Subchronic effects of ligands of cannabinoid receptors on learning and memory processes of olfactory bulbectomized rats.

The brain endocannabinoid system has been shown to play a role in many physiological processes, including mood, learning and memory. It is also involved in the pathogenesis of anxiety, depression, mood disorders, as well as neurodegenerative disorders, although the exact mechanisms by which cannabinoid receptors interfere in these disorders are not well established. The aim of the present study was to evaluate the effects of cannabinoid ligands HU­210 (CB1 receptor agonist) and SR 141716A (CB1 receptor antagonist) on learning and memory processes of rats with depressive - like state, induced by bilateral olfactory bulbectomy. The bilateral olfactory bulbectomy (OBX) is a validated model of depression, which can be used also as an animal model of Alzheimer's disease. We found that the subchronic treatment of OBX rats with HU 210 and SR 141716A exerted modulatory effect on rat's performance in both active avoidance (shuttle box) and passive avoidance (step through) tests. HU 210 ameliorated the memory deficits of OBX rats; however, the scores of the sham­operated controls had not been reached. SR 141716A modified the avoidance performance in OBX rats and showed a memory enhancing effect in the sham­operated rats. Our findings suggest that CB1 receptors might be involved in avoidance learning and memory acquisition in OBX rats.

Subchronic Central Administration of Cannabinoid Ligands Modulates Nociception in Bulbectomized Rats.

INTRODUCTION: Endocannabinoid system is involved in neuropsychiatric disorders such as major depression. The bilaterally olfactory bulbectomized rat is widely used as an animal model of depression. The removal of the olfactory bulbs produces behavioural, physiological, and neurochemical alterations resembling clinical depression. There is increasing evidence that highlights the important role of cannabinoid signalling in depression and nociception. AIM: To investigate the effect of CB1 receptor agonist HU 210 and CB1 receptor antagonist SR 141716A administered icv subchronically (for 7 days) on nociception of rats with model of depression - bilateral olfactory bulbectomy (OBX). MATERIAL AND METHODS: Experimental model of depression - bilateral olfactory bulbectomy (OBX). Bilaterally olfactory bulbectomized rats were used as an experimental model of depression. HU 210 (5 µg) or SR 141716A (3 µg) were infused icv for 7 consecutive days, starting 15 days after the olfactory bulbectomy. Nociception was examined by applying paw pressure test (analgesy-meter) evaluating the rat pain threshold. On day 7, five minutes after the last microinjection, the rats were tested in an analgesy-meter and their mechanically evoked pain responses were measured in arbitrary units (AU). RESULTS: Microinjections of HU 210 (5 µg) significantly decreased the pain threshold in olfactory bulbectomized rats, while SR 141716A (3 µg) exerted antinociceptive effect by increasing the pain threshold. CONCLUSIONS: Data point to an involvement of CB1 receptors in depression-like behaviour and nociception in olfactory bulbectomized rats and support the data for the association between depressive disorder and pain pathways.

Involvement of hippocampal angiotensin 1 receptors in anxiety-like behaviour of olfactory bulbectomized rats.

BACKGROUND: Accumulated evidence suggests that the enhanced brain angiotensin II (Ang II) activity is associated with stress and anxiety. More recent reports demonstrated that Ang II function is elevated in depression, but the role of hippocampal Ang II and its receptors in this state is not well established. The present study investigated the effects of Ang II and losartan (a selective Аng II type 1 receptor antagonist) microinjected into the hippocampal CA1 area on the anxiety-like behavior in rats with a model of depression. METHODS: The bilateral olfactory bulbectomy (OBX) was used as a model of depression. The stereotaxic technique was used for bilaterally (right and left) implantation of guide cannulas into CA1 hippocampal area of the OBX rats. The anxiety state of OBX rats was studied using the elevated plus-maze test. RESULTS: Тhe bilateral infusion of Ang II (0.5µg) did not change the anxiety-like behavior of OBX rats, while losartan (100µg) showed an anxiolytic-like behavior, by increasing the number and time of open arms entries, the ratio of open/total entries and open/total time and decreasing the number and time of closed arm entries. CONCLUSIONS: These findings demonstrated that the inhibition of hippocampal AT1 receptors reduces the anxiety in OBX rats, which indicates involvement of AT1 receptors in the mechanisms of OBX-induced anxiety.

Hippocampal asymmetry in angiotensin II modulatory effects on learning and memory in rats.

Learning and memory effects of angiotensin II (Ang II) microinjected unilaterally (left or right) and bilaterally into hippocampal CA1 area on the background of the inhibited hippocampal angiotensin 1 receptors type (AT1) of male Wistar rats were studied. It was found that the combination (losartan 100 micrograms + Ang II 0.5 micrograms) microinjected bilaterally or into the left CA1 area improved learning and memory in shuttle-box and step through behavioral tests as compared to the respective controls. The effects were more pronounced after injection into the left CA1 area as compared to the right-side. These findings suggest that Ang II infused on the background of the inhibited CA1 hippocampal AT1 receptors ameliorated the cognitive processes. The data show also an asymmetric effect of Ang II on learning and memory processes in the hippocampus. The stronger modulating effect after microinjection of the combination (losartan + Ang II) into the left CA1 hippocampal area suggests a leftward bias in the rat. The results point to a differential distribution of angiotensin II receptors modulating the learning and memory processes in the left and right hippocampal CA1 area.

Memory effects of Aronia melanocarpa fruit juice in a passive avoidance test in rats.

AIM: To study the effect of Aronia melanocarpa fruit juice on memory in male Wistar rats. MATERIALS AND METHODS: The juice was administered orally for 7, 14, 21 and 30 days at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg. Memory was assessed in the one-way passive avoidance task (step through) which consisted of one training session and two retention tests (3 hours and 24 hours after training). The variables measured were the latency time to step into the dark compartment of the apparatus and the learning criterion (remaining in the illuminated compartment for at least 180 sec). RESULTS: Oral administration of Aronia melanocarpa fruit juice for 7 and 14 days resulted in a dose-dependent tendency to increase the latency time and the learning criterion compared to saline-treated controls but the effect failed to reach statistical significance. After 21 days of treatment, the juice dose-dependently prolonged the latency time at the retention tests, the effect being significant at doses of 5 ml/kg and 10 ml/kg. Applied for 30 days, the juice in all the tested doses increased significantly the latency time at the retention tests and the dose of 10 ml/kg significantly increased the percentage of rats reaching the learning criterion. CONCLUSION: These findings suggest that Aronia melanocarpa fruit juice could improve memory in rats. The effect is probably due to the polyphenolic ingredients of the juice which have been shown to be involved in learning and memory processes.

Modulatory effect of VIP injected into hippocampal CA1 area on anxiety in olfactory bulbectomized rats.

Vasoactive intestinal peptide (VIP) is a neuropeptide, which is widely distributed in the central nervous system and peripheral tissues, acting both as a neurotransmitter and neuromodulator. Despite its extensive expression in the hippocampus, amygdala and other limbic system structures, the effects of VIP on anxiety and depression have not yet been fully investigated. The aim of the present study was to evaluate the involvement of VIP and VIP receptors in the mechanism of anxiety in rats with a model of depression (bilateral olfactory bulbectomy), using the elevated plus-maze test. VIP and a non-specific antagonist of VIP receptors (VIP6-28) were administered unilaterally into the hippocampal CA1 area of bulbectomized (OBX) rats. VIP (10 ng) showed a tendency for an anxiety-modulatory effect upon right side injection, by reducing significantly the closed arm time and increasing the open arm time. VIP (100 ng) injected unilaterally (left or right) into CA1 area induced an anxiolytic-like effect on the activity of OBX rats (increased the number of open arms entries, open arm time and the ratio open/total number of entries). VIP6-28 failed to antagonize the anxiety-related behavior of OBX rats in the plus maze. An unexpected finding in our study was that upon pretreatment with VIP6-28, VIP (10 ng), injected unilaterally (left or right) exerted an anti-anxiety like effect (increased the number of open arm entries, open arm time and the ratio open/total number of entries). Our data point to a possible involvement of hippocampal VIP-ergic neurons in modulating emotional processes or adaptive responses to stressful stimuli in a rat model of depression.

Lateralized hippocampal effects of vasoactive intestinal peptide on learning and memory in rats in a model of depression.

RATIONALE: Findings of pharmacological studies revealed that vasoactive intestinal peptide (VIP) plays a modulatory role in learning and memory. A role of the peptide in the neurobiological mechanisms of affective disorders was also suggested. OBJECTIVE: The objectives are to study the involvement of VIP in learning and memory processes after unilateral and bilateral local application into hippocampal CA1 area in rats with a model of depression (bilateral olfactory bulbectomy--OBX) and to test whether VIP receptors could affect cognition. RESULTS: VIP (50 ng) and combination (VIP(6-28) 10 ng + VIP 50 ng) microinjected bilaterally or into the right CA1 area improved the learning and memory of OBX rats in shuttle-box and step-through behavioral tests as compared to the saline-treated OBX controls. Left-side VIP microinjections did not affect the number of avoidances (shuttle box) and learning criteria (step through) as compared to the left-side saline-treated OBX controls. The administration of the combination into left CA1 influenced positively the performance in the step-through task. VIP antagonist (VIP(6-28), 10 ng) did not affect learning and memory of OBX rats. These findings suggest asymmetric effect of VIP on cognitive processes in hippocampus of rats with OBX model of depression. CONCLUSION: Our results point to a lateralized modulatory effect of VIP injected in the hippocampal CA1 area on the avoidance deficits in OBX rats. The right CA1 area was predominantly involved in the positive effect of VIP on learning and memory. A possible role of the PAC1 receptors is suggested.

Transport of animals between rooms: a little-noted aspect of laboratory procedure that may interfere with memory.

This study investigated the effects of transporting animals from the experimental room to the animal facility in between experimental sessions, a procedure routinely employed in experimental research, on long-term social recognition memory. By using the intruder-resident paradigm, independent groups of Wistar rats exposed to a 2-h encounter with an adult intruder were transported from the experimental room to the animal facility either 0.5 or 6h after the encounter. The following day, residents were exposed to a second encounter with either the same or a different (unfamiliar) intruder. Resident's social and non-social behaviors were carefully scored and subjected to Principal Component Analysis, thus allowing to parcel out variance and relatedness among these behaviors. Resident rats transported 6h after the first encounter exhibited reduced amount of social investigation towards familiar intruders, but an increase of social investigation when exposed to a different intruder as compared to the first encounter. These effects revealed a consistent long-lasting (24h) social recognition memory in rats. In contrast, resident rats transported 0.5h after the first encounter did not exhibit social recognition memory. These results indicate that this common, little-noted, laboratory procedure disturbs long-term social recognition memory.

Lateralized learning and memory effects of vasoactive intestinal peptide infused into the rat hippocampal CA1 area.

The effects of VIP microinjected unilaterally (left or right) and bilaterally (left and right) at a dose of 50 ng into hippocampal CA1 area of male Wistar rats on learning and memory (shuttle-box) were studied. Bilateral VIP microinjections impaired learning and memory, i.e., decreased the number of avoidances during the second training day and memory tests, compared to the respective controls. When infused into the left CA1 area, VIP exerted a marked inhibitory effect. Right-side VIP microinjections did not change the number of avoidances during the learning and memory tests. Compared to the right-side, left-side VIP infusions provoked a threefold decrease of the number of avoidances on the second training day and on the memory tests (24 h after the 2nd training day and on 7th day). These findings reveal lateralized inhibitory effects of VIP on cognitive processes in hippocampus.

Differential involvement of hippocampal vasoactive intestinal peptide in nociception of rats with a model of depression.

The effects of VIP microinjected unilaterally (left or right) into the hippocampal CA1 area at a dose of 10 and 100 ng or bilaterally (10 ng), on nociception of male Wistar rats with a model of depression (bilateral olfactory bulbectomy-OBX) were studied. Nociception was examined applying mechanical pressure on the left hind paw of the rat (analgesy-meter test). It was found that in OBX rats the pain threshold is increased. VIP showed differential effects depending on the side and dose of administration. The pain threshold after left-side microinjections of VIP into the hippocampal CA1 area of OBX rats was significantly higher than that after injections into right-side. There are no significant differences between right-side VIP-treated and OBX rats. Bilateral microinjections of VIP also exerted antinociceptive effect. These findings suggest that the hippocampal lateralized antinociceptive effect of VIP in OBX rats depends on the hemisphere of injection and suggest that VIP-ergic neurons in the hippocampal CA1 area may play differential role in nociception of rats with a model of depression.

A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum.

BACKGROUND: Chronic, intermittent exposure to psychostimulant drugs results in striatal neuroadaptations leading to an increase in an array of behavioral responses on subsequent challenge days. A brain-specific striatal-enriched tyrosine phosphatase (STEP) regulates synaptic strengthening by dephosphorylating and inactivating several key synaptic proteins. This study tests the hypothesis that a substrate-trapping form of STEP will prevent the development of amphetamine-induced stereotypies. METHODS: A substrate-trapping STEP protein, TAT-STEP (C-S), was infused into the ventrolateral striatum on each of 5 consecutive exposure days and 1 hour before amphetamine injection. Animals were challenged to see whether sensitization to the stereotypy-producing effects of amphetamine developed. The same TAT-STEP (C-S) protein was used on acute striatal slices to determine the impact on long-term potentiation and depression. RESULTS: Infusion of TAT-STEP (C-S) blocks the increase of amphetamine-induced stereotypies when given during the 5-day period of sensitization. The TAT-STEP (C-S) has no effect if only infused on the challenge day. Treatment of acute striatal slices with TAT-STEP (C-S) blocks the induction of long-term potentiation and potentates long-term depression. CONCLUSIONS: A substrate trapping form of STEP blocks the induction of amphetamine-induced neuroplasticity within the ventrolateral striatum and supports the hypothesis that STEP functions as a tonic break on synaptic strengthening.

Hippocampal asymmetry in exploratory behavior to vasoactive intestinal polypeptide.

The effects of vasoactive intestinal polypeptide (VIP) microinjected uni- or bilaterally into the CA1 hippocampal area of male Wistar rats at a dose of 10, 50 and 100 ng on exploratory behavior were examined. VIP microinjected bilaterally at a high dose (100 ng) significantly decreased the horizontal movements, while at low doses (10 and 50 ng) had no effect on the exploratory activity. Microinjections of VIP into the left hippocampal CA1 area at doses 50 and 100 ng suppressed the exploratory activity, while right-side VIP administration at a dose 100 ng significantly increased horizontal movements compared to the respective controls. Vertical activity was stimulated only by VIP administered into the right hippocampal CA1 area at the three doses used. Neither bilateral nor left injections of VIP induced changes in the vertical movements. The main finding was the presence of hippocampal asymmetry in exploratory behavior to unilateral microinjections of VIP depending on the dose and the microinjected hemisphere.

Gastric antisecretory effects of synthetic cannabinoids after central or peripheral administration in the rat.

Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 microg/kg) and HU-210 (25, 50 and 100 microg/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 microg/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 microg/kg) or HU-210 (10-100 microg/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB(1)-receptor antagonist SR141716A (1000 microg/kg, i.v.). These results show that CB(1)-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.

Differential effects of somatostatin on exploratory behavior after unilateral injections in to rat neostriatum.

The effects of somatostatin (SRIF) microinjected unilaterally (left or right) at a dose of 10, 50, and 100 ng into the neostriatum of male Wistar rats on exploratory behavior were studied. Unilateral injections of SRIF suppressed dose-related the exploratory activity as decreased the number of horizontal and vertical movements compared to the respective controls. The effect was more pronounced when SRIF was microinjected into the right neostriatum as compared to the left neostriatum. These findings suggest some asymmetric effects of SRIF, depending on the dose and the microinjected hemisphere.