R. Schreiber

Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance.

An essential element of the signalling cascade leading to synaptic plasticity is the intracellular second messenger molecule guanosine 3,5-cyclic monophosphate (cGMP). Using the novel, potent, and selective inhibitor Bay 60-7550, we show that the enzyme 3,5-cyclic nucleotide phosphodiesterase type 2 (PDE2) is responsible for the degradation of newly synthesized cGMP in cultured neurons and hippocampal slices. Inhibition of PDE2 enhanced long-term potentiation of synaptic transmission without altering basal synaptic transmission. Inhibition of PDE2 also improved the performance of rats in social and object recognition memory tasks, and reversed MK801-induced deficits in spontaneous alternation in mice in a T-maze. Our data provide strong evidence that inhibition of PDE2 can improve memory functions by enhancing neuronal plasticity.

5-HT1A Receptors in Anxiety

Brain 5-HT receptors have been classified in at least six subtypes (5-HT1A, 1B, 1C, 1D, 2 AND 3; Peroutka, 1988), among which the 5-HT1A subtype has been the focus of intense research during the last few years. This receptor type is located both presynaptically on the 5-HT cell bodies (somatodendritic receptors), predominantly in the dorsal and median raphe nuclei and postsynaptically, predominantly in the limbic system (Verge et al., 1985; Weissmann-Nanopoulos et al., 1985). Activation of presynaptic 5-HT1A receptors with 5-HT1A ligands inhibits serotonergic neurotransmission (Hamon et al., 1988; Hjorth and Magnusson, 1988; Sharp et al., 1989a, b) and the physiological role of these receptors is probably to provide the brain with an autoinhibitory feedback system controlling 5-HT neurotransmission. At the postsynaptic level, activation of 5-HT1A receptors results in neuronal inhibition, the consequences of which are not well understood (e.g. Sprouse and Aghajanian, 1988; Martin and Mason, 1987).

5-HT1A receptors are differentially involved in the anxiolytic- and antidepressant-like effects of 8-OH-DPAT and fluoxetine in the rat

Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.

Somatodendritic 5-HT1A receptors are critically involved in the anxiolytic effects of 8-OH-DPAT.

In the rat shock-induced ultrasonic vocalization test, the anxiolytic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) obtained after systemic (IP) and intracerebral injection into the dorsal raphe nucleus (DRN) were selectively abolished by pretreatment with the 5-HT1A receptor antagonist WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride]. This blockade was demonstrated both after systemic and DRN application of WAY-100635. Therefore, it is concluded that the anxiolytic effects of 8-OH-DPAT are mediated by activation of somatodendritic 5-HT1A receptors.

Differentiation of 8-OH-DPAT and Ipsapirone in Rat Models of 5-HT1A Receptor Function

Because the anxiolytic/antidepressant profile of 5-HT1A receptor ligands may be related to their intrinsic activity at 5-HT1A receptors, we characterized the apparent intrinsic activities of 8-OH-DPAT and ipsapirone in several models reflecting pre- or postsynaptic 5-HT1A receptor activation. Presynaptically, as measured with electrophysiological techniques, 8-OH-DPAT and ipsapirone acted as full agonists; whereas in some behavioral models, which presumably reflect postsynaptic activity (i.e., 5-HT syndrome or circling behavior), as well as in the hippocampal adenylate cyclase assay, ipsapirone but not 8-OH-DPAT had mixed agonist/antagonist properties. In a drug discrimination and body temperature model, however, 8-OH-DPAT and ipsapirone appeared to be full agonists both after systemic administration and local application into the dorsal raphe nucleus and the hippocampus. Similar results have been obtained when 8-OH-DPAT and ipsapirone were applied after lesion of the brain serotonergic system by 5,7-DHT. These results suggest that ipsapirone may act as a full agonist at some post-synaptic 5-HT1A receptors. The experiments confirm earlier suggestions that the apparent intrinsic activity of a 5-HT1A ligand may differ at pre- vs postsynaptic 5-HT1A receptors. In addition, it is suggested that the compound’s intrinsic activity also may differ at various postsynaptic 5-HT1A receptor populations. Whether this finding reflects the occurrence of regio-specific spare receptors and/or the existence of subtypes of 5-HT1A receptors is presently unclear.

5-HT1A receptors and alcohol preference

Abstract Microinjection and lesion studies support the involvement of presynaptic 5-HT1A receptors in the reduction of ethanol (EtOH) intake induced by the selective 5-HT1A receptor agonists 8-OH-DPAT and ipsapirone in selectively bred Wistar rats, with high preference for EtOH over water in a two-bottle free choice situation.

Serotonin und Angst: Die Rolle von Serotonin1A-Rezeptoren am Beispiel von Ipsapiron

Vor ca. drei Jahrzehnten begann mit der Entdeckung der Anxiolytika vom Benzodiazepin-Typ eine neue Ara in der Psychopharmakologie (Sternbach 1973). Bis heute gelten Pharmaka dieser und einiger anderer Substanzklassen als Mittel der Wahl zur Behandlung von Angstzustanden; sie werden in groser Zahl verschrieben und dominieren das Feld der Tranquilizer und Hypnotika. Gemeinsam ist diesen Substanzen die Wechselwirkung mit spezifischen Bindungsstellen im Gehirn, den sog. Benzodiazepin-Rezeptoren. Sie sind ein Teil des GABA-Rezeptor/Cl--Ionenkanal-Komplexes. Anxiolytisch wirksame Benzodiazepine fordern die Bindung des Neurotransmitters Gamma-Aminobuttersaure (GABA) an seinen Rezeptor (GABAA-Rezeptor) und verstarken so die inhibitorische GABAerge Neurotransmission, welche mit einem vermehrten Einstrom von Cl--Ionen verbunden ist (Tallman u. Gallager 1985). Diese Forderung der GABA-Wirkung liegt auch der Anxiolyse durch Benzodiazepine zugrunde.