Clinical data and animal studies on adaptive receptor changes occurring in depression and after antidepressive treatment: A hypothesis of antidepressive action

Abstract

The clinical and animal studies on the effects of antidepressant treatments on receptor-related changes in the functioning of central neurotransmitter systems, are reviewed. The great variability in individual clinical responses make it impossible to formulate one coherent hypothesis about adaptive receptor changes occurring in human beings. Nevertheless, it is concluded that neuroadaptive responses found in the catecholaminergic systems (dopaminergic and adrenergic alpha-1 receptors) might be important as the underlying mechanism for therapeutic efficacy in depression of antidepressant drugs (AD) and electroconvulsive shock treatment (ECS). The animal studies conducted in our laboratory over the last decade provide evidence for the existence of limbic neurotransmitter modulatory mechanism of action of AD and ECS. It is suggested that at least in the limbic areas (i.e. in the hippocampus and nucleus accumbens, the main structures of the mesolimbic system), AD and ECS produce bidirectional effects. On the one hand they were found to reduce 'inhibitory' signals mediated through serotonergic, GABA-ergic and alpha-2 adrenergic receptors while on the other hand they enhanced 'excitatory' central processes mediated via the dopaminergic and adrenergic alpha-1 receptors. Confirmation of this hypothesis was obtained from behavioral experiments (locomotor and exploratory activity), consisting of microinjections of selective receptor agonists and antagonists into the hippocampus and nucleus accumbens, following the chronic administration of different AD'S and ECS. We propose, therefore, that the mechanism of action of antidepressant therapies should be considered from the anatomical and receptor viewpoint, the crucial element being the 'tuning' of the signals within the limbic areas. The consequence of this mechanism is an enhancement of these processes which can be defined as 'activatory', in terms of their mood elevating effects. The final effect of antidepressant therapy emerges as a result of transmitter interactions and disinhibitory processes. The 'limbic modulatory neurotransmitter mechanism' is thus suggested to be responsible for the effect of antidepressant treatment.