S. J. Enna

Huntington's chorea. Changes in neurotransmitter receptors in the brain.

Neurotransmitter-receptor binding sites for apparent muscarinic cholinergic, beta-adrenergic, gamma-aminobutyric acid and serotonin receptors were measured in the caudate nucleus and frontal cerebral cortex from post-mortem brains of 16 patients with Huntingtons chorea and 16 controls. In addition, the samples were assayed for the gamma-aminobutyric-acid-synthesizing enzyme, glutamic acid decarboxylase, and for the acetylcholine-synthesizing enzyme, choline acetyltransferase. In the caudate nucleus of choreic brain, both enzyme activities were markedly lower, with significant decreases in muscarinic cholinergic and serotonin receptor binding, whereas enzyme activities and receptor binding were unchanged in the cerebral cortex. By contrast, gamma-aminobutyric acid and beta-adrenergic receptor binding were not significantly different in choreic and control caudate nucleus or cortex, suggesting that, despite the loss of gamma-aminobutyric-acid-synthesizing ability in the corpus striatum, gamma-aminobuytric acid mimetic drugs might alleviate the movement disorders in Huntingtons chorea.

Multiple Bradykinin Receptors: Results of Studies Using a Novel Class of Receptor Antagonists

Bradykinin is a nonapeptide that is generated in plasma and tissues in response to injury and infection. Once released, bradykinin exhibits physiological effects suggesting it is a mediator of the pain and inflame-mation associated with a variety of pathological conditions. Physiological effects include the stimulation and sensitization of nociceptive afferent neurons, vasodilation, increased vascular permeability and enhanced fluid secretion from epithelia. These actions are mediated by specific membrane receptors for bradykinin that exist in many tissues, including the nervous system, smooth muscle, epithelia and fibroblasts. Recently, a series of bradykinin analogues was described (Vavrek and Stewart, 1985) which includes specific, competitive antagonists of bradykinin-induced contraction of guinea pig ileum and rat uterus in vitro and of bradykinin-induced hypotension in vivo. These compounds hold great promise as novel analgesic/ anti-inflammatory agents and permit, for the first time, assessment of the physiological and pathophysiological roles of bradykinin. In the present report we describe results of studies of the effects of the antagonists on bradykinin receptor binding, receptor-coupled transduction systems, isolated smooth muscle, and in vivo animal models of pain and hyperalgesia. The results suggest that pharmacologically distinct types of bradykinin receptors may exist in different tissues.

(±)-Terodiline; an Mi-selective muscarinic receptor antagonist. In vivo effects at muscarinic receptors mediating urinary bladder contraction, mydriasis and salivary secretion

The affinity and selectivity of racemic terodiline (N-tert-butyl-1-methyl-3,3-diphenylpropylamine HCl) for muscarinic receptor subtypes was determined from functional responses of rabbit vas deferens (M1), guinea pig atria (M2) and bladder detrusor muscle (M3). (+/-)-Terodiline was found to be about as potent as pirenzepine in the rabbit vas deferens (Kb = 15 and 31 nM, respectively) and at least as selective for M1 relative to M2 (11-fold) and M3 (19-fold) receptors. Like pirenzepine, (+/-)-terodiline does not distinguish between M2 and M3 receptors in vitro. The peripheral actions of (+/-)-terodiline were evaluated in vivo in terms of its ability to induce mydriasis, and to inhibit salivary secretion and urinary bladder contraction. (+/-)-Terodiline given s.c. was equipotent in inhibiting intravesical bladder pressure and carbachol-induced salivary secretion (ID50 = 24 and 35 mg/kg, respectively), and in increasing pupil diameter (ED50 = 59 mg/kg). These results suggest that the in vivo actions of racemic terodiline at (M3) receptors mediating bladder contraction may not be separable from its actions at receptors mediating mydriasis and salivation. Moreover, its effects on the pupil and salivary glands are apparently not mediated through M1 receptors. Together, these findings help clarify the action of (+/-)-terodiline in the treatment of neurogenic bladder.

The influence of electroshock on adrenoceptor function in rat brain cerebral cortex: selectivity for the α-adrenoceptor site

The present study was undertaken to examine the effect of electroshock on adrenoceptor-mediated cAMP and inositol phosphate accumulation in rat brain cerebral cortical slices. Under the conditions of these experiments, isoproterenol-induced cAMP accumulation was unaltered by electroshock, although there was a significant reduction in the norepinephrine- and isoproterenol + 6-fluoronorepinephrine-stimulated responses. No change in alpha-adrenoceptor-mediated inositol phosphate accumulation was noted. The results indicate that electroshock selectively modifies an alpha-adrenoceptor system in brain that differs from that associated with inositol phosphate accumulation.

An in vivo procedure for the selective inactivation of rat brain cerebral cortical α-adrenoceptors using N-ethoxycarbonyl-2-ethoxy1,2-dihydroquinoline (EEDQ)

Intraperitoneal administration of 0.8 mg/kg N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats significantly reduced alpha-adrenoceptor binding in cerebral cortical membranes without affecting beta-adrenoceptor sites. A selective reduction in alpha 1-adrenoceptors was achieved by injecting yohimbine prior to EEDQ, whereas prazosin pretreatment yielded a selective reduction in alpha 2-adrenoceptor binding. Administration of EEDQ decreased norepinephrine-stimulated inositol phosphate and cyclic adenosine monophosphate (cAMP) accumulation in cerebral cortical tissue as well as the cAMP response to isoproterenol in combination with 6-fluoronorepinephrine without modifying the second messenger response to isoproterenol alone. The results suggest that, under the proper conditions, EEDQ administration can selectively diminish rat brain alpha-adrenoceptor number and function, yielding a procedure that may be useful for defining the behavioral and physiological properties of these sites.