Central Effects of Neuropeptide K on Water and Food Intake in the Rat

Brain Research Bulletin, Vol. 28, pp. 299-303. 0 Pergamon Press plc, 1992. Printed in the U.S.A. 0361-9230192 $5.00 + .oO

Central Effects of Neuropeptide K on Water and Food Intake in the Rat

M. ACHAPU, P. POMPEI, C. POLIDORI, G. DE CAR0 AND M. MASSI’

Istituto di Farmacologia, Facolta’ di Farmacia, Universita’ di Camerino, Via Scalzino 5, 62032 Camerino (MC) Italy

Received 14 March 1991

ACHAPU, M., P. POMPEI, C. POLIDORI, Cl. DE CAR0 AND M. MASSI. Central effects of neuropeptide K on water and food intake in the rat. BRAIN RES BULL 28(2) 299-303, 1992.-The present study investigated the effect on water and food intake in the rat of the intracerebroventricular (XV) injection of neuropeptide K (NPK), the N-terminally extended form of neurokinin A. NPK inhibited water deprivation-induced water intake even at 31.2 @at. At higher doses, it inhibited also water intake induced by ICV angiotensin II or by subcutaneous hypertonic NaCl, and food-associated drinking, the threshold dose being 125 @rat. In response to 125 @rat, food intake following 16 h food deprivation was not reduced. NPK inhibited food intake only at 500 @rat, a dose that evoked excessive grooming in treated animals. Thus NPK is a potent inhibitor of water deprivation-induced drinking and at higher doses it exerts a general antidipsogenic effect towards several dipsogenic determinants, without affecting food intake. On the other hand, it inhibits food intake only at high doses, 500 nglrat or more, but this inhibition might be just related to the intense grooming evoked. The effects of NPK on ingestive behavior are markedly different from those of neurokinin A, which selectively inhibits osmotic drinking and food-associated drinking. These differences suggest that NPK itself may exert its effects on the central nervous system, not necessarily through the conversion to neurokinin A.

Neuropeptide K Tachykinins Water intake Food intake Rat

NEUROPEPTIDE K (NPK) is a 36 amino acid peptide (30,31), belonging to the tachykinin (TK) peptide family (14). Recent genomic cloning experiments have shown that substance P (SP), neurokinin A (NKA) and NPK are derived from preprotachyki- nin (PPT) A gene. Alternate RNA splicing of primary transcripts of the gene results in the production of a-, B- and y-PPT mRNA. NPK contains the sequence 72-107 of B-PPT (16), and represents an amino-terminally extended form of NKA, to which it can be converted (6). In spite of the wide distribution of NPK in the cortex, hippocampus, striatum, substantia nigra, dorsal root ganglia, dorsal and lateral horns of the spinal chord and in the cerebrospinal fluid (2, 5, 32, 33), the physiological func- tions of this neuropeptide are still unknown. Moreover, it is not clear whether NPK itself might exert its physiopharmacological effects or whether conversion to NKA is required for biological activity.

TKs, such as SP, eledoisin, physalaemin, kassinin and NKA, exert potent effects on the rat ingestive behavior. Their intracerebroventricular (ICV) injection markedly inhibits drinking (7- 13, 25), as well as salt appetite (21-23). SP, physalaemin and eledoisin appear to be general antidipsogens since they inhibit drinking evoked by several dipsogenic challenges, while NKA selectively inhibits drinking induced by cell dehydration and food-associated drinking, but does not affect drinking induced by other dipsogenic treatments (25).

The present study was aimed at evaluating the effects of ICV injection of NPK on water intake evoked by a variety of dipso- genie treatments and on food intake evoked by food deprivation.

METHOD

Animals

Male albino Wistar rats (Charles River, Calco, Como, Italy), averaging 250-275 g at the moment of intracranial surgery, were employed. They were housed individually in temperature-con- trolled room on a 12:12 light-dark cycle. Food in pellets (Mill, Morini, Reggio Emilia, Italy) and tap water were available ad lib.

Drugs

NPK and Ile’-angiotensin II (Ang II) were purchased from Peninsula Lab. Inc., Belmont, CA.

Surgery

All the animals employed were anaesthetized with Equith- esin, 3 ml/kg body weight (b.wt.) intraperitoneally, and fitted by stereotaxic surgery with a stainless steel cannula (o.d. 600 p), aimed at 1 mm above the lateral ventricle. The guide-cannula was attached to the skull by jewelry screws and dental acrylic cement. The rats were allowed 1 week to recover from surgery before testing began. During the postoperative period the animals were handled and mock-injected to adapt them to the testing procedure.

Intracranial Injections

NPK and Ang II were dissolved in sterile isotonic saline and were administered through a stainless steel injector (o.d. 300 p),

II ^ . . . . -Kequests tar reprmts should be addressed to Dr. Maurizio Massi, Istituto di Farmacologia, Universita’ di Camerino, Via Scalzino 5, 62032 Cam-

erino (MC) Italy.

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temporarily inserted into the guide-cannula and protruding 2 mm beyond the tip of the cannula. The injector was longer than the guide-cannula in order to reduce the possibility of back-flow of the injectate into the guide-cannula. All the drugs were given in a constant volume of 1 pl.

Experimental Procedure

Experiment I. Effect of NPK on drinking induced by subcutaneous (SC) hypertonic NaCl. Hypertonic NaCl (I ..5 M; 1 ml/ 100 g b.wt.) was given SC (25) in the loose skin of the back. After the SC injection the animal was returned to its cage from which water had been temporarily removed. Fifteen minutes after the administration of NaCl the animal received an ICV injection of NPK or of isotonic saline (controls) and immediately aftenvards they had access to water. The intake of water was measured at 15, 30, 60, 90 and 120 min after access to water.

The experiment was carried out according to a within subject design: the rats employed received all the doses of NPK and isotonic saline at intervals of 4-5 days.

Experiment 2. Effect of NPK on Ang II-induced drinking. Ang II (100 ng/rat) was given by ICV injection 1 min after that of NPK or that of isotonic saline (controls). Immediately after the second ICV injection the animals had free access to water and food. Water intake was measured at 15, 30 and 60 min after the administration of Ang II.

Again, the experiment was carried out according to a within subject design, and the animals employed were treated at intervals of 4-5 days with isotonic saline, as well as with all the doses of NPK.

Experiment 3. Effect of NPK on water deprivation-induced drinking. Animals were deprived of water, but not food, for 16 h (between 18:OO p.m. and 10:00 a.m. of the following day). The rats employed in this experiment had already experienced 1 water deprivation before been tested. The ICV injection of NPK or of isotonic saline was given just before access to water. Intakes of water were recorded at 15, 30 and 60 min after access to it. The animals employed received all the different treatments at intervals of 7 days.

Experiment 4. Effect of NPK on food intake and on food-associated drinking following food deprivation. The intake of food was elicited by depriving the animals of food, but not of water (25), for 16 h (between 18:00 p.m. and 10:00 a.m. of the following day). The treatment took place after they had experienced one previous food deprivation. The ICV injection of NPK, or of isotonic saline, was given immediately before access to food. The intake of food, as well as the associated intake of water, was measured at 15, 30, 60, 90, 120 min after food presenta- tion. Animals received 3 NPK treatments (3 1.2. 125 and 500 ng/rat) at intervals of 7 days.

Experiment 5. Behavioral alterations following ICV injection of NPK. Water and food replete rats were treated with ICV injection of isotonic saline (controls) or of NPK 31.2, 125 and 500 ng/rat. Following injection animals were returned to their home cages where their behaviors were systematically observed, classified and recorded once each minute during a predeter- mined, programmed-tone-cued 0.6 s interval, with a fixed 1-min interobservation interval. The categories of behavior recorded were those previously described (1,15) and included: feeding, drinking, grooming, resting, locomotion, rearing, sniffing, lick- ing, standing, urination, defecation, stretching, yawning, treading, head and body shaking, coprophagia and miscellaneous other behaviors. Data were expressed as total number of observations for each category in 15 consecutive programmed intervals. Different animals were employed for each pharmacological

treatment. Five rats were tested with NPK 3 I .2 or 125 ng/rat. 6 rats with NPK 500, while 9 animals were used as controls.

Sequence of Testing

Experiments l-4 were repeated measures experiments in which all the doses employed were represented on a treatment day. To balance the order in which treatments were given, a) the number of animals at the beginning of the each experiment was a multiple of the number of treatments, b) rats were assigned at ran- dom to different groups, whose number was equal to the number of treatments and c) the order of treatments for every group on different days was determined by the use of Latin squares (29).

Validation of ICV injections

At the end of each experiment, animals received an ICV injection of 100 ng/rat of Ang II to behaviorally validate the cannula placement.

Following this test, each animal received an ICV injection of 1 p,l of India ink and was immediately sacrificed with an over- dose of Equithesin. The brain was rapidly removed and dissected to determine the diffusion of the dye in the ventricular space.

Statistical Analysis

Data are presented as averages (means -+ SEM). Statistical analysis of the data was performed by the analysis of variance (ANOVA). A multifactor repeated measures ANOVA was used for Experiments l-4, to account for multiple measures from the same rat in different experimental sessions. Data of Experiment 5 were analysed by a randomized design ANOVA. Planned pairwise comparisons were made by means of t-tests. Statistical significance was set at p<O.O5.

RESULTS

Experiment I. Effect of NPK on Drinking Induced by SC Injection of Hypertonic NaCl

The overall analysis of variance revealed a powerful treatment effect, F(3,15) = 9.111, p<O.O05, together with a significant treatment-time interaction, F( 1260) = 2.064, pcO.05. The ICV injection of NPK, in the range of doses between 31.2 and 500 ng per rat, produced a dose-related suppression of drinking induced by SC injection of hypertonic NaCl (Fig. 1). Only small and not statistically significant inhibitions were observed at 31.2 ng/rat. Following 125 ng/rat, an almost complete inhibition @<O.OOl) was observed at 15 min after drug administration and the effect was statistically significant up to 30 min. At 500 ng/ rat NPK produced a complete (100%) suppression of drinking in the first 15 min and the effect was statistically significant for every observation time up to 2 h.

Experiment 2. Effect of NPK on ANG II-Induced Drinking

NPK, at doses that markedly suppressed drinking induced by SC injection of hypertonic NaCl, produced also an inhibitory effect on ANG II-induced drinking (Fig. 2). The overall analysis of variance revealed the presence of a statistically significant treatment effect, F(3,24) = 34.834, p<O.OOOl, in the presence of treatment-time interaction, F(6,48) = 5.985, p<O.OOl. At the dose of 3 1.2 ng/rat the intake of treated rats was statistically in- distinguishable from that of controls. Marked inhibition of Ang II-induced drinking was observed at 125 and 500 ng/rat, which gave highly significant inhibition all over the 60 min period of observation.

CENTRAL EFFECTS OF NEUROPEPTIDE K 301

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0 0 15 30 60 90 120

FIG. 1. Cumulative water intake in response to SC hypertonic NaCl load in rats treated with ICV injection of isotonic saline (ISO) or of different doses of NPK (@at). Values are means 2 S.E.M. of 6 subjects. Differ- ence from controls: “pcO.01; ‘p<O.O5; where not indicated, difference from controls was not statistically significant.

Experiment 3. Effect of NPK on Water Deprivation-Induced Drinking

The results are reported in Fig. 3. The analysis of variance revealed a significant treatment effect, F(3,15) = 27.877, p<O.OOOl, in the presence of significant treatment-time interaction, F(6,30)=6.158, p<O.O05. At the dose of 31.2 @rat, NPK significantly reduced water intake in the fist 15 min after access to water. At doses of 125 and 500 ng/rat, NPK com-

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31.2 ng

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125 ng

506 ng

0 15 36 66 min

FIG. 2. Cumulative water intake in response to ICV Ang II in rats treated with ICV injection of isotonic saline (ISO) or of different doses of NPK (ngkat). Values are means? S.E.M. of 9 subjects. Difference from controls: “pcO.01; where not indicated, difference from controls was not statistically significant.

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I

60 min

3. Cumulative water intake induced by water deprivation in rats treated with ICV injection of isotonic saline (ISO) or of different doses of NPK (tip/rat). Values are meanskS.E.M. of 6 subjects. Difference from controls: -p<O.Ol; ‘p<O.O5; where not indicated, difference from controls was not statistically significant.

pletely suppressed drinking in the first 15 min and the inhibition remained statistically significant for every observation time up to 60 min.

Experiment 4. Effect of NPK on Food Intake and on Food-Associated Drinking Following Food Deprivation

The analysis of variance showed a significant treatment effect on food-intake, F(3,30)=29.87, p<O.OOl. At the dose of 31.2 and of 125 ng/rat, no significant reduction of food intake was observed. On the other hand, at the dose of 500 ng/rat, NPK evoked a complete suppression of food intake in the first 15 min of observation. Afterwards, the animals began to consume some food, but the intake was very low, and significantly lower than that of controls, even at 2 h after injection (Fig. 4).

In the same experiment, together with food intake, also food-associated drinking was measured. At the end of the experiment, the effect of NPK on food-associated drinking was evalu- ated only at the doses of 31.2 and 125 @rat, that is at doses that did not affect food intake (Fig. 5).

The analysis of variance showed a nonsignificant overall treatment effect, F(2,18) = 2.089, p>O.O5, and a significant treatment-time interaction, F(8,72) = 2.042, pcO.05. NPK reduced food-associated drinking during the first 60 min after injection of 125 ng/rat. The lower dose of 31.2 ng/rat produced only small, non significant modifications of drinking.

Experiment 5. Behavioral Alterations Following ICV Injection of NPK

Four behavioral categories were consistently observed in our experimental animals: grooming, resting, locomotion and treading (Fig. 6). Taken together they accounted for more than 93% of the observations made.

The one-way analysis of variance revealed a significant treatment effect on grooming, F(3,2)=27.867, p<O.OOl. No significant difference was observed in response to 31.2 @rat of NPK.

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0 15 30 60 90 120 min

FIG. 4. Cumulative solid food intake in food-deprived rats, treated with ICV injection of isotonic saline (ISO) or of different doses of NPK (ng/ rat). Values are meanskS.E.M. of 11 subjects. Difference from controls: “~~0.01; where not indicated, difference from controls was not statistically significant.

On the other hand, grooming was significantly and progressively increased at higher doses, 125 and 500 @rat. Again, a significant txeatment effect, F(3,21) =4.933, pcO.01 was observed on resting, that was significantly reduced by 125 and 500 ng/rat.

On the other hand, locomotion and treading were not significantly affected by NPK at the different doses tested. Other behaviors were only occasionally and sporadically observed, and the paucity of observations did not allow a statistical evaluation.

DISCUSSION

The results of the present study show that ICV injection of NPK exerts a potent inhibitory effect of water deprivation-

0 15 30 60 90 120 min

FIG. 5. Cumulative food-associated drinking following ICV injection of isotonic saline (ISO) or of different doses of NPK (@rat). Values are meanskS.E.M. of 10 subjects. Difference from controls: “p<O.Ol; l p<O.O5; where not indicated, difference from controls was not statistically significant.

I , ,

0 31.2 125 500 “g

FIG. 6. Effect of ICV injection of different doses of NPK (ng/rat) or of isotonic saline (0) on grooming, resting, locomotion and treading. Val- ues are means of observations + S.E.M. in 5-9 subjects (see the Method section). Difference from controls: “p<O.Ol; .p<O.O5; where not indicated, difference from controls was not statistically significant.

induced drinking. NPK inhibited also drinking in response to ICV Ang II, to cellular dehydration and food-associated drinking, but at higher doses.

Finally, NPK reduced food intake induced by food deprivation, but only at 500 ng/rat, that is at a dose higher than those necessary to inhibit water intake. Our study showed that 500 ng/ rat of NPK produces intense, compulsive grooming so that the effect on food intake might be, at least in part, expression of interference of competing behaviors.

Indeed, a significant increase in the occurrence of grooming was observed also in response to 125 ng/rat, which inhibited drinking evoked by all the dipsogenic determinants employed. However, the same dose did not modify feeding, thus suggest- ing that this dose did not generally impair the rat ingestive behavior or, in other words, that the effects on water intake observed in response to 125 ng/rat can be considered expression of a selective behavioral effect. On the other hand, our study does not provide any evidence for the behavioral selectivity of the inhibitory effect of ICV NPK on food intake, already reported by Sahu et al. (28).

An interesting finding of the present study is that the spectrum of antidipsogenic activity of NPK is different from that of NKA. Experiments done in our laboratory have repeatedly con- firmed that NKA exerts a selective effect on ingestive behavior, being very potent in inhibiting osmotic drinking and food-asso-

ciated drinking, while being inactive or eliciting just small effects on drinking induced by ICV Ang II and by water deprivation, as well as on food intake (25). NPK exerted effects similar to

CENTRAL EFFECTS OF NE~OPE~IDE K 303

those of NKA only on osmotic drinking and on food-associated drinking. If the differences in molecular weight are taken into account, the 2 peptides are roughly equipotent. On the other hand, NPK inhibited also drinking to water deprivation and to ANG II thus acting, unlike NKA, as a general antidipsogenic agent.

The different spectrum of action of NPK and NKA suggests that the biological actions of NPK on the central nervous system might he due at least in part to the molecule itself, without conversion into NKA. In keeping with this hypothesis, immuno- chemical studies showed a large content of NPK in the rat central nervous system (2, 5, 33), including the hypothalamus. Moreover, NPK is also present in the cerebrospinal fluid (32).

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from which it can get access to the ci~umven~cul~ stntctures

involved in Ang II- and in cell dehydration-induced drinking. Marked differences between NPK and NKA have also been

observed for the sialagogic potency of the 2 peptides by Krause and Takeda (17), who have hypothesized that NPK might exert its action by interacting with a “novel” TK receptor different from those so far proposed, that is the NK-I, NK-2 and NK-3 (18-20, 26, 27). The hypothesis of Krause and Takeda might also explain the differences observed in our studies in the spectrum of biological activity of NPK and NKA. On the other hand, the high affinity of NPK for NK-2 receptors (3,4), might account for similar action of the 2 peptides on osmotic drinking, which appears to be mediated by NK-2 receptors (24).

REFERENCES

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Central Effects of Neuropeptide K on Water and Food Intake in the Rat