We are using an in vitro model to study the release of acetylcholine (Ach) and norepinephrine (NE) from isolated strips of the rat urinary bladder. In preliminary experiments, Ach release evoked by electrical stimulation of the parasympathetic postganglionic nerve terminals in the urinary bladder was modulated in an entirely different way that in terminals in other organs such as the heart or gut. We found that presynaptic facilitatory M1 and inhibitory M2 muscarinic receptors operate in the rat bladder and subsequent reproduced this finding in the human bladder. We propose that the inhibitory M2 receptors operate when there are low levels of Ach as during urine storage, whereas during micturition high endogenous levels of Ach activate the facilitatory M1 mechanism and induce facilitation of Ach release. Thus, these presynaptic sites could be the primary target for drugs used to control bladder hyperactivity. The facilitated release is inhibited by muscarinic antagonists, drugs frequently used in the treatment of bladder dysfunction. In addition, we have found facilitatory alpha1 adrenoceptors on the parasympathetic nerve endings in the bladder. Both groups of receptors may exhibit plasticity in response to pathophysiologic changes in the bladder. This may explain for example, the observation that the selective alpha1 antagonist, terazosin significantly diminishes bladder pressure in patients with neuropathic but not normal bladders. Our aim is to examine plasticity of these modulatory receptors in rat models of obstructed micturition and neuropathic bladder function following spinal cord injury. Our hypotheses are a) that the facilitatory M1 and inhibitory M2 receptors will downregulate due to higher levels of Ach (bladder hyperactivity) thereby reducing both facilitation and inhibition, b) NE release will be increased due to down-regulation of inhibitory presynaptic M2 receptors on adrenergic nerve terminals, c) the increased release of NE will enhance ACh release through an effect at presynaptic alpha1 adrenoceptors. Presynaptic modulation of ACh release in the hyperactive bladder offers an alternative mechanism of action for drugs used in the treatment of these disorders and opens new avenues for development of drugs acting selectively on cholinergic nerve terminals.