through serotonergic and noradrenergic effects with the additional possibility of a role for dopamine.Increased synaptic dopamine has often been invoked as relevant to the efficacy of MAOIs. B.RECEPTOR AND POSTRECEPTOR EFFECTS Considerable attention has been paid to the long-term postsynaptic effects of increased neurotransmitters in the synapses.In tests of postsynaptic effects,especially of the tricyclics,cAMP concentrations have consistently decreased rather than increased.In addition,the number of receptors for the neurotransmitters can decrease over the same time course as clinical improvement in patients.Thus,the initial increase in neurotransmitter seen with some antidepressants appears to produce,over time,a compensatory decrease in receptor activity,ie,down-regulation of certain postsynaptic as well as presynaptic receptors. It has long been thought that enhanced serotonergic transmission,albeit mediated through diverse mechanisms,might be a common effect of antidepressants even without an increase in synaptic serotonin.Moreover,selective antagonism of either norepinephrine or serotonin receptors as opposed to that of the 5-HT transporter may lead to enhanced extracellular serotonin due to the complex manner in which these neurotransmitters are regulated. Most recently,long-term intracellular changes involving phosphorylation of various regulatory elements,including those within the nucleus,have been implicated as relevant to antidepressant action.It is possible that effects on certain neurotrophic factors%factors critical to sustained survival and function of neurons in the adult nervous system%may be central to the actions of antidepressants. Clinical studies have indirectly tested the relevance of findings from animals for norepinephrine or serotonin function.The approach has been to reduce the amino acid precursor of serotonin,tryptophan,in the diet and,by implication,the amount of available neurotransmitter in the brain,since tryptophan availability can be rate-limiting in the formation of serotonin.Severely tryptophan-depleted diets reduce plasma tryptophan and acutely reverse antidepressant responses to SSRIs but not to NET inhibitors.Similarly,depletion of the norepinephrine amino acid precursor tyrosine can reverse antidepressant effects of the relatively selective NET inhibitor, desipramine.These findings support the hypothesis that enhanced serotonin and norepinephrine throughput is necessary for the antidepressant actions of the respective transporter inhibitors.However,tryptophan depletion does not consistently worsen the condition of unmedicated depressed patients.Thus,there is still no clear relationship between serotonin and depression or antidepressant mechanisms in general. C.EFFECTS OF SPECIFIC ANTIDEPRESSANTSthrough serotonergic and noradrenergic effects with the additional possibility of a role for dopamine. Increased synaptic dopamine has often been invoked as relevant to the efficacy of MAOIs. B. RECEPTOR AND POSTRECEPTOR EFFECTS Considerable attention has been paid to the long-term postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, especially of the tricyclics, cAMP concentrations have consistently decreased rather than increased. In addition, the number of receptors for the neurotransmitters can decrease over the same time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of certain postsynaptic as well as presynaptic receptors. It has long been thought that enhanced serotonergic transmission, albeit mediated through diverse mechanisms, might be a common effect of antidepressants even without an increase in synaptic serotonin. Moreover, selective antagonism of either norepinephrine or serotonin receptors as opposed to that of the 5-HT transporter may lead to enhanced extracellular serotonin due to the complex manner in which these neurotransmitters are regulated. Most recently, long-term intracellular changes involving phosphorylation of various regulatory elements, including those within the nucleus, have been implicated as relevant to antidepressant action. It is possible that effects on certain neurotrophic factors¾factors critical to sustained survival and function of neurons in the adult nervous system¾may be central to the actions of antidepressants. Clinical studies have indirectly tested the relevance of findings from animals for norepinephrine or serotonin function. The approach has been to reduce the amino acid precursor of serotonin, tryptophan, in the diet and, by implication, the amount of available neurotransmitter in the brain, since tryptophan availability can be rate-limiting in the formation of serotonin. Severely tryptophan-depleted diets reduce plasma tryptophan and acutely reverse antidepressant responses to SSRIs but not to NET inhibitors. Similarly, depletion of the norepinephrine amino acid precursor tyrosine can reverse antidepressant effects of the relatively selective NET inhibitor, desipramine. These findings support the hypothesis that enhanced serotonin and norepinephrine throughput is necessary for the antidepressant actions of the respective transporter inhibitors. However, tryptophan depletion does not consistently worsen the condition of unmedicated depressed patients. Thus, there is still no clear relationship between serotonin and depression or antidepressant mechanisms in general. C. EFFECTS OF SPECIFIC ANTIDEPRESSANTS