Acetylcholine Metabolism of a Sympathetic Ganglion

Abstract

The synthesis, storage, and release of acetylcholine (ACh) were studied in perfused and intact superior cervical ganglia of cats. ACh was determined by bio-assay in ganglion extracts and in the venous effluent from ganglia perfused with fluid containing an anticholinesterase drug. Of the extractable ACh in a normal ganglion, about 85% is "depot ACh" available for release by nerve impulses. This must be located in the nerve endings; most of the remainder is in the intraganglionic portions of the preganglionic axons. The depot ACh exists as two fractions, of which one, the smaller, is the more readily available for release by nerve impulses. ACh synthesis and release go on at a measurable low rate in the absence of nerve impulses; both are greatly accelerated by activity. Under physiological conditions of excitation and perfusion, ACh release does not outrun ACh synthesis; but synthesis is slowed, with consequent depletion of depot ACh and reduction in ACh release, if choline is absent from the extracellular fluid, or if the hemicholinium base HC-3 is present. The latter compound specifically inhibits ACh synthesis by competing with choline; as a result it produces delayed block in repetitively activated cholinergic pathways. For efficient synthesis of ACh during experiments lasting an hour or so, a ganglion need be supplied with no substances other than choline and the constituents of Locke's solution; for the efficient release of ACh, the perfusion fluid must also contain CO2and an unidentified factor present in plasma. ACh accumulates above the resting level in a ganglion whose cholinesterase has been inactivated, provided that the perfusing fluid is one that supports ACh synthesis; the additional ACh is not immediately available for release by nerve impulses. Under physiological conditions of perfusion the amount of ACh set free by each maximal preganglionic volley is highest in a ganglion that has been at rest, and is then independent of stimulation frequency; after repetitive activation for several minutes the volley output is lower and is only frequency-independent at rates of excitation below 20/second. Consideration is given to the probable intracellular locations of the several fractions of the ganglionic ACh, and to their interrelationship.

Limit on the Role of Activity in Controlling the Release-Ready Supply of Synaptic Vesicles

“…They provide support for the general concept that the neurotransmitter used for synaptic signaling is drawn from a nonarbitrary RRP (Birks and MacIntosh, 1961;Elmqvist and Quastel, 1965) and for our particular model of RRP replenishment (Eq. 1).…”

“…Previous studies have primarily measured the time it takes for the RRP to refill during periods of rest, most finding that recovery from depletion takes at least several seconds (Birks and MacIntosh, 1961;Elmqvist and Quastel, 1965;Stevens and Tsujimoto, 1995;Rosenmund and Stevens, 1996;Wu and Borst, 1999). The residual calcium that is cleared slowly from synaptic terminals after bouts of intense activity has been shown to accelerate the replenishment process several-fold (Dittman and Regehr, 1998;Wesseling, 1998, 1999a;Wang and Kaczmarek, 1998).…”

Drug‐induced Changes in Brain Acetylcholine

“…In a dose equimolar to that of atropine, benactyzine caused no significant change in the level of acetylcholine in the brain. Schueler (1961) has suggested that hemicholinium inhibits the synthesis of acetylcholine, and Birks & Macintosh (1961) have shown that, in the cat, the inhibition of synthesis of acetylcholine by hemicholinium leads to a decreased output of acetylcholine in the perfusate from the perfused superior cervical ganglion in situ.…”

Synaptic activity slows vesicular replenishment at excitatory synapses of rat hippocampus

“…Although it is not clear if the vesicular dynamics are the same at all synapses, our results show that the recruitment of more synapses does not lead to different dynamics. Early kinetic studies suggested the existence of multiple vesicular pools, since depression has 2-3 kinetic phases (Birks and MacIntosh 1961;Dittman and Regehr 1998;Kasai 1999), each taken to indicate the depletion of vesicles from the corresponding pool (Heinemann et al 1993;Horrigan and Bookman 1994;Oheim et al 1999;Parsons et al 1995). The fractional release can be estimated using 'tetanic rundown' (Christensen and Martin 1970), but this method is accurate only if the replenishment of the RRP during the rundown plays just a minimal role.…”

“…As the readily releasable pool (RRP) becomes depleted, its replenishment becomes a more important component of synaptic transmission (Birks and MacIntosh 1961;Larkman et al 1991). The replenishment rate, which influences the fast component of synaptic depression and determines the steady state level, is typically unknown.…”