Biology ETDs

Publication Date

11-29-1979

Abstract

Barbiturates are widely used drugs, both as anticonvul­sants and anesthetics. However, their mechanisms of action are presently unclear although a number of hypotheses have been proposed to explain their effects. These hypotheses have primarily viewed the synapse as the site of barbiturate action.

The aim of this study was to elucidate some cellular mechanisms of action of the barbiturates and to suggest some correlations to their clinical properties. The effects of sodium phenobarbital and sodium pentobarbital on responses to iontophoretically applied neurotransmitters, primarily acetylcholine and gamma aminobutyric acid, were studied. The use of voltage clamp techniques in single neurons of the mollusc, Aplysia californica, allowed precise measurement of postsynaptic response resulting from the application to these neutrotransmitters. These same techniques also made possible a study of barbiturate effects on membrane parameters.

Sodium phenobarbital and sodium pentobarbital (.025 to 3mM) depressed both cholingeric and GABAergic responses: 1) in a dose dependent reversible fashion; 2) independent of the neurotransmitter; 3) without effect on the reversal potential of the response; 4) and independently from or in the absence of, membrane effects. Sodium dependent excitatory and chloride dependent inhibitory responses were similarly depressed by a given dose of drug. In contrast, the potassium dependent inhibitory responses were much less sen­sitive to depression by all barbiturates tested. The sensitivity of the fast responses (sodium dependent excitatory and chloride dependent inhibitory) to barbiturate action is approximately 6.5 times greater than that of the slow potas­sium dependent responses, based on the dose required to depress a given response fifty percent. This marked depression of sodium and chloride dependent response with relative sparing of potassium dependent responses results in a predominance of slow inhibitory transmission during exposure to barbiturate. This pattern of barbiturate 5-(2 cyclohexylideneethyl) -5- ethyl barbituric acid (CHEB). A hypothesis of barbiturate anesthetic action is proposed based on these data.

Only small differences in relative potency were observed between sodium phenobarbital and sodium pentobarbital on iontophoretic responses. Sodium pentobarbital was approximately 1.5 times more potent on all responses than sodium phenobarbital.

The effects of sodium pentobarbital and sodium phenobarbital on membrane parameters were also studied. Barbiturates potentiate a slowly developing outward current occurring near threshold potential. Sodium pentobarbital is three to five times more potent than sodium phenobarbital in enhancing this outward current. This difference in potency is marked, especially in contrast to the small difference in the effect of sodium phenobarbital and sodium pentobarbital on postsynaptic responsiveness. The implications of these differences in potencies are discussed in terms of anticonvulsant and anesthetic properties.

Language

English

Document Type

Dissertation

Degree Name

Biology

Level of Degree

Doctoral

Department Name

UNM Biology Department

First Committee Member (Chair)

Lloyd Donald Partridge

Second Committee Member

Donald Victor Priola

Third Committee Member

Heather Mae Murray

Fourth Committee Member

W. A. Wilson

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