526 



PHYSIOLOGY OF GONADS 



Nor is it influenced by severe trauma, heat, 

 cold, or formalin injection coincident with 

 the known "critical period" (Everett, un- 

 published). 



2. Central Depressants and Ovulation 



Reported evidence of a blocking action 

 of barbiturates on ovulation traces back 

 to experiments by Westman (1947) who in- 

 jected female rats with Prominal twice 

 daily for 3 weeks. Approximately 30 per 

 cent of these rats experienced prolonged 

 vaginal estrus and had ovaries containing 

 only follicles at the end of the experiment. 

 Almost identical results were reported by 

 Doring and Goz (1952) when rats were 

 treated daily with phenobarbital. The agree- 

 ment is not unexpected in view of the fact 

 that in the body Prominal is quickly de- 

 methylated to phenobarbital. It was shown 

 by Everett and Sawyer (1950) that when 

 administration of barbiturates to rats is 

 critically timed with respect to stage of the 

 cycle and the time of day, blockade of ovu- 

 lation can be accomplished at will in short- 

 term experiments (Fig. 8.10). Chronic 

 administration introduces considerable un- 

 certainty for reasons that are not yet clear 

 (Everett, 1952b). In the rabbit, the rapid 

 intravenous injection of pentobarbital or 

 Pentothal, within as short a time as 12 

 seconds after coitus, generally failed to 

 block ovulation (Sawyer, Everett and 

 Markee, 1950) . However, it was later shown 

 that barbiturate anesthesia will prevent the 

 ovulation that is otherwise caused in the 

 estrogen-primed rabbit by mechanical 

 stimulation of the vagina, the anesthesia 

 t)eing induced in advance of the stimulation 

 (unjuiblished i. 



Other central dcpi-es^ants reported to 

 block ovulation in the rat are morj^hine, 

 reserj^ine, chlorpromazine (Barraclough and 

 Sawyer, 1955; Barraclough, 1955, 1956), 

 and even meprobamate acting synergis- 

 tically with an anticholinergic drug (Gitscli, 

 1958). Special interest attaches to the 

 mori)hine work, in that anicnoi'i lica and 

 sterility often a('C()in|)any moiphinc addic- 

 tion in the human female. Related studies 

 (Sawyer, Critchlow and Barraclough, 1955), 

 in which recordings were made of electi'ical 

 acti\ity in various regions in the bi-ain. 



demonstrated in rats that morphine acts 

 nmch like the barbiturates in depressing 

 activity in the reticular activating system. 

 The effect was also shown by atropine, in 

 doses that would block ovulation. The in- 

 ference is that all three agents block by 

 striking at the same central elements of 

 the LH-release apparatus. 



An interesting peculiarity of domestic 

 hens with respect to barbiturates was en- 

 countered by Fraps and Case (1953), who 

 noted that pentobarbital induces ovulation 

 jirematurely, and that pentobarbital and 

 progesterone supplement each other in this 

 capacity. Although these developments may 

 represent pharmacologic curiosities limited 

 to the bird, the possibility should be seri- 

 ously considered that similar effects may 

 occur in other animals. In fact, pento- 

 barbital in rabbits facilitates the release of 

 hypophyseal gonadotrophin in response to 

 intraventricular injection of histamine, 

 seemingly by an effect in the rhinencephalon 

 (Sawyer^ 1955). 



3. The Central Xervous System as a Timing 

 Mechanism for Oi'ulation 



In the rat and the hen and probably many 

 other species the pro-ovulatory excitation of 

 the hypophysis is dejiendent in large meas- 

 ure on time of day. 



In the rat, the blocking agents have 

 served to delimit a critical period on the day 

 of proestrum, before which ovulation can be 

 blocked and after which it will occur in 

 sjiite of injection of the blocking agent. 

 Under controlled illumination for 14 hours 

 daily, this critical period extends from 

 about 2 P.M. to 4 P.M. Administration of 

 either atroi^ine or i^entobarbital at 2 p.m. 

 consistently blocks ovulation (Fig. 8.10), 

 whereas injections later in the period are 

 progressively less eff"ecti\-e ( l']\-erett and 

 Sawyer, 1950, 1953; Everett, 1956b). Such 

 l)redictability of the hour of pituitary acti- 

 vation is, in itself, evidence of a relationship 

 between this event and diunial physiologic 

 I'liythnis. 



Furthei' e\-i(lence is seen in the seciuelae 

 of pentobarbital injection (Fig. 8.11). Rep- 

 etition at 2 P.M. on successive days re- 

 sults in a follicular cycle and prolonged 

 vaginal estrus with eventual atresia of all 



