Noradrenergic augmentation strategies in the pharmacological treatment of depression and schizophrenia : an experimental study

Abstract

The pharmacological treatment of depression and schizophrenia, two major psychiatric disorders, is largely based on modulation of central monoaminergic neurotransmission. However, currently available pharmacological treatment alternatives possess a relatively modest clinical efficacy, making them less than optimal. The present series of studies, using in vivo electrophysiological, biochemical and behavioral techniques in rats, aim at the disclosure of mechanisms whereby an augmented clinical efficacy of antidepressant, as well as antipsychotic, drugs may be achieved.

Pindolol, a partial beta-adrenoceptor agonist with affinity for the serotonin (5-HT) ]A receptor, has been claimed to shorten the clinical onset of action of selective serotonin reuptake inhibitors (SSRIs); an effect suggested to result from an antagonistic action of pindolol on somatodendritic 5-HT1A autoreceptors, reversing the acute, inhibitory, effect of SSRIs on serotonergic neuronal activity. However, upon systemic administration, pindolol, in contrast to the selective 5-HT1A receptor antagonist WAY 100635, was unable to reverse the inhibitory effect of an SSRI on 5-HT neuronal activity. This observation, in conjunction with other data from our laboratory, rather indicates that pindolol exerts a weak agonistic activity on sontatodendritic 5-HT1A autoreceptors and thus may shorten the delayed onset of action of SSRIs by a mechanism unrelated to 5-HT1A receptor blockage.

In other experiments, repeated treatment with a noradrenaline reuptake inhibitor (NRI), was found to cause a gradual increase in noradrenaline nerve-terminal output and a partial recovery of the initially suppressed noradrenergic electrophysiological activity during the course of the treatment, consonant with a partial desensitization of the presynaptic inhibitory feedback mechanism. Administration of a low dose of an alpha2-adrenoceptor antagonist enhanced noradrenaline neuronal activity, as well as nerve-terminal. release, most markedly in chronically, but also acutely, treated animals; tentatively indicating an advantageous effect of this drug combination in the treatment of at least some forms of depression.

Modulation of central serotonergic function is thought to mediate the clinical action of several classes of antidepressant drugs, and previous data demonstrate a central noradrenergic regulation of midbrain scrotonergic neurons. We have now observed that acute administration of die highly selective NRI reboxetine increases the firing rate of serotonin neurons in the dorsal raphe nucleus, which, in turn, results in an enhanced cortical output of serotonin; effects that may have bearing on the clinical action of selective NRls. Analogous studies of the effects of NRIs on the function of the mesolimbocortical dopamine system revealed several effects. Thus, acute administration of reboxetine increased burst firing, but not basal firing rate, of dopamine neurons in the ventral tegmental area and concomitantly enhanced doparmine output in the prefrontal cortex, but not in the nucleus accumbens, This effect of reboxetine on cortical dopamine release is similar to that caused by alpha2-adrenoceptor antagonists as well as most atypical antipsychotic: drugs.

Previous observations have shown that concomitant treatment with an cc, adrenoceptor antagonist my markedly enhance the effect of a dopamine D2 receptor antagonist, i.e. a classical antipsychotic drug, on prefrontal dopamine output as well as in the conditioned avoidance response (CAR) test, a preclinical test of antipsychotic efficacy with high predictive validity, supporting the observed advantageous clinical antipsychotic effect of this drug combination. Given the similar effects of alpha2-adrenoceptor blockage and noradrenaline reuptake inhibition on cortical dopamine function, we investigated the effect of reboxetine in the same experimental paradigm. Pretreatment with reboxetine significantly enhanced the effect of the D 2 receptor antagonist on cortical dopamine output as well as in the CAR test, without affecting catalepsy scores. Our data thus indicate that noradrenaline reuptake inhibition may augment the clinical effect of classical antipsychotic drugs in the treatment of schizophrenia, tentatively with particular regard to negative and cognitive symptoms.