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BILATERAL 6-OHDA LESIONS TO THE HIPPOCAMPUS ATTENUATE THE FACILITATORY EFFECT OF CCK-8 US AND CAERULEIN ON MEMORY IN RATS
Pharmacological Research, Vol. 41, No. 3, 2000 doi:10.1006rphrs.1999.0591, available online at http:rrwww.idealibrary.com on
BILATERAL 6-OHDA LESIONS TO THE HIPPOCAMPUS ATTENUATE THE FACILITATORY EFFECT OF CCK-8US AND CAERULEIN ON MEMORY IN RATS ´ MARIA M. WINNICKAU and KONSTANTY WISNIEWSKI Department of Pharmacology, Medical Academy of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland Accepted 31 August 1999
The involvement of dopaminergic projection to the hippocampus in the facilitatory effect of cholecystokinin-unsulphated octapeptide ŽCCK-8US. and caerulein ŽCER. on memory motivated affectively was investigated in male rats. CCK-8US and CER were given subcutaneously at the doses of 10 m g kgy1 and 0.5 m g kgy1 , respectively, immediately after a single learning trial in a passive avoidance situation, after bilateral 6-OHDA lesions to the dentate gyrus of the hippocampus. In order to protect noradrenergic neurones against destruction by neurotoxin, 30 min before surgery rats were pre-treated intraperitoneally with 25 mg kgy1 of desmethylimipramine, an inhibitor of noradrenaline uptake. Bilateral 6-OHDA lesions to the hippocampus significantly attenuate the facilitatory effect of CCK-8US and CER on retention of passive avoidance behaviour evaluated 24 h after the learning trial. Neither, destruction of dopaminergic endings in the hippocampus, nor application of CCK-8US and CER changed the spontaneous psychomotor activity of rats estimated in an ‘open field’ test. These results may indicate that the facilitatory effect of CCK-8US and CER on memory motivated affectively is, in part, mediated by dopaminergic projection from the ventral tegmental area to the dentate gyrus of the hippocampus. Q 2000 Academic Press KEY
WORDS:
CCK-8US, CER, hippocampus, 6-OHDA lesions, passive avoidance, locomotor activity, rats.
INTRODUCTION Cholecystokinin ŽCCK. is the most widespread and abundant neuropeptide in the central nervous system. High concentration of CCK and CCK mRNA have been identified throughout the brain including: cerebral cortex, hippocampus, olfactory bulb, olfactory tubercle, amygdala, hypothalamus, ventral mesencephalon, nucleus tractus solitarius and periaquaductal grey w1]5x. In the brain, CCK exists mainly as an octapeptide, both in sulphated and unsulphated form w1x. The receptors for CCK have been divided into two types: the CCK A receptor subtype which was found in periphery and some brain regions; and widely distributed in the brain CCK B receptor subtype. Sulphated CCK-8 and amphibian decapeptide caerulein ŽCER. have been served as unselective U
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CCK receptors agonists, whereas unsulphated CCK-8 ŽCCK-8US., CCK-4, BC 264 and BC 197 have been used as selective CCK B receptors agonists w6]8x. It has been shown that CCK may control various physiological functions, e.g. pain perception w9x, feeding and satiety w10x, hypothermia w11x, and sedation w12x. Recent investigations have shown that CCK takes part in anxiety and panic attacks w13, 14x. The increasing evidence supports the involvement of CCK on cognitive processes. Early studies have shown that peripheral injections of CCK-8 impaired acquisition and facilitated extinction of an active avoidance behaviour w15x. In a passive avoidance situation, CCK-8 improved retention when it was injected either after the single learning trial w15x or before the retention testing w16x. Moreover, CCK-8 given either intracerebroventricularly or subcutaneously prevented experimental amnesia induced by electroconvulsive shock, carbon dioxide inhalation, or cycloheximide injection w17, 18x and reduced Q 2000 Academic Press
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amnesia induced by scopolamine administration w19x. Also subcutaneous injection of CER diminished amnesia induced by NMDA receptor antagonists in a passive avoidance task w20x. Central administration of CCK-8 antagonists, L-354 718, CR 1409 and proglumide, produced pronounced memory deficit in a passive and an active avoidance tasks w21, 22x, and local injection of anti-CCK-8 antiserum to the posterior cingulate cortex was shown to produce learning impairment in the discrimination appetitive task w23x. There is support for the notion that CCK may act as a neurotransmitter or neuromodulator, and appears to modulate the action of other neurotransmitters such as dopamine, excitatory amino acids, serotonin, GABA, and endogenous opioids w24, 25x. Several reports indicate that CCK may exert the modulatory action of nigrostriatal and mesolimbic dopaminergic systems w24, 26, 27x. Furthermore, it has been shown that CCK could function as a transmitter or co-transmitter at conventional excitatory synapses w28x. Dentate gyrus of the hippocampus is a structure, which receives dopaminergic projection from ventral tegmental area w29, 30x, and also contains a considerable amount of CCK-interneurons and CCKcontaining nerve terminals w31, 32x. Since modulation of dopaminergic neuronal activity by glutamate receptors subtypes was demonstrated w33x, and CCK has been shown to interact with both of them, it seems to be possible that dentate gyrus of the hippocampus is a structure in which takes place an interaction between dopamine, glutamate and CCK. Therefore, in the present study the involvement of dopaminergic projection to dentate gyrus of the hippocampus, in the facilitatory effect of CCK-8US and CER, given after a single learning trial, on retention of information in a passive avoidance situation was evaluated.
MATERIALS AND METHODS
Animals Male Wistar rats of laboratory strain, after 5 days of acclimatization to the laboratory conditions were used. On the day of surgery their weight was 160]165 g and at the time of behavioural testing 180]185 g. They were housed in plastic cages Ž50 = 40 = 20 cm., four animals per cage, in the temperature controlled room Ž228C. on a 12-h light]dark cycle beginning at 07:00 h. Food and water were freely available.
Surgery The rats were anaesthetized with chloral hydrate and were placed in a Kopf stereotaxic apparatus with the tooth bar 5 mm above the interaural line. The skull was exposed, and burr holes 1.5 mm in diameter were drilled above the appropriate coordi-
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nate targets. The coordinates Žin millimetres. for the dentate gyrus of the hippocampus, anterior ŽA. from bregma, lateral ŽL. to the midline and below ŽV. the skull surface were selected with the aid of the atlas of Konig ¨ and Klippel w34x at A: y3.5, L: 2.0, and V: 3.2. Each site was infused with 1 m l of 0.9% NaCl containing 8 m g of 6-OHDA Žfree base, Sigma.. The neurotoxin was dissolved in a vehicle solution containing 5 mg mly1 of ascorbic acid, to prevent oxidation of 6-OHDA, and injected over 10 min through stainless steel cannula Žo.d.s 0.3 mm. at the rate of 0.1 m l miny1 . The cannula was left in place for an additional 5 min after the end of the infusion. Thirty randomly selected rats received 6-OHDA, the remaining 30 sham-operated control rats underwent the same procedure except that they only received the vehicle solution. Thirty minutes before surgery rats were pre-treated with an intraperitoneal injection of 25 mg kgy1 of desmethylimipramine ŽSigma., an inhibitor of norepinephrine ŽNE. uptake, which has been shown to protect NE neurones from destruction by 6-OHDA w35x. Behavioural testing started after 10 days of recovery period. Unsulphated cholecystokinin octapeptide ŽCCK-8US, RBI. and caerulein ŽCER, Serva. dissolved in 0.9% NaCl were given subcutaneously Žs.c.. in an amount of 10 m g kgy1 and 0.5 m g kgy1 , respectively, immediately after the learning trial. One group of lesioned as well as one group of sham-operated rats received 0.9% NaCl at the same time.
Beha¨ ioural testing Locomotor and exploratory activity was measured in a square open field, 100 = 100 cm, with a white floor divided by eight lines into 25 equal squares and surrounded by a 47-cm high wall. Four plastic bars, 20 cm high, were designed as objects of possible interest for the animals and fixed perpendicularly, parallel to each other, in four lines crossing in the central area of the floor. Immediately after testing the animals in a passive avoidance task rats were placed in the centre of the floor and following 1 min of adaptation crossings, rearings and bar approaches were counted manually for 10 min. The crossing of the square was counted, when the animal crossed the line with all four paws and the bar approach was considered, when the rat directed its head toward the bar, approached and touched it with its nose. Passi¨ e a¨ oidance Passive avoidance performance was studied in a one trial step-through passive avoidance situation w36x. The apparatus consisted of an illuminated Ž25-W bulb, 20 cm above. platform attached to a large dark compartment. After 2 min of habituation to the dark compartment the rats were placed on the platform and were allowed to enter the naturally preferred dark compartment. Two more approach trials with 2-min intervals were given on the following day. At the end
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of the second trial an inescapable, scrambled electric footshock Ž0.5 mA for 3 s. was delivered through the grid floor of the dark compartment Žlearning trial.. Retention of passive avoidance behaviour was tested 24 h after the single learning trial by measuring the latency to re-enter the dark compartment up to a maximum of 300 s.
Histology Placement of the cannula was examined histologically. At the end of the behavioural testing, the rats were killed and the brains were removed and fixed in 10% formaldehyde for 7 days. Subsequently, coronal sections Ž20 m m thick. of the cannula tract were cut using the frozen sectioning method, saving every fifth section through the lesion, mounted on slides, and stained with cresyl violet. Rats in which the cannula tip was located outside the centre of target structure were excluded from the experimental data. According to Agid et al. w37x the location of the tip of the cannula is particularly critical for reproducibility of the decrease in dopamine levels in lesioned structures. After infusion of 1 m l of 6OHDA, the distribution of neurotoxin has spherical shape with a diameter of 3.0 mm. A typical localization of the tip of cannula into dentate gyrus of the hippocampus is shown in Fig. 1.
Statistical analysis The results of experiments were evaluated by twoway analysis of variance ŽANOVA. followed by Newman]Keuls test. F-ratios, degrees of freedom, and P-values are reported only for significant differences. In all comparisons between the groups a probability of 0.05 or less was considered significant.
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RESULTS
In the final analysis 25 lesioned and 26 sham-operated animals were included. Each group consisted of eight to ten rats.
Passi¨ e a¨ oidance The passive avoidance performance was significantly different between the groups. ANOVA of three lesioned and three sham-operated groups of rats, injected s.c. with CCK-8US, CER or saline, yielded F1,45 s 153.02, P- 0.0001 and F2,45 s 77.66, P- 0.0001, when the influence of lesions and the influence of s.c. injections on rats’ performance in a passive avoidance task were evaluated, respectively. Further post hoc comparisons between these groups, made with the Newman]Keuls test, revealed significant increase of the mean step-through latency in both lesioned and sham-operated groups of rats injected with CCK-8US and CER as compared with respective saline injected groups ŽFig. 2.. Nevertheless, the improving memory effect of both peptides was significantly attenuated in lesioned groups of rats in comparison to the peptides injected sham-operated controls. Sham-operated injected with CCK-8US and CER rats stayed on the illuminated platform more than four times longer than sham-operated injected with saline rats, while lesioned injected with both peptides rats stayed on the platform only approximately twice longer than injected with a saline lesioned ones.
Locomotor acti¨ ity The spontaneous locomotor and exploratory
Fig. 1. Typical localization of the tip of cannula Žarrows. of 6-OHDA infusions into dentate gyrus of the hippocampus.
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ences between peptides and saline injected subgroups both, in lesioned and sham-operated groups of rats.
DISCUSSION
Fig. 2. Effect of 10 m g kgy1 of CCK-8US and 0.5 m g kgy1 of CER, given s.c. immediately after the single learning trial, on the re-entry latencies in a passive avoidance situation in rats after bilateral 6-OHDA lesions to dentate gyrus of the hippocampus. Columns represent means " SEM of the values obtained from eight to ten rats. U P- 0.05 ¨ s lesioned injected with saline group and ¨ s sham-operated injected with CCK-8US and CER groups of rats, U P- 0.01 ¨ s sham-operated injected with saline group of rats ŽANOVA and Newman]Keuls test..
activity of rats evaluated in the open field test Žcrossings of squares, rearings, and bar approaches. did not differ between lesioned to dentate gyrus of the hippocampus and sham-operated control group of animals ŽTable I.. Moreover, there were no differ-
Both, lesioned to the hippocampus and sham-operated rats injected with CCK-8US and CER stayed on the illuminated platform significantly longer than respective saline injected controls. Bilateral 6OHDA lesions to the dentate gyrus of the hippocampus on their own insignificantly attenuated the retrieval process. However, the lesions significantly diminished the stimulatory effect of CCK-8US and CER on memory Žmeasured by the re-enter latency in a passive avoidance task. in comparison to the injected with the peptides sham-operated animals. These results may point to the involvement of the dopaminergic innervation of the dentate gyrus of the hippocampus in the facilitatory effect of CCK8US and its analogue CER on memory motivated affectively. The improvement of performance after application of both peptides was demonstrable when the treatment was administered after the learning trial. According to McGaugh and Dawson w38x, it is an indication that the effect was memory-specific, since the substances were administered after the learning experience, unspecific effects resulting from altered perception, motivation and emotion can be ruled on. Since motor performance of animals is essential for expressing memory, their locomotor and exploratory activity was evaluated in an ‘open field’ test immediately after testing the animals in a passive avoidance situation. Neither, destruction of dopaminergic endings in the hippocampus, nor application of CCK-8US and CER changed the spontaneous psychomotor activity of rats. There is support for the notion that hippocampus plays an important role in cognitive processes. One view proposes that the hippocampus exclusively mediates or codes all information, including a variety of
Table I Effect of 6-OHDA lesions to the dentate gyrus of the hippocampus on the locomotor activity of rats in an ‘open field’ test Group
Crossings
Rearings
Bar approaches
Sham-operated Injected with 0.9% NaCl Injected with CCK-8US Injected with CER
39.61 Ž5.78. 43.21 Ž6.41. 41.93 Ž5.21.
10.45 Ž0.86. 11.20 Ž1.02. 9.56 Ž0.79.
4.67 Ž0.58. 4.02 Ž0.41. 3.76 Ž0.39.
Lesioned Injected with 0.9% NaCl Injected with CCK-8US Injected with CER
35.71 Ž4.73. 34.27 Ž4.42. 36.76 Ž5.98.
9.66 Ž0.64. 10.32 Ž0.95. 8.78 Ž0.75.
4.64 Ž0.31. 4.97 Ž0.42. 3 21 Ž0.27.
Notes: Values are means from eight to ten rats and "SEM in parentheses.
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attributes: spatial, temporal, response, sensory] perceptual and affect w39, 40x. Another view proposes that there are different neuronal substrates that mediate these different attributes w41x. According to the latter view, the hippocampus mediates a memory representation of allocentric spatial and temporal attributes, and it is probably also influenced by sensory]perceptual attribute information. Dentate gyrus of the rat hippocampus contains CCK interneurons and a considerable amount of CCK-containing nerve terminals w31, 32x. CCK-containing nerve terminals are located on the dendrites of the granule cells and concentrated at two locations where pathways, thought on a number of grounds to be excitatory terminate. One of these pathways, the medial perforant path, originates in the entorhinal cortex w42, 43x, and there is a body of evidence that the neurotransmitter released by its nerve endings is glutamate w44]46x. Dodd and Kelly w47x have demonstrated that the tetra- and octapeptide C-terminal fragments of CCK are potent excitant of the CA1 piramidal cells of the rat hippocampus. In 1985 Brooks and Kelly w28x extended this earlier study to the dentate gyrus and put forward the hypothesis that CCK could function as a neurotransmitter or co-transmitter at conventional excitatory synapses. Moreover, dentate gyrus of the hippocampus receives dopaminergic innervation arising in the A10 neurones of the ventral tegmental area and A9 neurones of substantia nigra w29, 30x. Co-localization of CCK and dopamine in the neurones of ventral tegmental area and the ascending mesolimbic pathways w2, 3, 48x suggests that CCK could act as a neuromodulator of the dopaminergic transmission. These dopaminergic pathways have been closely related to motivational mechanisms of reward w49x and, thus, CCK would have a place in the regulation of affectively motivated behaviour. Anatomical, biochemical and electrophysiological studies have demonstrated also an interaction between glutamatergic and dopaminergic system. It has been demonstrated that stimulation of glutamatergic receptors on dopaminergic neurones, either by direct injection of glutamatergic agonists, or stimulation of glutamatergic afferents, increases the release of dopamine in both substantia nigra w50, 51x and dopaminergic innervated areas w52]55x. Meltzer et al. w33x have shown that in ¨ itro studies NMDA, kainate or AMPA evoked a large increase in firing rate of dopaminergic neurones. However, they were unable to induce the burst-firing, what implies that other neuromodulators, whose action was removed in the ¨ itro situation play an important role in mediation of burst-firing. Since CCK has been shown to induce burst-firing of dopaminergic neurones after iontophoretic application w56x it may point to the involvement of CCK in the unique
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excitatory interaction between glutamatergic and dopaminergic systems in which CCK may play a role of neuromodulator. Attenuation of the facilitatory effect of CCK-8US and CER on memory motivated affectively observed in our investigations after removal of dopaminergic projection from dentate gyrus of the hippocampus suggests that this interaction may be involved in CCK improvement of cognitive processes.
ACKNOWLEDGEMENTS This work was supported by AMB project NR 310686.
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BILATERAL 6-OHDA LESIONS TO THE HIPPOCAMPUS ATTENUATE THE FACILITATORY EFFECT OF CCK-8US AND CAERULEIN ON MEMORY IN RATS ´ MARIA M. WINNICKAU and KONSTANTY WISNIEWSKI Department of Pharmacology, Medical Academy of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland Accepted 31 August 1999
The involvement of dopaminergic projection to the hippocampus in the facilitatory effect of cholecystokinin-unsulphated octapeptide ŽCCK-8US. and caerulein ŽCER. on memory motivated affectively was investigated in male rats. CCK-8US and CER were given subcutaneously at the doses of 10 m g kgy1 and 0.5 m g kgy1 , respectively, immediately after a single learning trial in a passive avoidance situation, after bilateral 6-OHDA lesions to the dentate gyrus of the hippocampus. In order to protect noradrenergic neurones against destruction by neurotoxin, 30 min before surgery rats were pre-treated intraperitoneally with 25 mg kgy1 of desmethylimipramine, an inhibitor of noradrenaline uptake. Bilateral 6-OHDA lesions to the hippocampus significantly attenuate the facilitatory effect of CCK-8US and CER on retention of passive avoidance behaviour evaluated 24 h after the learning trial. Neither, destruction of dopaminergic endings in the hippocampus, nor application of CCK-8US and CER changed the spontaneous psychomotor activity of rats estimated in an ‘open field’ test. These results may indicate that the facilitatory effect of CCK-8US and CER on memory motivated affectively is, in part, mediated by dopaminergic projection from the ventral tegmental area to the dentate gyrus of the hippocampus. Q 2000 Academic Press KEY
WORDS:
CCK-8US, CER, hippocampus, 6-OHDA lesions, passive avoidance, locomotor activity, rats.
INTRODUCTION Cholecystokinin ŽCCK. is the most widespread and abundant neuropeptide in the central nervous system. High concentration of CCK and CCK mRNA have been identified throughout the brain including: cerebral cortex, hippocampus, olfactory bulb, olfactory tubercle, amygdala, hypothalamus, ventral mesencephalon, nucleus tractus solitarius and periaquaductal grey w1]5x. In the brain, CCK exists mainly as an octapeptide, both in sulphated and unsulphated form w1x. The receptors for CCK have been divided into two types: the CCK A receptor subtype which was found in periphery and some brain regions; and widely distributed in the brain CCK B receptor subtype. Sulphated CCK-8 and amphibian decapeptide caerulein ŽCER. have been served as unselective U
Corresponding author.
1043]6618r00r030347]07r$35.00r0
CCK receptors agonists, whereas unsulphated CCK-8 ŽCCK-8US., CCK-4, BC 264 and BC 197 have been used as selective CCK B receptors agonists w6]8x. It has been shown that CCK may control various physiological functions, e.g. pain perception w9x, feeding and satiety w10x, hypothermia w11x, and sedation w12x. Recent investigations have shown that CCK takes part in anxiety and panic attacks w13, 14x. The increasing evidence supports the involvement of CCK on cognitive processes. Early studies have shown that peripheral injections of CCK-8 impaired acquisition and facilitated extinction of an active avoidance behaviour w15x. In a passive avoidance situation, CCK-8 improved retention when it was injected either after the single learning trial w15x or before the retention testing w16x. Moreover, CCK-8 given either intracerebroventricularly or subcutaneously prevented experimental amnesia induced by electroconvulsive shock, carbon dioxide inhalation, or cycloheximide injection w17, 18x and reduced Q 2000 Academic Press
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amnesia induced by scopolamine administration w19x. Also subcutaneous injection of CER diminished amnesia induced by NMDA receptor antagonists in a passive avoidance task w20x. Central administration of CCK-8 antagonists, L-354 718, CR 1409 and proglumide, produced pronounced memory deficit in a passive and an active avoidance tasks w21, 22x, and local injection of anti-CCK-8 antiserum to the posterior cingulate cortex was shown to produce learning impairment in the discrimination appetitive task w23x. There is support for the notion that CCK may act as a neurotransmitter or neuromodulator, and appears to modulate the action of other neurotransmitters such as dopamine, excitatory amino acids, serotonin, GABA, and endogenous opioids w24, 25x. Several reports indicate that CCK may exert the modulatory action of nigrostriatal and mesolimbic dopaminergic systems w24, 26, 27x. Furthermore, it has been shown that CCK could function as a transmitter or co-transmitter at conventional excitatory synapses w28x. Dentate gyrus of the hippocampus is a structure, which receives dopaminergic projection from ventral tegmental area w29, 30x, and also contains a considerable amount of CCK-interneurons and CCKcontaining nerve terminals w31, 32x. Since modulation of dopaminergic neuronal activity by glutamate receptors subtypes was demonstrated w33x, and CCK has been shown to interact with both of them, it seems to be possible that dentate gyrus of the hippocampus is a structure in which takes place an interaction between dopamine, glutamate and CCK. Therefore, in the present study the involvement of dopaminergic projection to dentate gyrus of the hippocampus, in the facilitatory effect of CCK-8US and CER, given after a single learning trial, on retention of information in a passive avoidance situation was evaluated.
MATERIALS AND METHODS
Animals Male Wistar rats of laboratory strain, after 5 days of acclimatization to the laboratory conditions were used. On the day of surgery their weight was 160]165 g and at the time of behavioural testing 180]185 g. They were housed in plastic cages Ž50 = 40 = 20 cm., four animals per cage, in the temperature controlled room Ž228C. on a 12-h light]dark cycle beginning at 07:00 h. Food and water were freely available.
Surgery The rats were anaesthetized with chloral hydrate and were placed in a Kopf stereotaxic apparatus with the tooth bar 5 mm above the interaural line. The skull was exposed, and burr holes 1.5 mm in diameter were drilled above the appropriate coordi-
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nate targets. The coordinates Žin millimetres. for the dentate gyrus of the hippocampus, anterior ŽA. from bregma, lateral ŽL. to the midline and below ŽV. the skull surface were selected with the aid of the atlas of Konig ¨ and Klippel w34x at A: y3.5, L: 2.0, and V: 3.2. Each site was infused with 1 m l of 0.9% NaCl containing 8 m g of 6-OHDA Žfree base, Sigma.. The neurotoxin was dissolved in a vehicle solution containing 5 mg mly1 of ascorbic acid, to prevent oxidation of 6-OHDA, and injected over 10 min through stainless steel cannula Žo.d.s 0.3 mm. at the rate of 0.1 m l miny1 . The cannula was left in place for an additional 5 min after the end of the infusion. Thirty randomly selected rats received 6-OHDA, the remaining 30 sham-operated control rats underwent the same procedure except that they only received the vehicle solution. Thirty minutes before surgery rats were pre-treated with an intraperitoneal injection of 25 mg kgy1 of desmethylimipramine ŽSigma., an inhibitor of norepinephrine ŽNE. uptake, which has been shown to protect NE neurones from destruction by 6-OHDA w35x. Behavioural testing started after 10 days of recovery period. Unsulphated cholecystokinin octapeptide ŽCCK-8US, RBI. and caerulein ŽCER, Serva. dissolved in 0.9% NaCl were given subcutaneously Žs.c.. in an amount of 10 m g kgy1 and 0.5 m g kgy1 , respectively, immediately after the learning trial. One group of lesioned as well as one group of sham-operated rats received 0.9% NaCl at the same time.
Beha¨ ioural testing Locomotor and exploratory activity was measured in a square open field, 100 = 100 cm, with a white floor divided by eight lines into 25 equal squares and surrounded by a 47-cm high wall. Four plastic bars, 20 cm high, were designed as objects of possible interest for the animals and fixed perpendicularly, parallel to each other, in four lines crossing in the central area of the floor. Immediately after testing the animals in a passive avoidance task rats were placed in the centre of the floor and following 1 min of adaptation crossings, rearings and bar approaches were counted manually for 10 min. The crossing of the square was counted, when the animal crossed the line with all four paws and the bar approach was considered, when the rat directed its head toward the bar, approached and touched it with its nose. Passi¨ e a¨ oidance Passive avoidance performance was studied in a one trial step-through passive avoidance situation w36x. The apparatus consisted of an illuminated Ž25-W bulb, 20 cm above. platform attached to a large dark compartment. After 2 min of habituation to the dark compartment the rats were placed on the platform and were allowed to enter the naturally preferred dark compartment. Two more approach trials with 2-min intervals were given on the following day. At the end
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of the second trial an inescapable, scrambled electric footshock Ž0.5 mA for 3 s. was delivered through the grid floor of the dark compartment Žlearning trial.. Retention of passive avoidance behaviour was tested 24 h after the single learning trial by measuring the latency to re-enter the dark compartment up to a maximum of 300 s.
Histology Placement of the cannula was examined histologically. At the end of the behavioural testing, the rats were killed and the brains were removed and fixed in 10% formaldehyde for 7 days. Subsequently, coronal sections Ž20 m m thick. of the cannula tract were cut using the frozen sectioning method, saving every fifth section through the lesion, mounted on slides, and stained with cresyl violet. Rats in which the cannula tip was located outside the centre of target structure were excluded from the experimental data. According to Agid et al. w37x the location of the tip of the cannula is particularly critical for reproducibility of the decrease in dopamine levels in lesioned structures. After infusion of 1 m l of 6OHDA, the distribution of neurotoxin has spherical shape with a diameter of 3.0 mm. A typical localization of the tip of cannula into dentate gyrus of the hippocampus is shown in Fig. 1.
Statistical analysis The results of experiments were evaluated by twoway analysis of variance ŽANOVA. followed by Newman]Keuls test. F-ratios, degrees of freedom, and P-values are reported only for significant differences. In all comparisons between the groups a probability of 0.05 or less was considered significant.
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RESULTS
In the final analysis 25 lesioned and 26 sham-operated animals were included. Each group consisted of eight to ten rats.
Passi¨ e a¨ oidance The passive avoidance performance was significantly different between the groups. ANOVA of three lesioned and three sham-operated groups of rats, injected s.c. with CCK-8US, CER or saline, yielded F1,45 s 153.02, P- 0.0001 and F2,45 s 77.66, P- 0.0001, when the influence of lesions and the influence of s.c. injections on rats’ performance in a passive avoidance task were evaluated, respectively. Further post hoc comparisons between these groups, made with the Newman]Keuls test, revealed significant increase of the mean step-through latency in both lesioned and sham-operated groups of rats injected with CCK-8US and CER as compared with respective saline injected groups ŽFig. 2.. Nevertheless, the improving memory effect of both peptides was significantly attenuated in lesioned groups of rats in comparison to the peptides injected sham-operated controls. Sham-operated injected with CCK-8US and CER rats stayed on the illuminated platform more than four times longer than sham-operated injected with saline rats, while lesioned injected with both peptides rats stayed on the platform only approximately twice longer than injected with a saline lesioned ones.
Locomotor acti¨ ity The spontaneous locomotor and exploratory
Fig. 1. Typical localization of the tip of cannula Žarrows. of 6-OHDA infusions into dentate gyrus of the hippocampus.
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ences between peptides and saline injected subgroups both, in lesioned and sham-operated groups of rats.
DISCUSSION
Fig. 2. Effect of 10 m g kgy1 of CCK-8US and 0.5 m g kgy1 of CER, given s.c. immediately after the single learning trial, on the re-entry latencies in a passive avoidance situation in rats after bilateral 6-OHDA lesions to dentate gyrus of the hippocampus. Columns represent means " SEM of the values obtained from eight to ten rats. U P- 0.05 ¨ s lesioned injected with saline group and ¨ s sham-operated injected with CCK-8US and CER groups of rats, U P- 0.01 ¨ s sham-operated injected with saline group of rats ŽANOVA and Newman]Keuls test..
activity of rats evaluated in the open field test Žcrossings of squares, rearings, and bar approaches. did not differ between lesioned to dentate gyrus of the hippocampus and sham-operated control group of animals ŽTable I.. Moreover, there were no differ-
Both, lesioned to the hippocampus and sham-operated rats injected with CCK-8US and CER stayed on the illuminated platform significantly longer than respective saline injected controls. Bilateral 6OHDA lesions to the dentate gyrus of the hippocampus on their own insignificantly attenuated the retrieval process. However, the lesions significantly diminished the stimulatory effect of CCK-8US and CER on memory Žmeasured by the re-enter latency in a passive avoidance task. in comparison to the injected with the peptides sham-operated animals. These results may point to the involvement of the dopaminergic innervation of the dentate gyrus of the hippocampus in the facilitatory effect of CCK8US and its analogue CER on memory motivated affectively. The improvement of performance after application of both peptides was demonstrable when the treatment was administered after the learning trial. According to McGaugh and Dawson w38x, it is an indication that the effect was memory-specific, since the substances were administered after the learning experience, unspecific effects resulting from altered perception, motivation and emotion can be ruled on. Since motor performance of animals is essential for expressing memory, their locomotor and exploratory activity was evaluated in an ‘open field’ test immediately after testing the animals in a passive avoidance situation. Neither, destruction of dopaminergic endings in the hippocampus, nor application of CCK-8US and CER changed the spontaneous psychomotor activity of rats. There is support for the notion that hippocampus plays an important role in cognitive processes. One view proposes that the hippocampus exclusively mediates or codes all information, including a variety of
Table I Effect of 6-OHDA lesions to the dentate gyrus of the hippocampus on the locomotor activity of rats in an ‘open field’ test Group
Crossings
Rearings
Bar approaches
Sham-operated Injected with 0.9% NaCl Injected with CCK-8US Injected with CER
39.61 Ž5.78. 43.21 Ž6.41. 41.93 Ž5.21.
10.45 Ž0.86. 11.20 Ž1.02. 9.56 Ž0.79.
4.67 Ž0.58. 4.02 Ž0.41. 3.76 Ž0.39.
Lesioned Injected with 0.9% NaCl Injected with CCK-8US Injected with CER
35.71 Ž4.73. 34.27 Ž4.42. 36.76 Ž5.98.
9.66 Ž0.64. 10.32 Ž0.95. 8.78 Ž0.75.
4.64 Ž0.31. 4.97 Ž0.42. 3 21 Ž0.27.
Notes: Values are means from eight to ten rats and "SEM in parentheses.
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attributes: spatial, temporal, response, sensory] perceptual and affect w39, 40x. Another view proposes that there are different neuronal substrates that mediate these different attributes w41x. According to the latter view, the hippocampus mediates a memory representation of allocentric spatial and temporal attributes, and it is probably also influenced by sensory]perceptual attribute information. Dentate gyrus of the rat hippocampus contains CCK interneurons and a considerable amount of CCK-containing nerve terminals w31, 32x. CCK-containing nerve terminals are located on the dendrites of the granule cells and concentrated at two locations where pathways, thought on a number of grounds to be excitatory terminate. One of these pathways, the medial perforant path, originates in the entorhinal cortex w42, 43x, and there is a body of evidence that the neurotransmitter released by its nerve endings is glutamate w44]46x. Dodd and Kelly w47x have demonstrated that the tetra- and octapeptide C-terminal fragments of CCK are potent excitant of the CA1 piramidal cells of the rat hippocampus. In 1985 Brooks and Kelly w28x extended this earlier study to the dentate gyrus and put forward the hypothesis that CCK could function as a neurotransmitter or co-transmitter at conventional excitatory synapses. Moreover, dentate gyrus of the hippocampus receives dopaminergic innervation arising in the A10 neurones of the ventral tegmental area and A9 neurones of substantia nigra w29, 30x. Co-localization of CCK and dopamine in the neurones of ventral tegmental area and the ascending mesolimbic pathways w2, 3, 48x suggests that CCK could act as a neuromodulator of the dopaminergic transmission. These dopaminergic pathways have been closely related to motivational mechanisms of reward w49x and, thus, CCK would have a place in the regulation of affectively motivated behaviour. Anatomical, biochemical and electrophysiological studies have demonstrated also an interaction between glutamatergic and dopaminergic system. It has been demonstrated that stimulation of glutamatergic receptors on dopaminergic neurones, either by direct injection of glutamatergic agonists, or stimulation of glutamatergic afferents, increases the release of dopamine in both substantia nigra w50, 51x and dopaminergic innervated areas w52]55x. Meltzer et al. w33x have shown that in ¨ itro studies NMDA, kainate or AMPA evoked a large increase in firing rate of dopaminergic neurones. However, they were unable to induce the burst-firing, what implies that other neuromodulators, whose action was removed in the ¨ itro situation play an important role in mediation of burst-firing. Since CCK has been shown to induce burst-firing of dopaminergic neurones after iontophoretic application w56x it may point to the involvement of CCK in the unique
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excitatory interaction between glutamatergic and dopaminergic systems in which CCK may play a role of neuromodulator. Attenuation of the facilitatory effect of CCK-8US and CER on memory motivated affectively observed in our investigations after removal of dopaminergic projection from dentate gyrus of the hippocampus suggests that this interaction may be involved in CCK improvement of cognitive processes.
ACKNOWLEDGEMENTS This work was supported by AMB project NR 310686.
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