Marie-Louise Wadenberg

Bio: Marie-Louise Wadenberg is an academic researcher from Stockholm University. The author has contributed to research in topics: Catalepsy & Raclopride. The author has an hindex of 8, co-authored 9 publications receiving 582 citations. Previous affiliations of Marie-Louise Wadenberg include Astra.

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

Abstract: 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

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

Abstract: 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 μg·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.

Abstract: 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.

Serotonin receptors: their key role in drugs to treat schizophrenia.

Abstract: Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.