounds chlorpromazine, clozapine, haloperidol, pimozide and sulpiride upon the retention of two-way active avoidance (conditioned avoidance responses, CARs) were studied in male rats. The dose-dependent effects of remoxipride as well as haloperidol and chlorpromazine on the acquisition of CARs were also studied. The acquisition and retention of CARs were tested in shuttleboxes using a 1.0-mA shock intensity and a 10-stone signal (1000 Hz). All the compounds studied, including remoxipride, caused a dose-dependent impairment of acquisition and retention of CARs. The effect of remoxipride on CAR acquisition correlated with remoxiprides effectiveness to block the hyperactivity induced by the dopamine (DA) agonist apomorphine. Unlike chlorpromazine and haloperidol, the potency of remoxipride and clozapine for antagonising CAR retention was found at dose levels much lower than those producing cataleptic effects or blocking apomorphine-induced stereotypies. Based on the DA receptor blocking profile and the relative effectiveness to block CAR it is concluded that the mechanism(s) by which clozapine and remoxipride affect CAR differ from typical neuroleptic drugs. This difference may reflect an action upon different subtypes of functionally coupled DA D2 receptors.

Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior

Male rats were given 6-hydroxydopamine-induced lesions of the locus coeruleus (LC) or the dorsal noradrenergic bundle (DNAB), prior to the measurement of locomotor and rearing activity induced by D-amphetamine. The increased locomotor activity induced by D-amphetamine (1.8 mg/kg) was significantly attenuated by both the LC and the DNAB lesions. The stimulatory effect of the 7.2 mg/kg dose of amphetamine was attenuated by the LC lesion, whereas the DNAB lesion potentiated this effect. The LC lesion also attenuated rearing induced by the 7.2 mg/kg dose of amphetamine. These results suggest some involvement of central noradrenergic neurons in the activity induced by amphetamine in the rat.

The putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin antagonizes the antinociceptive effect of morphine **

The effect of the selective 5-hydroxytryptamine (5-HT-1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on nociception and morphine analgesia was tested with the tail-flick method in mice. 8-OH-DPAT (0.06-1.0 mg/kg) had no apparent effect on the general behavior of the animals and did not change their reactivity to stimulation with noxious radiant heat. The compound did, however, dose-dependently attenuate the antinociception induced by administration of morphine hydrochloride (5.0 and 10.0 mg/kg). Thus, stimulation of a subpopulation of serotonin receptors may counteract the antinociceptive effect of morphine in the tail-flick test.

Involvement of spinal serotonergic pathways in nociception but not in avoidance learning

The effects of selective lesions of the descending serotonergic (5-HT) pathways on analgesia and avoidance deficit induced by the 5-HT releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) were investigated in male rats. Intrathecal injection of 5,6-DHT (20 μg/rat) reduced the uptake of labelled 5-HT into spinal synaptosomes by approximately 85% but did not significantly affect the uptake of noradrenaline. The lesions produced a significant hyperalgesia and strongly attenuated the analgesic effect of PCA in the hot-plate test. In the flinch-jump test 5,6-DHT lesioned rats receiving PCA did not differ from the saline control group. Spinal lesioning did not, however, affect one-way active avoidance performance and did not prevent the marked impairment of avoidance performance induced by PCA. Thus, the avoidance deficit caused by PCA is independent of the descending serotonergic pathways and of the analgesia induced by PCA. These results support the view of a differential involvement of the ascending and descending serotonergic projections in behavioural processes controlled by aversive stimuli.