Marie-Louise Wadenberg

Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat

The present paper reviews a series of experiments aimed at elucidating the interaction between specific dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors in the mediation of extrapyramidal motor functions in the rat. There is strong evidence to suggest that (1) the catalepsy produced by dopamine D1 or D2 receptor antagonists can be completely antagonized by the administration of 5-HT1A receptor agonists acting at 5-HT autoreceptors in the median raphe nucleus; (2) the catalepsy produced by a dopamine D2 receptor antagonist can be completely antagonized by treatment with a 5-HT2A/C receptor agonist; and (3) the catalepsy produced by blockade of either dopamine D1 or D2 receptors is not affected by the administration of a 5-HT2A/C receptor antagonist. The emerging picture of DA/5-HT receptor interactions in the mediation of extrapyramidal motor functions is of great interest in relation to present efforts to develop new atypical neuroleptics with affinity for brain 5-HT receptor subtypes, and also for the observations that new serotonin selective re-uptake inhibiting antidepressants can produce parkinson-like symptoms in vulnerable individuals.

Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg−1 sc −20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg−1 sc. The number of intertriai crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg−1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg−1 sc, or by 8-OH-DPAT, 0.1 mg kg−1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in “immobility” (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg−1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg−1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg−1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg−1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects

Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat.

The local application of (-)sulpiride, 200 ng side-1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompanied by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (-)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [(DO-PAC + HVA) DA-1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-)sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum.

Effects of 8-OH-DPAT on motor activity in the rat.

The administration of 8-OH-DPAT to rats produced a dose-dependent suppression of spontaneous locomotor activity in an open field arena. 8-OH-DPAT was administered in the dose range 12.5-1,600 micrograms.kg-1 SC. Vertical activity (rearing) was more sensitive to the treatment than horizontal activity (locomotion), both in terms of potency and efficacy. The activity along the walls of the open field arena (peripheral activity) was increased, and the rearing activity was decreased, relative to total horizontal activity and total activity, respectively. There were no effects by 8-OH-DPAT on treadmill locomotion. The rectal temperature was decreased by 8-OH-DPAT administration, not only in animals tested in the open field, but also in animals with an increased body temperature, produced by treadmill locomotion.

Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat

In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mgkg−1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg−1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg−1 sc) nor that induced by SCH 23390 (0.2 mg kg−1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13–2.0 mg kg−1 sc). Administration of SCH 23390 (0.0125–0.2 mg kg−1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertriai crosses. At the higher doses, 0.05 and 0.2 mg kg−1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg−1 sc) and SCH 23390 (6 μg kg−1 sc) in the present study.

Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat.

The effects of 5-HT2 receptor blockade on the ability of a dopamine (DA) D2 receptor antagonist to produce suppression of conditioned avoidance response (CAR) and to produce catalepsy in rats were examined. It was found that ritanserin (2 mg kg-1 s.c.) enhanced the raclopride (0.1 mg kg-1 s.c.)-induced suppression of CAR without affecting raclopride-induced catalepsy at either maximal (4 mg kg-1 s.c.) or submaximal (0.2 mg kg-1 s.c.) doses. Considering the CAR performance as an index of mesocorticolimbic dopaminergic functions, it is concluded that 5-HT2 receptor blockade confers a limbic profile on the DA D2 receptor antagonist.

Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat

Administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg kg-1 SC) completely antagonised the catalepsy produced by the dopamine (DA) D2 receptor antagonist raclopride (16 mg kg-1 SC). This effect by 8-OH-DPAT was in turn completely antagonised by treatment with the new 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin [(S)-UH-301] (3.5 mg kg-1 SC), but not by the mixed 5-HT1 receptor/beta-adrenoceptor antagonist (-)pindolol (2.0 mg kg-1 SC). The failure by (-)pindolol to antagonise the effects of 8-OH-DPAT on raclopride-induced catalepsy could be due to its beta-receptor-blocking properties, since by themselves both (-)pindolol and the selective beta-adrenoceptor antagonist betaxolol (4 mg kg-1 SC) at least partially antagonised the raclopride-induced catalepsy. The present results provide further support for specific interactions between 5-HT1A and DA D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat.

Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat

The local application of 8-OH-DPAT (0.5 or 2.5 micrograms/rat, 10 min) into the median, but not the dorsal, raphe nucleus resulted in a reversal of the catalepsy induced by the DA D2 receptor blocking agent raclopride (16 mg kg-1 s.c., 60 min). The local application of 8-OH-DPAT into serotonergic projection areas of the forebrain (dorso-lateral neostriatum, accumbens core; 0.5 or 2.0 micrograms/side) did not affect raclopride-induced catalepsy. Thus, the 5-HT1A autoreceptor in the median raphe nucleus is an important site of action for the reversal of DA D2 receptor antagonist-induced catalepsy by systemic administration of 5-HT1A receptor agonists, in the rat.

Suppression of conditioned avoidance by 8-OH-DPAT in the rat

Rats were trained to perform an aversely motivated discriminative task in a shuttle-box. The conditioned avoidance response was selectively suppressed by 8-OH-DPAT in a dose-dependent manner (25–100 μg·kg−1). There were no statistically significant deficits in discriminative performance. The present results suggest antipsychotic-like properties of 8-OH-DPAT.

Supraspinal mediation of dopamine-serotonin interactions in extrapyramidal motor functions in the rat

The effects of intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administrated 8-OH-DPAT on catalepsy, induced by the specific DA D2 antagonist raclopride (16 mg kg-1 s.c.), were studied in rats. It was found that 8-OH-DPAT (0.5 or 2.0 micrograms kg-1) injected by the i.c.v. route produced a statistically significant of raclopride-induced catalepsy at both doses. In contrast, 8-OH-DPAT (0.2 or 2.0 micrograms kg-1) given by the i.t. route had no statistically significant effect on the raclopride-induced catalepsy. These results suggest that the antagonistic effect of 8-OH-DPAT on catalepsy, induced by DA blocking agents, is primarily mediated at the supraspinal level.