CKS DEPRESSANTS IN ANUIALS 333 the threshold of EEG arousal reaction caused by hypothalamic stimulation, it only elevated the stimulation threshold of the reticular activating system, while sham rage and olfactory response were inhibited by the drug.

REFEREXCES

1 R. KIDO .~NDK. Y.DIA:\IOTO, Intern. J. Neuropharmacot., I (I962) 49. 2 T. TOKlZA:-lE, H. K.""W.BWRAAXD G. bLDlURA, Neurologia, Med=Chir., 2 (I960) 63. 3 E. Y,ULUIOTO, Ann. Report Sliionogi Res. Lab., 9 (I9j9) I I2j. 4 K Y.Du:vroTo A~D R Kmo, Brain Nave (Tokyo), I6 (I964) 4+

EFFEC,TS OF CENTRALLY ACTING DRUGS ON' ACQUIS.ITION OF A PASSI'VE AVOIDANCE REACTION IN THE RAT

R.W.BRIMBLECOMBE Ministry of Defence, Chemical Defence Experimental Establishment, Porion Down, Salisbu-ry [Great Briiain }

The apparatus used was essentially that described by KURTZ AND PEARl> It consist- ed (Fig. r) of a large well-lit box connected to a smaller, dark compartment. Naive male rats placed in the large compartmen t tended to withdraw into the smaller one. The total time allowed in the apparatus was 2 minutes and at the end of this time the rat was enclosed in the smaller box and shocked through its feet. When re-in trocluced

'-r-r I I

I

rI i b o <')

I

14---,,---- 30em

.' Fig. I. Diagram of apparatus used.

References p. 336 334 R. \V. BRI:MBLECOMBE into the apparatus 24 hours later there was a tendency to avoid entry into the smaller box. The effects of drugs upon the acquisition of this passive avoidance reaction were studied by administering the drugs by injection to the rats at such times that the peak effects were exerted at the time of the shock. Results of a typical experiment are shown in Figure 2 where 100 ,ug/kg LSD 25 produced some block of acquisition of the avoidance reaction without affecting the responses of rats which had not been shocked. Other drugs shown to affect this acquisition (Fig. 3) were phencyclidine (2 mgjkg, 30 min before shock) and chlorpromazine (I mgfkg, three and a half hours before shock). The exact actions of the above-mentioned drugs on the brain are not clearly under- stood, so discussion of these results is difficult. Figure 4 illustrates results from experiments with atropine sulphate (100 mgjkg, 30 min before shock) and N-methyl-3-piperidyl benzilate (2 mgjkg, 30 min before shock). Both these substances are anticholinergic in their action and both produced definite block of the acquisition of the avoidance reaction. Similar results have been reported by MEYERS et al, 3 with scopolamine and I-hyoscyamine and by BUREsov.<\.ei all with atropine sulphate. Atropine sulphate exerted its most marked effect when injected go minutes before shock (Fig. 5). At this time after injection other responses 100[ 100

75 75

2 nd day 50 50 t s t day

25 25

I OL C5 CUS T5 TU5 0.1 mg/kg LSD-25 S.C 30 min before (1 st. day)

I:;'ig.2. Effect uS 1-,S1) 23 on acquisition of passive avoidance reaction. o. I n1g/kgILS:D- 25 s.c. 30 min before ~JJ(Jck(rst. clay). CS = Control shocked. CCS = Control not shocked. TS = Treated shocked. TUS = Treated not shocked.

lOOi J

2 nd day day 50 50

25

o CS CUS TS TUS 2 mg/kg phencyclidine 30 min before 1 mg /kg chlorpromazine 3.5 h before shock (1 s t. day) shock (1 st day)

Fig. 3. Effects of phencyclidine and chlorpromazine on acquisition of passive avoidance reaction. CENTRALLY ACTING DRUGS lei THE Ri,T 335

lOOr I 7t

50~ 2r.d day 2nd day j CS CUS TS TUS CS CUS TS TUS 100 mg!kg atropine sulphate 321 min before 2rr.g/kg N-methyl-3- piperidyl berizito t e shock (tst day). 30 rrun before shock (, st. day)

Fig. 4· Effects of atropine sulphate and X-methyl-3-piperidyl benzilate on acquisition of passive avoidance reaction.

100

2nd doy

40 20 10 CS ~ m;n mg/kg Atr-opine eutpho te 20 rr.S;/kg {Ls t . day) Atropine sulphate 30 rnirt before (1 st. day)

Fig. 5· Effects of atropine sulphate injected at different times before shock and in different doses on acquisition at passive avoidance reaction. to atropine (e.g. mydriasis) were most marked, so presumably the effect of the atropine (having its peak effect at the time of shock) was on the acquisition of the response rather than on its retention. If atropine and similar drugs blocked acquisition of the avoidance response by virtue of their anticholinergic action then facilitation of the acquisition might be expected to be produced by stimulation of muscarinic cholinergic activity. This was achieved indirectly by giving the anticholinesterase sarin (Fig. 6) and at a dose of O.OIS mg/kg there was some tendency for increased acquisition of the response. With physostigmine, however, no such facilitati.on occurred (Fig. 7) and direct increase in cholinergic activity achieved by administering oxotremorine, a muscarinic substance known to produce central effects, likewise had little or no effect on the acquisition of the response. . The results indicated that it was possible to.interfere.with acquisition of a passive avoidance response under the conditions described by administration of a number of centrally acting drugs. Anticholinergic compounds appeared to be particularly effec- tive and there was some slight evidence for facilitation of acquisition of the response when central cholinergic activity was increased.

References p. 336 - ._._-----_. ---- R. W. BRDIBJ_ECOMBE

2 nd day 2nd day

o 06 0.03 00;'5 ~ mgjkg 0.015 mg/kg sarin 30 mill before Ser-io 30 r-run be fore shock (i s t day) shock (j st day)

Fig. 6. Effects of sarin on acquisition of passive avoidance reaction.

CIJS CS TS TUS CS cus TS TUS O.15rng/kg phys ostiqrnine 30min before 0.1 mg/kg oxotremorine 30 min before shock (1 st. dOY) shock (1 st. day)

Fig. 7. Effects of physostigmine and oxotremorine on acq uisitiou of passive avoidance reaction.

If this situation can be related to the learning or memory process, and this is not necessarily the case, it would seem most likely that the drugs affected the stage of perseveration rather than the stage of consolidation and the results would not be at variance with the idea 4 that learning efficiency depends on the ratio of acetylcholine to cholinesterase in the central nervous system.

REFEl

1 O. BURTiSovA, J. BURES, Z. BOHDANECKY "ND T. V/ETSS, Psvchopharmacologia, 5 (r964) 255. J. [-1. KURT2. A;-;IDJ. PEARL, J. Camp. Physiol. Psychoi., 53 (1960) 201. 3 8. :HEYERS, K. H. ROBERTS, R. H. R1CIPUTl Al'J) E. F, Dm.HNO, Psychoph arnuicologia, 5 (1g64) 289. 4 R. B, Ross, Nature, 201 (lg64) 109.