Identification of adrenoceptor subtype-mediated changes in the density of synapses in the rat visual cortex.

Both serotonin and noradrenaline affect synapse formation and maintenance in the CNS. Although we previously demonstrated that serotonin regulates synaptic density via activation of serotonin(2A) receptor, it was still unclear which receptor subtype mediates the function of noradrenaline. In the present study we tried to identify the noradrenaline receptor (adrenoceptor) subtype, which could regulate the density of synapses in the rat visual cortex. Selective antagonists and/or agonists of adrenoceptor subtypes were administered to six weeks old rats. Changes in the density of axodendritic synapses were quantitatively examined in lamina I, where noradrenaline rather than serotonin is known to regulate the density of synapses. The alpha1 adrenoceptor antagonists (prazosin and 2-{[b-(4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone) decreased the number of synapses in a dose-dependent manner. In contrast, administrations of the alpha1-agonist (methoxamine) increased the density of synapses. The beta1 adrenoceptor antagonist (atenolol) had no effect on the density of synapses. The alpha2-antagonist (rauwolscine) increased synaptic density, whereas the beta2-antagonist (ICI-118,551) decreased synaptic density. Simultaneous treatments with the alpha1-antagonist and alpha1-agonist caused the alpha1-agonist to competitively block the effect of the alpha1-antagonist and recover the density of synapses to the control values. In addition, the alpha1-antagonist/agonist appeared to show a reverse effect on the changes in synaptic density following alpha2- or beta2-antagonist treatment by acting via the alpha1 receptor. Moreover, decreased synaptic density when a selective noradrenergic neurotoxin (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) was counterbalanced by the alpha1-agonist. These data suggest that noradrenaline regulates the density of synapses in the rat visual cortex primarily via the alpha1 receptor subtype. Both serotonin(2A) and alpha1 receptors are known to couple with phospholipase C, which has been shown to increase intracellular calcium. It may help us to understand the underlying mechanisms for synaptic plasticity in the CNS.