| Description |
Low-frequency electroshock seizure threshold (EST) and pentylenetetrazol (Metrazol) seizure threshold (PST) were employed to measure the effects of chronic administration of meprobamate (Miltown, Equanil), phenaglycodol (Ultran), and promazine (Sparine) and of their subsequent withdrawal on the sensitivity of the central nervous system in mice. To provide a basis of reference, the effects of single dose of these same agents on brain excitability, as measured by the EST and PST tests, were also estimated. The EST was determined by means of a Grass stimulator (model S4B). The stimulus parameters employed consist of unidirectional pulses of 0.2 millisecond duration delivered for 3 seconds, through corneal electrodes, at a frequency of 6 pulses per second. The PST was determined by the intravenous infusion of a 0.5% solution of pentylenetetrazol at a rate of 0.005 ml per second until each mouse exhibited persistent clonus for 3 seconds. The animals were chronically-treated for 2 to 3 weeks; drug administration was abruptly terminated and the EST and PST were measured at predetermined periods. The results obtained were expressed as threshold ratios (threshold drug group/threshold control group). The results of the electroshock and chemoshock studies indicate that both meprobamate and phenaglycodol increase EST and PST. Chronic administration of either drug for approximately 2 weekly decreased the EST- and PST-raising effects of both drugs, i.e. resulted in development of tolerance. When chronic administration of either agent was abruptly terminated the EST and PST were decreased; this response was interpreted as withdrawal hyper-excitability or physical dependence. In contrast, promazine decreased the EST and PST. Chronic administration of this drug over a period of approximately 3 weeks had no significant effect on the EST- and PST- lowering effect. This observation indicates that tolerance to the threshold-lowering effect of promazine either did not occur or could not be measured by the experimental technic employed. Upon abrupt termination of promazine administration, the EST and PST were increased; this response was interpreted as withdrawal hypo-excitability of physical dependence. The effects of s single dose of meprobamate or promazine and of the chronic administration of these same agents on electrolyte and water concentration in plasma and cerebral tissue of mice were studied in an effort to reveal changes which might explain, at least in part, the phenomena of tolerance and physical dependence. The results of the electrolyte studies indicate that there is no consistent correlation between brain electrolyte alterations and brain excitability. Indeed, some of the alteration in brain Na ratio were seemingly contradictory to the accepted concept that and increased Na ratio is associated with an increased EST. However, it was quite likely that the acute nature of the electrolyte studies, i.e. the short interval between drug treatment and sacrifice of the animals for analysis, may have compromised the results. Since the blood barrier retards the rate of electrolyte movement from plasma into the brain extracellular compartment, it was obvious that the electrolyte studies reported were done while brain water and electrolytes were in an unsteady state. The data presented indicate that both the electroshock and the chemoshock technic may prove useful to the determination of tolerance and withdrawal hyper-excitability induced by the administration of large does of drugs which depresses the central nervous system. On the other had, these same technic may prove useful for the detection of withdrawal hypo-excitability induced by chronic administration of large does of drugs which stimulates the central nervous system. |
