The Differential Effects of Nitrazepam on Certain Inhibitory and Excitatory
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hooded rats from the population bred The differential effects of nitrazepam on in the Psychology Vivarium, University of Washington. An additional two Ss became resistant to certain inhibitory and excitatory behaviors* maze running before the experiment could be completed and their data, though much like that of the others, is ROBERT J. DOUGLAS and DAVID w. SCOTT not included. Half were assigned The University of Washington, Seattle, Wash. 98105 randomly to Group 1 and the remainder to Group 2. Each S was Nitrazepam, mixed with food, was orally administered to rats in doses of 0, individually housed with continuous 10, and 50 mg/kg. Both doses, but especially the higher one, had obvious access to water. arousal-reducing effects in most Ss. Paradoxically, however, the 50-mg dose APPARATUS produced apparent "rage" behavior in several rats while seeming to "tranquilizeH A standard T-maze was used with its or depress the others. At the higher dose, there also was a marked depression in main alley 16 in. long and its side locomotor, postural, or righting behavior. Despite these obvious overall effects, alleys 18 in. in length. The alleys were neither dose had any reliable effect on spontaneous alternation, a response 5% in. high and 4% in. wide. A highly related to hippocampal damage or malfunction. Our results are at least guillotine door was used between the consistent with the idea that the drug alters the function of the amygdala, but startbox and the main alley and also they are decidedly in opposition to suggestions in the literature that nitrazepam between the choice point and each either inhibits or enhances the function of the hippocampus. side alley. The maze was surrounded by brown craft paper, and the only Nitrazepam, one of the new class of consensus of the literature and our illumination was provided by a hooded drugs known as benzodiazepines, is own extensive experience reveals that 15-W light suspended above the choice believed by many investigators to the normal rat generally alternates point. especially affect the limbic system about 85% of the time or that 85% of PROCEDURE (e.g., Morillo, 1962; Schallek, a group of rats will alternate on any An alternation test consisted of two Zabransky, & Kuehn, 1964; Schallek, one test of the phenomenon. In trials. For the first trial, S was placed Thomas, Kuehn, & Zabransky, 1965). contrast, large hippocampal lesions in the startbox and the door to the One might suspect this possibility reduce this rate to somewhere near a main alley was raised. When S entered purely on the basis of the general chance 50% (Roberts, Dember, & a side alley, the door was lowered and anticonvulsant properties of these Brodwick, 1962; Douglas & Isaacson, the rat was confined there for 30 sec. compounds and their "taming" effect 1964). A similar loss occurs after S was then removed and replaced in on animals (Randall & Schallek, lesions of the closely related septal the startbox for a second, identical, 1968). In addition, however, it was region (Douglas & Raphelson, 1966), trial. Ss were tested for 7 weeks, with concluded from a study of amygdaloid bu t alternation is apparently five daily tests and 2 days of rest per stimulation and recording in the completely unaffected by a wide week. The schedule of testing for the hippocampus that nitrazepam might v ari e t y 0 f nonhippocampal-septal two groups is shown in Table 1. The simultaneously inhibit the amygdala lesions, including amygdala, neocortex procedure was basically as follows: and facilitate the hippocampus (various locations including frontal), During Week 1, all Ss were tested with ( M 0 r i 11 0 , 1 9 6 2 ) . An 0 p p osi te or cingulate gyrus (Douglas, Kowal, & no drug. Then for three pairs of weeks, conclusion regarding the effects of the Clark, 1968). Furthermore, the total the two groups were alternately under drug on hippocampal function might absence of alternation following large drugged or nondrugged conditions, be drawn from the finding of Steiner hippocampal lesions occurs whether with the dosage 10 mg/kg for the first & Hummel (1968) that nitrazepam the lesion is made in one stage or two, two pairs of weeks and increased to blocks the reception of visual input by in very young rats or in adults 50 mg/kg for, the last pair of weeks. the hippocampus. (Douglas & Peterson, 1969). Thus, we The replication at 10 mg/kg was None of these studies, however, gets reasoned that if nitrazepam had an because of some lingering uncertainty directly at the problem of whether the effect on hippocampal function, then about the results of the first test. contribution of the hippocampus to it might well show up in terms of DRUG PREPARATION behavior is enhanced, depressed, or changes in the alternation tendency. If AND ADMINISTRATION unaffected by the drug. Such a the hippocampus were inactivated, In order to facilitate drug question is more directly approached then spontaneous alternation should administration, the rats were first by administering the drug and then be greatly reduced or abolished. A placed on a diet of 30 g of standard rat testing the Ss on problems or facilitation of hippocampal function chow per day, with feeding taking responses which are highly dependent might manifest itself as an increase in place at the time when the drug would u p 0 nth e i n t e gr i t Y 0 f the the alternation rate to levels above the later be administered. Weight was hippocampus . typical 85%. Since the drug maintained by all Ss on this diet, but There is no known behavior more nitrazepam (Mogadon®) is highly all were eager to eat at the scheduled sensitive to hippocampal lesions than unstable in an aqueous solution, and time. Before testing, each S was the phenomenon of spontaneous since humans are typically given the carefully weighed and the appropriate alternation. As measured in the rat, drug orally, it was decided that an oral spontaneous alternation refers to the administration would be most powerful tendency of the rat to enter appropriate. Two different doses were Table 1 opposite alleys of a T-maze when given employed and the experiment halted Dose (mgjkg) Sequence two consecutive unrewarded trials. A when it became clear that the high Week dose produced grossly observable 1 2 3 4 5 6 7 *This research was supported in part by changes in either emotional behavior Group 1 Grant MH 18760-01 from NIMH to the or locomotor reflexes in nearly all 0 10 0 10 0 50 0 senior author. We are grateful to animals. Hoffman-La Roche, Inc. for promptly giving SUBJECTS Group 2 us a free supply of Mogadon® and relevant 0 0 10 0 10 0 50 information. The Ss were eight 90-day-old female 164 Psychon. ScL, 1972, Vol. 26 (3) amount of the drug mixture was Table 2 vestibular cues, and our results thus prepared. The dry crystalline powder Spontaneous Alternation Rates After suggest that vestibular input to the (nitrazepam supplied gratis by Drug or Placebo Treatments hippocampus is unimpaired by Hoffman-La Roche, Inc., Nutley, N.J.) Drugged Placebo nitrazepam. Since both the function of was mixed with unbleached white the hippocampus and the phenomenon flour to facilitate the weighing. For Pretest 83.8 of spontaneous alternation are the 10-mg dose, one part ("part" 10 mg/kg believed by many investigators to be 80.0 92.5 always refers to weight) nitrazepam (Test 1) basically inhibitory (see references), it was mixed with 999 parts flour, while 10 mg/kg would appear that at least one 87.5 77.5 for the 50-mg dose it was one part (Test 2) inhibitory brain mechanism is drug and 99 parts flour. The drug-flour unimpaired by nitrazepam. Since Total, both mixture was sifted and shaken up 83.8 85.0 emotional changes were readily many times. Before a test, S was 10 mg tests observable even at the low dose, carefully weighed and enough of the 50 mg/kg 75.0 92.5 however, it would appear that the drug mixture weighed out so that the Total,all has a potent effect on some aspect of a 80.8 86.6 appropriate amount of the drug was drug doses basically excitatory or arousal system. included. A rat weighing 150 kg, for While our observations leave no example, on a dose of 10 mg/kg would by the drug. Even with the 50-mg room for doubt that nitrazepam has received 1,500 mg of the mix (1.5 mg dose, alternation occurred at a rate direct or indirect effects on nitrazepam and 1,498.5 mg flour). The reliably above a chance 50% (t = 2.6, emotionality, we cannot be sure that drug-flour dose was then matched with p<.05). this implies an interference with an equal weight of powdered rat chow - In a sense, it must be considered to amygdaloid function, however and an equal weight of white refined be remarkable that alternation was suggestive the data seem of this sugar (sucrose). Then the weight of the apparently unaffected by nitrazepam. possibility. Our alternation data have entire mixture was matched by an The reason is that even at the 10-mg no bearing on this possibility because eq ual weight of water and the whole dose general changes in behavior were amygdala lesions do not appear to thing reduced to a paste. For example, noted, while at 50 mg these assumed affect the spontaneous alternation rate our rat above would finally get a paste an extreme form. That is, at the low (Douglas et al, 1968).