The effects of neurotensin, naloxone and haloperidol on elements of excessive grooming behavior induced by bombesin

The effects of neurotensin, naloxone and haloperidol on elements of excessive grooming behavior induced by bombesin

Peptides, Vol. 6, pp. 117%1183, 1985. e Ankho InternationalInc. Printed in the U.S.A. 01%-9781/85 $3.00 + .00 The Effects of Neurotensin, Naloxone a...

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Peptides, Vol. 6, pp. 117%1183, 1985. e Ankho InternationalInc. Printed in the U.S.A.

01%-9781/85 $3.00 + .00

The Effects of Neurotensin, Naloxone and Haloperidol on Elements of Excessive Grooming Behavior Induced by Bombesin T J . B . V A N W I M E R S M A G R E I D A N U S , D. K . D O N K E R , R. W A L H O F , J. C. A. V A N G R A F H O R S T , N . D E V R I E S , S. J. V A N S C H A I K , C. M A I G R E T , B. M. S P R U I J T A N D D. L. C O L B E R N

R u d o l f Magnus Institute for Pharmacology, Medical Faculty, University o f Utrecht Vondellaan 6, 3521 GD Utrecht, The Netherlands R e c e i v e d 25 J u l y 1985 VAN WIMERSMA GREIDANUS, TJ.B., D. K. DONKER, R. WALHOF, J. C. A. VAN GRAFHORST, N. DE VRIES, S. J. VAN SCHAIK, C. MAIGRET, B. M. SPRUIJT AND D. L. COLBERN. The effects ofneurotensin, naloxone and haloperidol on elements of excessive grooming behavior induced by bombesin. PEPT1DES 6(6) 1179-1183, 1985.--The influence of naloxone, haloperidol and neurotensin was investigated on bombesin-induced excessive grooming in rats. All three drugs reduced the amount of bombesin-induced grooming. Haloperidol induced a general reduction in excessive grooming as induced by bombesin, without changing the composition of grooming behavior, whereas naloxone and neurotensin suppressed bombesin-induced grooming and caused a shift in the distribution of grooming elements. The main suppressive effect of these latter drugs appeared to be on the element scratching. From these data it is suggested that bombesin-induced scratching is mainly displayed by activation of opiate receptor systems, whereas the other elements of bombesin-induced excessive grooming are mainly regulated by dopaminergic systems. Bombesin

Haloperidol

Naloxone

Neurotensin

Grooming behavior relative distribution of peptide-induced grooming elements occur due to the treatment with these substances.

T H E tetradecapeptide bombesin is one of the numerous brain and gastrointestinal peptides. It has a strong hypothermic action [2] and a role of bombesin in satiety has been suggested [18]. In addition, it induces behavioral effects following central administration, and one of these is the induction of excessive grooming [7, 10, 15, 16, 17, 18, 20, 25]. Bombesin is not the only neuropeptide inducing excessive grooming: ACTH, c~-MSH, endorphins, prolactin, substance P and eledoisin have also been shown to induce this behavioral effect [5, 6, 8, 9, 14]. However, it has been demonstrated that the excessive grooming induced by bombesin and that induced by ACTH are of a completely different nature [25]. The main component of bombesin-induced grooming is scratching, whereas ACTH and most other neuropeptides induces a more general type of excessive grooming by increasing the frequency of all or most elements of the grooming repertoire. Since dopaminergic as well as opiate receptor systems have been claimed to be involved in peptide (mainly ACTH)-induced grooming behavior [1, 3, 8, 23, 28], antagonists for opiate or for dopamine receptors were applied in the present study in order to establish whether or not interference with these receptor systems would affect bombesin-induced grooming. Since it has been reported by us that neurotensin also affects peptide-induced excessive grooming [24], this neuropeptide was included in the present study as well. In fact, we studied the influence of these drugs on the various elements of excessive grooming induced by bombesin and investigated whether or not changes in the

METHOD Male rats were used from an inbred Wistar strain (TNO, Zeist, The Netherlands) and weighing approximately 150 g. Cannulation of the brain ventricular system was performed 5 days prior to the behavioral experiments by placing a polyethylene cannula in the right lateral ventricle under Hypnorm ®, (5.0 mg fluanison and 0.2 mg fentanyl/0.5 ml/kg, SC; Duphar B.V., Amsterdam, The Netherlands) anesthesia. The animals were kept single-caged under standard lightdark conditions (light on 06.00 a.m., off 08.00 p.m.) with food and water ad lib. Rats were allocated randomly to different treatment groups and received intracerebroventricular (ICV) injections of 2 p.l. Bombesin (B 610; UCB; The Hague, The Netherlands) was ICV injected in doses grading from 10 ng, 30 ng to 100 ng. Pretreatment with naloxone was performed at 20 min prior to the ICV injection with bombesin. The dose used was 1 mg/kg body weight for subcutaneous (SC) injection or 1/.tg for ICV injection. In an additional experiment the effect of a dose of 10 tzg naloxone was investigated on grooming induced by 30 ng bombesin. Pretreatment with haloperidol was performed at 20 min prior to bombesin administration in a dose of 0.05 mg/kg body weight for SC administration, and of 1 /zg for ICV administration. Also, the effect of 10/zg ICV

1179

1180

VAN WIMERSMA GREIDANUS ET AL. TABLE1

CSF NAL l mg/kg B 10 ng BI0ng+NAL B 30 ng B 30 ng + NAL B 100 ng B 100ng+NAL

H

B

A

P

S

T

n

6.5 _+ 0.6 20.4% 3.8 _ 0.9 24.7% 17.9 _+ 0.9 16.8% 12.8-+1.4 * 27.9% 25.9 -+ 2.6 20.1% 22.1 -+ 3.1 26.6% 29.2 -+ 3.8 19.6% 26.2-+2.1 20.4%

13.5 _+ 2.6 42.5% 4.3 _+ 1.0¢ 28.0% 17.6 _+ 0.8 16.5% 11.3-+1.3" 24.1% 17.3 _+ 2.4 13.5% 10.2 -+ 2.1" 12.3% 11.4 -+ 2.0 7.6% 10.4-+0.9 8. I%

2.6 _+ 0.7 8.2% 1.7 _+ 0.6 11.0% 6.7 _+ 1.0 6.3% 2.1_+0.8 4.5% 7.6 -+ 2.0 5.9% 2.6 -+ 0.5t 3.1% 7.5 -+ 1.4 5.0% 5.0-+0.7 3.9%

6.0 _+ 0.7 18.9% 3.5 _+ 0.8 22.8% 12.2 _+ 1.4 11.4% 11.0-+1.9 29.5% 13,3 -+ 1.9 10.3% 18.8 -+ 1,8 22.6% 27.4 ~_ 2.7 18.4% 29.1-+3.0 22.6%

3.2 _+ 0.8 10.1% 2.1 _+ 0.7 13.6% 52.5 _+ 6.2 49.2% 9.7-+ 2.72 20.7% 64.5 -+ 10.7 50.2% 29.5 -+ 6.7t 35.5% 73.8 -+ 6.6 49.4% 57.8-+ 6.1 45.0%

31.8 _+ 3.9

13

15.3 _+ 2.9*

12

106.8 _+ 7.1 46.9-+

3.72

13 12

128.6 -+ 14.6

8

83.1 -+ 6.9t

12

149.3 _+ 7.0

12

128.5_+ 9.3

16

The influence of SC administration of naloxone (NAL) on the various elements of grooming behavior induced by graded doses of bombesin (B). H: head washing; B: bodily grooming; A: anogenital (=sexual) grooming; P: paw licking; S: scratching; T: total grooming scores. n = number of animals per treatment group. Grooming scores are indicated as mean _+ S.E.M. *p _-<0.05, tp _-<0.2, 2p =<0.01. (Peptide or placebo without drug pretreatment vs. peptides or placebo with drug pretreatment).

administered haloperidol was studied on grooming induced by 30 ng bombesin. Pretreatment with neurotensin (R 4322, Bachem, Torrance, CA) was performed immediately before b o m b e s i n administration in a dose of I /zg ICV. As placebo for ICV injections artificial C S F was used, w h e r e a s saline was injected as placebo for SC administration. The grooming test was p e r f o r m e d according to Gispen et al. [9]. Briefly, rats w e r e placed into perspex observation boxes ( 2 6 x 2 0 x 1 3 cm) immediately after ICV injection of b o m b e s i n or placebo. Using a 15 sec sampling time, the display o f groooming elements was r e c o r d e d for a period of 50 min starting l0 min after the m o m e n t the animals had been placed into the observation boxes. The following elements o f grooming were scored: head washing (H), paw licking (P), bodily grooming (B), sexual (anogenital) grooming (A) and scratching (S). The results are e x p r e s s e d as mean (_+ S . E . M . ) grooming score per treatment group for the total observation period of 50 min (maximum score: 200). Statistical analysis of the data was performed by using the analysis of variance ( A N O V A ) and D u n n e t t ' s test. RESULTS F r o m the data, it appears (Table 1) that SC administered naloxone was able to suppress significantly the e x c e s s i v e grooming induced by bombesin. This suppression following pretreatment with naloxone was mainly due to a suppression of the elements scratching and bodily grooming. This suppressive effect of naloxone on bombesin-induced e x c e s s i v e grooming was also o b s e r v e d w h e n naloxone was administered ICV in a dose of I p~g, albeit that this dose only reduced the e x c e s s i v e grooming induced by 10 ng bombesin (Table 2). H o w e v e r , the results from the additional experiments reveal that for the ICV route of administration a very high dose o f 10/~g naloxone suppressed grooming b e h a v i o r induced by 30 ng bombesin in a way which is more or less

similar to the effect of a SC administered dose o f I mg/kg naloxone. Again scratching and bodily grooming appeared to be the main elements involved in the suppressive effect of naloxone on bombesin-induced grooming. N a l o x o n e treatment also resulted in a slight, but significant, reduction of grooming in the CSF-treated rats. W h e n the relative distribution of the various elements of grooming was calculated in percentages o f the total grooming score, it appears that this relative distribution changed after pretreatment with naloxone. A strong shift in the distribution of grooming elements occurred when naloxone was SC administered. In this case, a relative increase in the elements head washing, bodily grooming and paw licking was o b s e r v e d at the cost of scratching in animals treated with 10 ng bombesin following pretreatment with naloxone. In the groups of rats treated with 30 ng bombesin the shift in the relative distribution of grooming elements following SC pretreatment with naloxone was m u c h like the shift seen in animals treated with 10 ng bombesin and I C V pretreated with 1 /~g naloxone, i.e., a reduction of the element scratching which was accompanied by a relative (but not absolute) increase in the elements paw licking and head washing. Hardly any difference in the distribution was seen b e t w e e n the groups of rats (1) treated with 30 ng bombesin with and without ICV pretreatment with I p~g naloxone or (2) treated with 100 ng bombesin and without ICV pretreatment with 1 g~g naloxone. SC pretreatment with haloperidol resulted in a significant reduction o f grooming in placebo-treated rats, as well as in rats treated with 10 ng or 30 ng bombesin (Table 3). This reduction in grooming affected more or less equally all grooming elements because the distribution of the elements o f grooming b e h a v i o r was not different in the various groups of r a t s . ICV pretreatment with 1/~g haloperidol did not result in any significant effect on the grooming scores; neither the

EXCESSIVE

GROOMING

AND BOMBESIN

1181

TABLE2

CSF N A L 1 tzg B 10ng B 10 ng + N A L B 30 ng B 30 ng + N A L B 100 ng B 100 ng + N A L CSF N A L 10/xg B 30 ng B 30 ng + N A L

H

B

A

P

S

T

n

6.9 _+ 1.2 20.5% 4.3 _+ 0.5* 20.9% 18.7_+ 2.6 16.5% 13.9 _+ 1.8 22.7% 25.9 _+ 2.8 22.0% 30.0 _+ 3.3 26.2% 39.1 _+ 2.8 24.0% 34.8 _+ 3.2 23.7% 7.1 _+ 0.6 22.4% 4.2 _+ 0.5* 21.0% 28.9 _+ 2.9 21.3% 19.8 _+ 2.8* 39.5%

10.7 -+ 1.6 31.8% 7.4 _+ 1.3 35.9% 19.4-+ 3.3 17.2% 12.1 _+ 1.6" 19.8% 16.6 _+ 2.9 14.1% 16.3 _+ 1.5 14.3% 13.3 _+ 2.7 8.2% 10.6 _+ 1.1 7.2% 9.0 _+ 1.3 28.4% 6.5 _+ 1.6 32.5% 15.8 _+ 1.2 11.7% 6.1 -+ 1.6" 11.9%

3.9 _+ 1.8 11.6% 1.9 _+ 0.4 9.2% 7.8 -+ 1.1 6.9% 4.1 _+ 0.7t 6.7% 8.1 -+ 2.8 6.9% 8.6 _+ 1.4 7.5% 5.8 -+ 1.0 3.6% 7.8 _+ 1.5 5.3% 3.6 _+ 1.1 11.4% 4.5 _+ 2.2 22.5% 6.6 - 2.0 4.9% 7.3 _+ 2.2 14.2%

8.1 _+ 1.6 24.1% 4.1 _+ 0.7* 19.9% 11.1 -+ 1.5 9.8% 9.6 _+ 1.4 15.7% 11.5 -+ 1.7 9.8% 11.2 _+ 1.5 9.8% 16.5 _+ 1.1 10.1% 12.7 _+ 1.8 8.6% 10.2 _+ 2.3 32.2% 4.8 _+ 2.5 24.0% 12.1 -+ 3.0 8.9% 10.9 -+ 2.1 21.2%

4.1 _+ 1.6 12.2% 2.9 _+ 1.1 )4.1% 56.1 -+ 5.6 49.6% 21.5 _+ 4.0t 35.1% 55.8 -+ 8.0 47.3% 48.4 _+ 5.4 42.3% 88.4 _+ 9.3 54.2% 81.0 _+ 10.3 55.1% 1.7 _+ 1.1 5.4% 0* -71.9 -+ 9.0 53.0% 7.3 _+ 3.35 14.2%

33.6 _+ 4.6

14

20.6 -+ 2.9*

22

113.1 _+ 6.0 61.2 _+ 5.55

7 13

117.9 _+ 8.7

8

114.5 _+ 7.7

10

163.0 _+ 7.5

8

146.9 _+ 12.2

10

31.7 _+ 4.1

14

20.0 _+ 3.0* 135.4 _+ 10.6 51.4 _+ 8.1t

6 9 11

The influence of ICV administration of naloxone (NAL) on the various elements of grooming induced by graded doses of bombesin (B). See for explanation of abbreviations etc. legend to Table 1.

TABLE3

CSF HP SC B l0 ng B 10 ng + HP B 30 ng B 30 ng + HP B 100 ng B 100 ng + HP CSF HPICV B 30 ng B 30 ng + HP

H

B

A

P

S

7.6_+ 1.4 24.8% 4.5 _+ 0.9 31.0% 25.0 -+ 2.3 23.1% 21.3 _+ 2.9 31.1% 32.0 - 2.7 22.4% 22.7 _+ 2.0* 24.6% 36.1 _+ 3.5 24.6% 36.2 -+ 3.1 28.1% 7.1 + 0.6 22.4% 2.8_+0.8 16.0% 28.9 _+ 2.9 21.3% 16.3 _+ 2.0* 19.4%

11.3 -+ 1.1 36.9% 3.7 _+ 0.75 25.5% 17.4 _+ 2.2 16.1% 9.6 + 1.3" 14.0% 15.7 _+ 1.7 11.0% 10.2 - 1.9" 11.0% 9.1 _+ 1.6 6.2% 6.6 _+ 0.9 5.1% 9.0-+ 1.3 28.4% 3.8_+1.1 21.7% 15.8 _+ 1.2 11.7% 7.1 _+ 1.0" 8.5%

2.6_+ 0.9 8.5% 1.8 _+ 0.3 12.4% 7.8 + 1.6 7.2% 3.6 _+ 0.8 5.3% 6.3 _+ 0.7 4.4% 3.4 _+ 0.9 3.7% 4.9 -+ 1.3 3.3% 3.1 - 1.0 2.4% 3.6_+ 1.1 11.4% 3.4_+0.9 19.4% 6.6 + 2.0 4.9% 5.8 _+ 1.7 6.9%

6.0_+ 0.6 19.6% 3.4 _+ 0.8* 23.4% 15.1 _+ 1.7 13.9% 8.4 _+ 1.7" 12.3% 12.7 + 1.5 8.9% 10.3 _+ 1.4 11.1% 19.4 _+ 3.0 13.2% 18.2 _+ 2.6 14.1% 1 0 . 2 - 2.3 32.2% 6.1_+1.3 34.9% 12.1 _+ 3.0 8.9% 12.5 -+ 3.4 14.9%

3.1 -+ 1.0 10.1 1.1 -+ 0.3* 7.6% 43.1 _+ 7.1 39.8% 25.6 -+ 5.8 37.4% 76.2 _+ 5.9 53.3% 45.8 _ 7.7t 49.6% 77.3 _+ 8.5 52.6% 64.8 _+ 8.3 50.3% 1 . 7 - 1.1 5.4% 1.3_+0.9 7.4% 71.9 _+ 9.0 53.1% 42.2 _+ 9.4* 50.3%

T 30.6_+

n 2.8

14.5 _+ 1.9¢ 108.4 _+ 6.5 68.4 _+ 7.9* 142.9 -

11 15 9 7

4.8

10

92.4 _+ 10.15

13

146.9 -+ 9.2

9

128.8 -+ 10.1

12

31.7-+

4.1

14

17.5-+

3.7

13

135.4 _+ 10.6

9

83.9 _+ 12.4"

17

The influence of haloperidol (HP, 0.05 mg/kg SC or 10/xg 1CV) on the various elements of grooming behavior induced by graded doses of bombesin (B). See for explanation of abbreviations etc. legend to Table 1.

1182

VAN WIMERSMA GREIDANUS ET AL. TABLE 4

CSF NT B 10 ng BI0ng+NT B 30 ng B 30 ng + NT B 100 ng B 100ng + NT

H

B

A

P

S

T

n

8.2 _-+0.9 20.9% 6.4 _+ 0.9 35.2% 15.4 _+ 3.0 28.1% 11.9_+1.9 35.7% 30.1 _+ 4.7 25.2% 22.9 -+ 2.9 25.7% 37.8 -+ 2.8 23.8% 34.5 _+ 3.5 28.7%

12.8 -+ 1.2 32.7% 6.1 -+ 1.0:~ 33.5% 13.6 _ 1.1 17.8% 8.8_+1.8" 26.4% 16.3 - 2.5 13.8% 11.8 _+ 1.9 13.2% 8.8 -+ 1.7 5.5% 6.0 _+ 1.2 5.0%

5.1 _+ 0.9 13.0% 2.7 _+ 0.9 14.8% 6.1 -+ 1.0 8.0% 3.8_+1.2 11.4% 7.5 -+ 1.2 6.3% 5.4 _+ 0.9 6.0% 6.4 _+ 1.6 4.0% 3.3 ___0.8 2.7%

7.1 _+ 1.3 18.1% 2.8 _+ 0.6t 15.4% 5.6 _+ 1.5 7.3% 7.4_+1.9 22.2% 13.3 -+ 2.0 11.1% 19.2 -+ 2.7 21.5% 17.4 _+ 2.5 11.0% 16.6 -+ 2.2 13.8%

5.9 -+- 1.3 15.1% 0.3 _+ 0.2:) 1.6% 35.8 _+ 5.5 46.8% 1.5_+ 0.8~: 4.5% 52.0 -+ 11.6 43.6% 30.3 _+ 6.9 33.8% 88.3 _+ 8.5 55.6% 59.7 _+ 9.2* 49.7%

39.2 _+ 3.9

18

18.2 _+ 2.85

18

76.5 _+ 9.0

8

33.3_+

8

2.4~:

119.2 -+ 12.9

8

89.6 _+ 10.2

11

158.7 _+ 5.8

9

120.2 _+ 9.1t

9

The influence of neurotensin (NT; 1 p.g ICV) on the various elements of grooming behavior as induced by graded doses of bombesin (B). See for explanation of abbreviations etc. legend to Table 1.

grooming score of placebo-treated rats, nor the e x c e s s i v e grooming induced by bombesin was suppressed. Likewise, no influence was o b s e r v e d on the relative distribution o f grooming elements following ICV haloperidol. H o w e v e r , I C V pretreatment with 10 p.g haloperidol resulted in a suppressive effect on bombesin (30 ng)-induced grooming comparable to the effect of 0.05 mg/kg SC haloperidol (see Table 3). Table 4 shows that neurotensin also suppressed bombesin-induced grooming mainly by reducing the elements scratching and to a lesser extent, bodily grooming. A shift in the distribution o f bombesin (10 ng)-induced grooming occurred after neurotensin treatment, consisting of a relative increase o f all elements, except scratching which was markedly reduced. Interestingly, a similar, but less p r o n o u n c e d shift was seen in the C S F and C S F + N T group.

%.

CSF

10nQ B

10~ 9 B

10n~ e

lo0~

m~

~i I

333

-. \

DISCUSSION Although it has been reported that diazepam and mepr o b a m a t e [4], but not naloxone, haloperidol [10,15], or neurotensin [15] affect bombesin-induced grooming, the present study clearly indicates that haloperidol, naloxone and neurotensin suppress grooming behavior. This suppression is o b s e r v e d on the basal level o f grooming as displayed by rats treated with placebo, but is very manifest on the e x c e s s i v e grooming induced by bombesin. The finding that naloxone and haloperidol reduce grooming displayed by C S F - t r e a t e d rats agrees nicely with the observation by Green et al. [11] that these drugs reduce novelty-induced grooming. Although all three drugs applied in the present study, naloxone, haloperidol and neurotensin, reduce the amount of bombesin-induced grooming, there is a marked difference in the composition of bombesin-induced grooming b e h a v i o r following pretreatment with these drugs. Whereas haloperidol suppresses the various elements more or less equally, not resulting in a shift in the pattern of grooming, pretreatment with naloxone or with neurotensin results in a marked

FIG. I. Comparison of the effects of naloxone (NAL; I mg/kg SC), haloperidol (HP; 0.05 mg/kg SC) and of neurotensin (NT; I ~g ICV) on composition of excessive grooming induced by ICV administration of 10 ng bombesin (B). Total grooming scores displayed by the various treatment groups are presented as 100% and indicated at the top of each subfigure. The various elements of grooming have been calculated as percentages of total grooming scores. H=head washing; B=bodily grooming; A=anogenital grooming; P=paw licking; S = scratching.

change in the distribution of grooming elements. This difference in the influence o f naloxone, haloperidol and neurotensin on bombesin induced grooming is best illustrated in Fig. 1, where the effect o f these drugs on the composition of grooming induced by 10 ng bombesin is depicted and compared. F r o m this figure it is clear that haloperidol induces a general reduction in grooming without changing the distribution o f grooming elements, whereas naioxone and neurotensin cause a marked reduction in the c o m p o n e n t scratching

EXCESSIVE GROOMING AND BOMBESIN

1183

accompanied by a relative (but not absolute) increase in head washing, bodily grooming and paw licking. The suppressive effect of haloperidol on bombesin-induced excessive grooming is in agreement with the reported antagonism of behavioral effects of bombesin by this drug [22] and with the observation that bombesin increases dopamine function in certain brain areas [27]. Moreover, the presently described suppressive effect of neurotensin on bombesin-induced grooming confirms the statement by Kalivas et al. [13] that neurotensin antagonizes behavioral hyperactivity regardless of the neurochemical initiation. Although naloxone, haloperidol and neurotensin also suppress excessive grooming induced by ACTH, hardly any effect of these drugs is observed on the composition of ACTH-induced°grooming behavior [26]. From the suppressive effect of naloxone on bombesininduced grooming it is tempting to assume that the element scratching is the component of grooming behavior, which is mainly displayed by activation of opiate receptor systems. This is in agreement with the finding that/3-endorphin induced grooming consists mainly of scratching, and can also be suprressed by naloxone [1,12]. Consequently, it seems that neurotensin is able to interfere with opiate receptor systems as well, at least with one of the behavioral results of

activation of such a system, i.e., scratching. The other elements of grooming behavior seem to be mainly displayed after activation of dopamine receptor systems as is suggested by the effect of pretreatment with haloperidol. In this respect it is worthwhile to notice that in the ontogeny of grooming behavior as well as in the sequence of elements of grooming behavior the element scratching takes a special position and appears to be organized in a way that is different from the other elements [21]. The present observation that the element scratching is differentially affected by naloxone and neurotensin on one hand and by haloperidol on the other, further supports the view that this element has a different place in the grooming repertoire than the other elements. Furthermore, it is evident from the present study that only relatively very high amounts (10 tzg) of naloxone and haloperidol are effective to significantly suppress bombesininduced grooming upon ICV administration. The strong lipophilic character of these drugs probably results in a weak penetration into the brain tissue after ICV administration. It may be that following such an administration the putative sites of action in the brain are difficult to be reached by these drugs, at least more difficult than after systemic administration.

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