Íåéðîíàóêè: òåîðåòè÷í³ òà êë³í³÷í³ àñïåêòè ÎÐÈòIÍÀËÜͲ²I ÄÎÑ˲²²IÄÆÅÍÍß BEHAVIORAL DISTURBANCES IN RATS INDUCED VIA THE INTRANIGRAL INJECTION OF Abstract. According to the experiments carried out on Wistar rats DSIP is expected to affect behavior and seizure (250-320 g) with the help of the EEG-, actometry recording susceptibility. Behavioral consequences of intraSNR and «open field» indices registration it was shown thatdilateral deltasleep-inducing injection resulted in oligo- administration are suggested also by known ability of akinesia, muscle tonus enhancement, decrease of wakefulness period and deep slow-wave sleep as well as paradoxal on.
homocarnosine in brain cortex, which developed as Unilateral dilateral deltasleep-inducing administration(5-20 nmole) into substantia nigre reticulation resulted in the a result of activation of GABA-decarboxylase and appearance of dose-dependent contralateral circlings, which decrease of GABA-transaminase activity [24, 25].
were blocked by naloxone (1.0 mg/kg). Haloperidol Hence the aim of the present investigation was to (1.0 mg/kg) caused the potentiation on keeping anuncomfortable position in animals with bilateral intra observe behavioral disorders induced by intraSNR substantia nigre reticulation dilateral deltasleep-inducing DSIP, with the emphasis on PD-connected deteriorations administration, while naloxone (1.0 mg/kg) markedly reduced and DSIP- induced effects, such as locomotion, sleep- this index. Analogous dilateral deltasleep-inducing intrastriatalinjection failed to induce the same behavioral disturbances.
wakefulness cycle, and antiseizure activity.
Intranigral dilateral deltasleep-inducing administration was followed by decreasing of seizure susceptibility to intra The experiments were carried out on male Wistar picrotoxin administration (2,0 mg/kg).
rats with the weight of 250-320 g. All the animals were Key words: delta sleep-inducing peptide, substantia nigra reticulata, kept at a constant room temperature of 22oC with circlings, naloxone, haloperidol, picrotoxin, seizures 12 hr artificial dark/light cycle and free access to astandard diet and tap water.
Substantia nigra (SN) continues to attract attention Procedures involving animals and their care were as a structure with the lowest threshold of a certain conducted according to University guidelines that reaction, such as rotation, which is considered to be comply with international laws and policies [European a “hemiparcinsonian” state [17]. Bilateral reduction Community Council Directive 86/609, OJ L 358, I, of SN dopamine output underlies behavioral December 12, 1987; National Institute of Health deteriorations, which are regarded as an experimental Guide for Care and Use of Laboratory Animals, US equivalent of Parkinsonian disease (PD) [27].
Inhibition of the dopaminergic neurons activity of SN Stainless steel guide cannulas (external diameter pars compacta might be achieved via pharmacological 0.5 mm) were implanted into the SNR and striatum modulation of SN reticular (SNR) neurons [7]. Thus, under hexenal anesthesia (100 mg/kg) in accordance bilateral stimulation of GABA-A or GABA-B receptors with the rat brain atlas [29]: (AP=-4.0; L=2.5; H=8.0 with muscimol and baclofen in SNR counteracted the and AP=0.8; L=3.0; H=4.5, correspondently). The evoked dopamine release [2]. Besides, baclofen cannulas were implanted bilaterally so that they did reduced, while muscimol intensified locomotor activity not cross the upper boundary of the structure under It is interesting to note that SN is a structure, which In order to identify the various stages of sleep converts peptidergic inputs into neuromediator outputs recording electrodes were implanted into the [10, 19, 20]. Hereby, peptidergic mechanisms are hippocampus (AP=-4.0; L=2.5; H=3.5), sensorimotor supposed to be also involved in the PD development, cortex and the neck muscles; an indifferent electrode and opiate- induced muscle rigidity is the most was attached to the nasal bones. Quick-soliding dental intensively discussed in that respect [18, 26].
plastic material was used for the fixation of the cannulas Several compounds, including those ones of peptide and electrodes to the skull. After the operations the rats nature, applied intranigrally caused antiseizure effects were caged in groups of 5-10 animals. Since a week after [5, 7, 9,-11, 23]. To some extent the intraSNR test could the surgery, the rats had been handled daily and adapted be regarded as discriminate for antiepileptics [8, 38]. In our experiments intranigral administration was used as Investigations were then started 1-2 weeks after the a screening test for antiepileptic potency of structural surgery. All the observations were performed from analogues of delta sleep-inducing peptide (DSIP) [33].
11.00 am to 5.00 pm. The number of rats in each The recent investigations revealed the DSIP group was 5-12. The analysis of circlings was confined ability to block seizures induced via stimulations of to estimate the number of rotations. It was performed the receptors of excitatory aminoacids [35, 37]. In this during the period of 20 min following the DSIP respect it is of interest to note that stimulation of injection into the left SNR. Locomotive activity was intraSNR excitatory aminoacid receptors resulted in evaluated quantitatively by means of seismorecorded generation of seizure activity [33]. Hence, intraSNR data registration for a period of 2 minutes after the Êîðåñïîíäåíö³ÿ: Å.Â. Êîáîëºâ, Ëüâ³âñüêèé íàö. ìåä. óí³âåð.,âóë. Ïåêàðñüêà, 69, Ëüâ³â, 79010, Óêðà¿íà Table 1. Effects of deltasleep-inducing injection (DSIP) and its combination with naloxone and haloperidol (*) - P<0.05 when compared with DSIP 5 nmol group (ANOVA test) placement of an animal on a movable floor. In USA) were injected intra in a dose of 1.0 mg/kg, addition «open field» data was determined by calculating 10 min before the DSIP administration.
the number of squares crossed during a period of At the end of the experiments, the rats were 2 minutes after placing the animal in the center of the anesthetized with pentobarbital sodium and perfused area3. Catalepsy was evaluated by determining the with paraformaldehyde. Frozen sections (32 mm) of duration of retention of an uncomfortable posture the brain were then prepared and every alternate [28]. Muscle tonus was estimated by clinically testing section mounted on gelatin-coated slides, stained with and recording the resistance of muscles to passive limb neutral red, covered with cover-slip, and examined by adduction. The number of animals with stereotype light microscopy. In all rats used in the analysis of behavior (i.e. sniffing, licking, and gnawing) was the data the cannula traces and electrodes were noted as an informative index for the identification identified at the appropriate location.
For data analysis, when appropriate, parametric The investigations of the sleep-wakefulness cycle statistic (Student’s t-test, analyses of variance) or the non-parametric statistic (Wilcoxon U-test) were electrographical and behavioral indices recorded after used. Krusckall-Wallis test was used in case of seizure the animals had been placed inside a sound-isolated severity estimation. P values <0.05 were considered box, with a constant level of artificial illumination.
Actometry and EEG-recordings were then carried out via signals sampling at 256 samples/s with the use of DSIP administration into the left SNR caused the a data acquisition board (National Instruments, manifestations of contralateral circlings, the intensity USA), and stored for off-line analysis. The signals of which depended on the dose peptide used. Circlings were band pass filtered, only frequencies between 0.5-40 Hz were allowed to pass. The polygraph administration, and their maximal intensity was records were inspected visually and epochs containing observed during 2-4 min after the moment of their artifacts discarded. Actometry recording was performed appearance. Circlings disappeared in 10-13 min after during the sleep-wakefulness cycle investigation.
the beginning of the observation (tab. 1). Periodical EEG was evaluated minimally during 50 sec [30]. Thestandard duration of the separate phases was ultimatelydetermined manually. Two phases of slow sleep were Tabl. 2. Effects of deltasleep-inducing injection determined in the followig way1: the light phase was (DSIP) and its combination with naloxone and characterized by the appearance of unstable, relatively haloperidol on the duration of uncomfortable position low-amplitude activity with separate theta and delta waves, the occurrence of which did not exceed 180 mcV; single alpha-rhythm spindles were also noted at this stage. The second phase - the deep slow wave stage was characterized by an increase in the number and amplitude of theta and delta waves: up to 200 mcV.
The latency in both falling asleep and paradoxal sleep Microinjections of DSIP (synthesized and purified by the method described above [33]) were conducted under mild ether anesthesia after fixing the animals in a stereotaxic device. Peptide was dissolved in saline in a volume of 1.0 mcl and injected in dosages of 5.0;10.0 and 20.0 nmole. The speed of injections was 0.5 mcl/min. Analogous administration of saline was performed on rats in the control groups. Haloperidol («Gedeon Richter», Hungary) and naloxone («Sigma», P was calculated using the ANOVA test.
Fig. 1. The influence of deltasleep-inducing injection injection into substantia nigre reticulation and caudate nuclei on locomotor A: Ordinate: the locomotor activity related pertaining to the indices of horizontal and vertical activity in animals treated with saline (control, 100%); Abscissa: time after pharmacons administration (hours); B: Ordinate: the same as in «A»; Abscissa: I - DSIP intraSNR administration in dose of 5,0 nmol; II- and III- DSIP administration into rostral part of n.caudatus in dosage of 5,0 and 10,0nmol correspondently.
The number of experimental animals are presented inside the bars. #-P<0,05 and ##-P<0,01 in comparison with the control group.
sniffings were observed in 2 of 8 animals and 3 animals motor functions, restricted limb movements and demonstrated chewing during their circlings. These decrease in size of steps taken were registered.
reactions did not differ from those in the control group, Significant resistance in passive limb adduction and where stereotype sniffings were recorded in 3 of 7 rats.
increase in muscle tonus occurred. Ptosis, periodical After the placement of the rats in an uncomfortable gnawing and sniffings were registered in 3 of 8 position (on the side or back) they retained it for animals. The mentioned above behavioral disturbances 17.9+3.2 sec a significantly longer period in comparison were observed during a period of 60-80 min after the with the analogous data obtained from the animals in DSIP microinjections with a continual decrease in the the control group (1.4+0.2 sec; F(1,12)=26.46, p<0.001; indices investigated later on. The absence of differences (tab. 2). After the preliminary naloxone administration between the experimental and control groups as well the animals failed to keep the uncomfortable posture as with the initial level was observed 3.5-6.0 hrs from imposed to them (F(1,12)=0.03, p>0.05; Table 2) and the moment of DSIP intra-SNR administration no circling behavior was observed (tab. 1). Stereotype (fig.1,A). An intranigral DSIP administration in a sniffings and gnawings were displayed by 3 of 7 rats.
dose of 5 nmole as well as a DSIP injection into the The DSIP injection which was administered after a rostral parts of the nucleus caudatus in a dose of 10 preliminary dose of haloperidol, resulted in much nmole did not result in a significant decrease of longer retention of uncomfortable posture - 179+35 locomotive activity in the animals (fig.1,B) and did sec (F(1,12)=25.74, p<0.001; Table 2). When the animals eventually regained a vertical position, markedly The sleep-wakefulness cycle investigations carried reduced locomotive activity was recorded - the rats out on 5 rats with intranigral DSIP microinjections remained immobile during all the period of observation revealed a significant decrease in active wakefulness (tab. 1). Paroxysmal gnawings were observed in 2 of (F(1,18)=36.13, p<0.001) and prolonged deep slow 8 rats and 2 rats displayed stereotype sniffings.
wave sleep and paradoxal one (F(1,18)=11.08, p<0.01 3-10 min after the DSIP injection into the SNR and F(1,18)=8.00, p<0.05), correspondently, compared paroxysmal arrest reactions with a duration of 10-20 to the analogous indices of the animals in the control sec to 5.0-6.5 min were observed. After the placement group (injected intranigrally with saline) (fig. 2,A).
of the rats into the center of the «open field», 4 of 10 These changes were recorded in the background of the animals remained as placed throughout observation decrease in locomotive activity (fig. 2,B).
(2 min). The average number of squares crossed Picrotoxin (2,0 mg/kg) produced the first convulsive decreased significantly in comparison with the reactions at average 22,1+ 1,0 min after dosage in analogous index in the animals of the control group control animals (saline injected into SNR). The which decreased respectively from 547+130 to 129+46; intensity of seizures increased over the next F(1,18)=9.01, p<0.01; (fig.1,A) as well as with its 10-15 min, and generalized convulsive attacks occurred initial value in the animals of the experimental group.
in 15 of 17 rats with latent period of 35,0+ 1,5 min.
Furthermore, a significant decrease in vertical bars The mean intensity of convulsions was 4,0+0,1 was observed (fig.1,A) compared both with the points. The other two rats had clonic convulsions of background level and with the activity in the control group (from 27.3+2.5 to 10.9+4.5 (F(1,18)=10.15, Convulsant treatment of rats given bilaterally p<0.01). During locomotion the slowing-down of intranigrally DSIP led to the formation of seizures Fig. 2. Sleep-wakefulness cycle characteristics under condi- Fig.3. Seizure manifestations induced by picrotoxin (2,0 tions of deltasleep-inducing injection injection into substantia mg/kg. i.p.) administration to rats treated intranigrally substantia nigre reticulation with deltasleep-inducing injection (10 nmol).
A: Ordinate: seconds; Absciss: 1- wakefulness; 2- latency of Ordinate- indices under investigation in % pertained to sleep precipitation; 3- superficial, and 4- deep stages of slow- corresponded ones in the control group of animals (100 %).
wave sleep; 5- latency of paradoxal sleep precipitation; #-P<0.05; ###-P<0,001 in comparison with the control 6- paradoxal sleep; B: Ordinate: actometry data; Abscissa: time after pharmacons administration (minutes).
#-P<0,05 in comparison with the control group.
with a latent period which was 24% greater than that excluded. The opioid nature of other DSIP-induced in control animals (F(1,25)=6.61, p<0.05) (fig. 3).
effects, namely sleep induction, were also suggested [1].
Rats showed intense clonic convulsions of the In the case of intranigral DSIP injection a muscles of the trunk and hindlimbs; two of ten significant decrease in wakefulness and increase in animals developed generalized convulsive seizures.
both deep slow-wave and paradoxical sleep occurred.
The latency of generalized clonic-tonic fits exceeded This data testifies to the fact that SNR structures do that one in control group by 61,0% (F(1,25)=62.80, take part in deep slow-wave and paradoxal sleep, p<0.001). The mean severity of seizures was 20% which are known to enlarge after systemic DSIP lower than that in control animals (H=14.52, p<0,001).
administration [22, 39]. It should be noted that the Our investigations have shown that unilateral DSIP muscle tonus reduction, which is characteristic of administration into the SNR caused contralateral precipitation of the paradoxal sleep [16] is apparently rotations of a dose-dependent character. The efficacy contrary to the muscle rigidity induced after DSIP of naloxone in relatively low dosage (1.0 mg/kg) in intra-SNR administration. Such a contradiction preventing any circlings suggests that the opioid could be explained by the periodical DSIP-induced mechanisms activated by the intranigral DSIP testify activation of the endogenous system, which controls to their development. Haloperidol was also effective in the decreasing of muscle tonus (presumably - part this way. But the simultaneous participation of of nuclei involved in PS-precipitation). Such an dopaminergic mechanisms as alternative cause of the induction could be secondary resulting from a circlings could hardly be suggested because the consequence of the primary mechanisms of muscle haloperidol and DSIP-treated animals retained their uncomfortable posture significantly longer than those The activation of the mechanisms of paradoxal treated with separately administrated drugs. It might be sleep is shown to cause anticonvulsive effects [3, 36].
that the locomotive disabilities were influenced by the According to it [16] the turn on-off mechanisms of circlings. Therefore, the potentiation of haloperidol- paradoxical sleep are determined by noradrenergic induced catalepsy by intra-SNR DSIP could be brain systems. On the other hand, it has been shown supposed and the neuroleptic mode of DSIP-induced that the antiepileptic effects of intranigral muscimol effects could be suggested. This suggestion is supported are blocked by yohimbine (alpha-2-adrenoreceptor by the data showed a marked increase of DSIP-like antagonist), which results in the disinhibition of immunoreactivity in the hypothalamic region after noradrenergic terminals [6, 31]. Thus, it could be systemic haloperidol administrations [40].
assumed that the antiseizure effect of intranigral DSIP It should be noted that stereotypic sniffings and administration, together with the application of other gnawings were observed after the haloperidol application drugs, may be achieved via the paradoxal sleep following the intranigral opioid peptides administration mechanisms disinhibition as a result of the presynaptic [18, 26]. Therefore, the participation of opioid inhibition of corresponding noradrenergic mechanisms in such behavioral changes is not to be mechanisms. From the viewpoint of the above discussion the ability of DSIP to modulate the ðàëüíîå ââåäåíèå äåëüòàñîí-èíäóöèðóþùåãî ïåï- adrenoreceptor activity [14] as well as dopaminergic òèäà òàêæå óìåíüøàëî ñóäîðîæíóþ ãîòîâíîñòü êðûñ â îòíîøåíèè âíóòðèáðþøèííîãî ïðèìåíå- íèÿ ïèêðîòîêñèíà (2,0 ìã/êã). (Íåéðîíàóêè: òåîð.
Hence, the participation of the opiatergic and êëèí. àñï.— 2006. — Ò. 2, ¹ 1-2. — Ñ. 14-19).
catecholaminergic mechanisms in the creation of Êëþ÷åâûå ñëîâà: äåëüòàñîí-èíäóöèðóþùèé ïåï- behavioral effects of intra-SNR administered DSIP òèä, ðåòèêóëÿðíàÿ ÷àñòü ÷åðíîãî âåùåñòâà, ðîòà- was supposed. Besides, DSIP intensifies GABA synthesis öèè, íàëîêñîí, ãàëîïåðèäîë, ïèêðîòîêñèí, ñóäî- [24, 25], which could be suggested as the motive of the display of the stereotype behavior described above [6].
The role of DSIP-induced restriction of elaboration of ILs can not be excluded [41]. Finally, the interaction Ïîâåä³íêîâ³ ïîðóøåííÿ, âèêëèêàí³ ó ùóð³â between opioid, GABA systems realized with thealpha-2-adrenoreceptors was reported [4, 19].
âíóòð³øíüîí³ãðàëüíèì çàñòîñóâàííÿì The above- mentioned scheme of consequences is äåëüòàñîí-³íäóêóþ÷îãî ïåïòèäó congruent with the antiepileptic mechanisms realized Ó äîñë³äàõ íà ùóðàõ ë³í³¿ ³ñòàð (250- 320 ã) çà via action of different substances upon SNR. As, for äîïîìîãîþ ìåòîä³â ÅÅÃ-ðåºñòðàö³¿, àêòîìåòð³¿, the cause of antiepileptic effects such mechanisms as äîñë³äæåíü ïîêàçíèê³â ó «â³äêðèòîìó ïîë³» áóëî activation of GABA mediation [6, 17, 31], kappa- âñòàíîâëåíî, ùî á³ëàòåðàëüíå çàñòîñóâàííÿ äåëü- opioid receptors [5] along with blocking of excitatory òàñîí-³íäóêóþ÷îãî ïåïòèäó âèêëèêàëî, îë³ãî- àê- mechanisms [9], substance P [11] should be mentioned.
³íåç³þ, çá³ëüøóâàëî òîíóñ ìÿç³â, çìåíøóâàëî ïå- Besides, effects of different peptides intranigrally is ð³îä íåñïàííÿ ³ âèêëèêàëî ãëèáîêèé ïîâ³ëüíîõâè- ëüîâèé ñîí, à òàêîæ ïàðàäîêñàëüíèé ñîí. Îäíî- resulted in antiseizure action; kyotorphin and its ñòîðîííº çàñòîñóâàííÿ äåëüòàñîí-³íäóêóþ÷îãî structural analogues [13], somatostatin, neurotensin ïåïòèäó (5-20 íìîëü) â ðåòèêóëÿðíó ÷àñòèíó ÷îð- [34] as well as activation of benzodiazepine receptors íî¿ ðå÷îâèíè âèêëèêàëî ïîÿâó êîíòðëàòåðàëüíèõ [23] heve been described. Mentioned induction of ðîòàö³é, ÿê³ áóëè äîçà-çàëåæíèìè òà áëîêóâàëèñü neurotransmitter-involved mechanisms is attracted çà äîïîìîãîþ íàëîêñîíó â äîç³ 1,0 ìã/êã. Ãàëîïå- for the explanation of the action of each of peptides.
ð³äîë (1,0 ìã/êã) ïîòåíö³þâàâ çäàòí³ñòü âíóòð³ø- íüîí³ãðàëüíîãî çàñòîñóâàííÿ äåëüòàñîí-³íäóêó- It should be stressed that neurodegeneration, þ÷îãî ïåïòèäó âèêëèêàòè òðèâàëå óòðèìóâàííÿ which is pertinent to PD, is opposite to effect of òâàðèí â íåçðó÷í³é ïîç³, â òîé ÷àñ ÿê íàëîêñîí neuroprotection induced by DSIP [37]. Hence, to çìåíøóâàâ âêàçàíèé åôåêò äåëüòà-ñîí ³íäóêóþ÷î- support the role of DSIP in PD related disturbances ãî ïåïòèäó. Àíàëîã³÷íå âíóòð³øíüîñòð³àðíå çàñ- pathogenesis means to support the secondarily character òîñóâàííÿ äåëüòàñîí-³íäóêóþ÷îãî ïåïòèäó íå âèê- of DSIP-like neuropeptides rising in zone of primarily ëèêàëî ïîä³áíèõ ïîâåä³íêîâèõ ïîðóøåíü. Âíóòð³- øíüîí³ãðàëüíå ââåäåííÿ äåëüòàñîí-³íäóêóþ÷îãî increasing of neurotoxicity. In this case all DSIP- ïåïòèäó òàêîæ çìåíøóâàëà ñóäîìíó ãîòîâí³ñòü ùóð³â ùîäî âíóòð³øíüîî÷åðåâèííîãî çàñòîñó- hypercompensative state of peptidergic systems in âàííÿ ï³êðîòîêñèíó (2,0 ìã/êã). (Íåéðîíàóêè: òåîð.
SNR. In the course of exhausting of their activity, êë³í. àñï.— 2006. — Ò. 2, ¹ 1-2. — Ñ. 14-19).
neurotoxicity resulted in stable degenerative neuronal Êëþ÷îâ³ ñëîâà: äåëüòà ñîí-³íäóêóþ÷èé ïåïòèä, deteriorations and substitution of «compensative» ðåòèêóëÿðíà ÷àñòèíà ÷îðíî¿ ðå÷îâèíè, ðîòàö³¿, íàëîêñîí, ãàëîïåð³äîë, ï³êðîòîêñèí, ñóäîìè symptoms by stable «pathogenic» ones.
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