Fridolin Sulser

A possible common mechanism of action of antidepressant treatments

SummaryThe response of the norepinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electroconvulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after the administration of a single dose or short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.

Action of mianserin and zimelidine on the norepinephrine receptor coupled adenylate cyclase system in brain: Subsensitivity without reduction in β-adrenergic receptor binding

The present experiments were undertaken to ascertain whether non-tricyclic, clinically effective, antidepressant drugs such as the tetracyclic mianserin and the serotonin uptake inhibitor, zimelidine, cause alterations of central noradrenergic receptor systems similar to those elicited by classical tricyclic antidepressants, MAO inhibitors and ECT. Like desipramine (DMI), mianserin and zimelidine caused, after chronic administration, a significant reduction in the sensitivity of the cyclic AMP response to (R)-norepinephrine while a single dose of the drugs did not affect the neurohormonal response. The basal levels of the nucleotide were not changed by the antidepressant drugs following acute or chronic administration. While the noradrenergic subsensitivity caused by DMI was linked to a reduction in the Bmax value of 3H-dihydroalprenolol binding, the subsensitivity caused by mianserin and zimelidine was not associated with a decreased density of β-adrenergic receptors. In accord with these data on β-adrenergic receptor binding, the responsivenss of the adrenergic cyclic AMP generating system to the β-adrenergic agonist, (R)-isoproterenol, was significantly reduced following chronic treatment with DMI but not with mianserin or zimelidine. The results provide further evidence for the theory that the delayed therapeutic action of different prototypes of antidepressant treatments may be related to the delayed change in noradrenergic receptor function and that a reduction in the density of β-adrenergic receptors is only one mechanism by which the sensitivity of the system is regulated.

Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain.

Abstract The i.p. administration of a single dose of 10 mg/kg of p-chloroamphetamine to rats causes a reduction in the activity of cerebral tryptophan hydroxylase and a decrease in the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain for as long as 4 months after injection. 2 weeks after injection, the activity of tryptophan hydroxylase and the level of 5-hydroxytryptamine in brain are reduced by 59 and 53% respectively. The irreversible tryptophan hydroxylase inhibitor, p-chlorophenylalanine, also decreases the brain level of 5-hydroxytryptamine; however, this effect has disappeared 2 weeks after injection.

ADAPTIVE MECHANISMS OF THE NORADRENERGIC CYCLIC AMP GENERATING SYSTEM IN THE LIMBIC FOREBRAIN OF THE RAT: ADAPTATION TO PERSISTENT CHANGES IN THE AVAILABILITY OF NOREPINEPHRINE (NE)

Abstract— The noradrenergic cyclic AMP generating system in slices of the limbic forebrain of rats displays characteristics which are compatible with those of a central NE receptor. The cyclic AMP response to a Kmax concentration of NE (concentration of NE which elicits maximal increase in the level of cyclic AMP) is significantly enhanced in slices from reserpinized animals, although the Ka value of NE (concentration of NE eliciting half‐maximum response) was not significantly changed. Chemosympathectomy with 6‐hydroxydopamine (6‐OHDA) significantly enhanced the activity of the system to NE and isoproterenol but not to adenosine and reduced the Ka value for NE. The changes in the reactivity of the cyclic AMP generating system following 6‐OHDA administration appear to be related to a decrease in the availability of NE and not to that of other neurotransmitters as protection by desipramine (DMI) of noradrenergic neurons against the neurotoxic action of 6‐OHDA prevented the development of supersensitivity to NE. Conversely, and independent of the actual concentration of NE in brain tissue, a persistent increase in the availability of NE caused by prolonged MAO inhibition lead to a marked decrease in the reactivity of the cyclic AMP generating system. The results provide further evidence for a regulatory mechanism in the CNS involving the noradrenergic receptor that adapts its sensitivity to NE in a manner inversely related to the degree of its stimulation by the catecholamine.

The noradrenergic cyclic AMP generating system in the limbic forebrain: Pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.

The relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine

SummaryThe relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine has been investigated. The blockade of norepinephrine synthesis by the tyrosine hydroxylase inhibitor α-MT abolishes the central stimulatory action of amphetamine but not that evoked by tetrabenazine in DMI pretreated rats. In contrast, depletion of norepinephrine by α-MMT prevents the central stimulation evoked by the DMI-tetrabenazine combination but not that elicited by amphetamine. The α-methylated tyrosine derivatives do not interfere with either the metabolism of amphetamine and DMI or their entry into the brain. The results of the present studies, thus, are consistent with the views that the central action of amphetamine requires an uninterrupted synthesis of brain norepinphrine whereas a rapid release of norepinephrine from its storage sites is essential for the behavioral stimulation elicited by tetrabenazine in DMI pretreated rats.

p-Chloroamphetamine—inhibition of cerebral tryptophan hydroxylase

Abstract Earlier experiments have suggested that the simultaneous decrease in the levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindole acetic acid (5HIAA) in brain following the administration of p -chloroamphetamine and p -chloromethamphetamine may be the consequence of an inhibition of the synthesis of cerebral 5HT. In the present investigations, the effects of these drugs have been examined on the activity of cerebral tryptophan hydroxylase. The addition in vitro of either p -chloroamphetamine or p -chloromethamphetamine does not reduce the activity of tryptophan hydroxylase isolated from brainstems of rats. Under similar conditions, p -chlorophenylalanine causes marked inhibition. However, when tryptophan hydroxylase was assayed in preparations obtained from brains of rats treated 16 hr previously with p -chloroamphetamine, a dose-related reduction in the activity of the enzyme was observed. Experiments involving various combinations of enzyme preparations from control rats and from rats pretreated with p -chloroamphetamine do not indicate the presence of an inhibitor in the preparations isolated from rats pretreated with the drug. Moreover, the reduction in enzyme activity was not removed by dialysis. Kinetic studies showed that the K m values for tryptophan and DMPH 4 were the same for the enzyme isolated from control rats and from rats pretreated with p -chloroamphetamine. The reduction of cerebral 5HT and the decrease in the activity of tryptophan hydroxylase occur simultaneously; both effects are still present 6 days following a single dose of 10 mg/kg of p -chloroamphetamine. It is concluded that the inhibition of cerebral tryptophan hydroxylase by p -chloroamphetamine can satisfactorily explain the prolonged reduction in the levels of 5HT and 5HIAA in brain

Regulation of recognition and action function of the norepinephrine (NE) receptor-coupled adenylate cyclase system in brain: Implications for the therapy of depression

Abstract In this paper, the characteristics and the regulation of the norepinephrine (NE) receptor-coupled adenylate cyclase system with its β-adrenoceptor sub-population in brain are reviewed. While α-adrenoceptors in brain are not clearly coupled in an inhibitory fashion to adenylate cyclase, gb-adrenoceptors and a non-β-population of NE receptors in brain tissue are coupled to adenylate cyclase. The NE receptor-coupled adenylate cyclase system displays remarkable plasticity. Both supersensitivity and subsensitivity of the NE-sensitive adenylate cyclase system are of the “homologous” type. Most, if not all, clinically effective antidepressant treatments, including ECT, cause upon chronic administration subsensitivity of the system accompanied by a decrease in the density of β-adrenoceptors. The formation of the NE receptor complex is a prerequisite for the regulation of both the sensitivity of the system and the number of its β-adrenoceptor population. In addition, serotonergic neuronal input is co-required for the down-regulation of β-adrenoceptors by DMI-like drugs, but not for the up-regulation by propranolol. In the absence of serotonergie neuronal input, β-adrenoceptors display characteristics of “uncoupled” receptors. Steroid hormones (adrenocorticoids, sex steroids) have also been shown to alter the biological responsiveness of the system and/or the density of the β-adrenoceptor population, and β-adrenoceptor-mediated phospholipid methylation has been implicated in the regulation of the NE signal transfer through the membrane. The regulation of the number of NE membrane receptors and the efficacy of their coupling to adenylate cyclase represent physiologically important steps in the transfer of the NE signal through the membrane. Consequently, the changes induced by antidepressants at the level of membrane receptor regulation are altering the intensity of the signal transfer and appear to represent a therapeutically relevant biochemical action.

On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain.

The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED100 for striatal HVA increase and the ED50 for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED100 for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol > pimozide > chlorpromazine > thioridazine > clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.

Modification by psychotropic drugs of the cyclic AMP response to norepinephrine in the rat brain in vitro

Tissue slices were prepared from paired areas of the rat hypothalamus and brain stem. Exposure of the brain slices for 6 min to 5×10−5 M norepinephrine (NE) consistently resulted in a 3- to 5-fold increase in the level of adenosine 3′,5′monophosphate (cyclic AMP). Prochlorperazine and 7-hydroxychlorpromazine at 10−5 M antagonized the increase of the cyclic nucleotide elicited by NE in the hypothalamus and the brain stem (p<0.01), while 8-hydroxychlorpromazine and imipramine were effective in only the hypothalamus. The remaining metabolites of chlorpromazine (CPZ), 7-methoxy-CPZ, 3,7-dihydroxy-CPZ, 7-hydroxy-8-methoxy-CPZ, 8-hydroxy-7-methoxy-CPZ, and 7,8-dihydroxypromazine failed to modify the NE-induced cyclic AMP response at 10−5 M. d-Amphetamine and p-chloroamphetamine at a concentration of 10−5 M did not affect the levels of cyclic AMP either in the precence or absence of NE. High concentrations of lithium antagonized the cyclic AMP response to NE in the hypothalamus. None of the drugs altered the basal levels of the cyclic nucleotide in vitro; p-chloroamphetamine, however, markedly reduced the basal level of cyclic AMP after the intraperitoneal injection of the drug.