Grazyna Biala

The novel object recognition memory: neurobiology, test procedure, and its modifications

Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.

Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats

Nociceptin (also called orphanin FQ), a 17-amino-acid peptide, is the natural ligand of the nociceptin opioid peptide (NOP) receptor. This peptide shows similarities, in its structure, to opioid peptides, mainly to dynorphin A. However, unlike opioid peptides, it does not produce a conditioned place preference or aversion but inhibits rewarding effect of drugs of abuse. The present study was designed to examine the ability of nociceptin to block the acquisition of amphetamine-induced place preference, and the development of amphetamine-induced sensitization to stereotypy in rats. Our experiments indicated that repeated administration of nociceptin at increasing doses during conditioning significantly attenuated the reinforcing effect of amphetamine in conditioned place preference paradigm. Nociceptin did not change the acute effect of amphetamine-induced stereotypy but prevented the development of sensitization to stereotypy measured on the challenge day. Our results suggest the involvement of nociceptin in long-lasting neuronal adaptation after repeated amphetamine treatment.

Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice

RationaleImperatorin, a naturally occurring furanocoumarin, inactivates gamma-aminobutyric acid transaminase and inhibits acetylcholinesterase activity.ObjectivesThe purpose of our experiment was to examine the influence of imperatorin on cognitive impairment and oxidative stress in the brain induced by scopolamine in male Swiss mice.MethodsIn the present studies, we used scopolamine-invoke memory deficit measured in passive avoidance (PA) paradigm as an animal model of Alzheimer disease (AD).ResultsOur finding revealed that imperatorin administered acutely at the doses of 5 and 10 mg/kg prior to the injection of scopolamine (1 mg/kg) improved memory acquisition and consolidation impaired by scopolamine. Furthermore, repeatable (7 days, twice daily) administration of the highest dose of imperatorin (10 mg/kg) significantly attenuated the effects of scopolamine on memory acquisition, whereas the doses of 5 and 10 mg/kg of this furanocoumarin were effective when memory consolidation was measured. Imperatorin, administered with scopolamine, increased antioxidant enzymes activity and decreased concentration of malondiamide, an indicator of lipid peroxidation level.ConclusionsThese results demonstrate that imperatorin may offer protection against scopolamine-induced memory impairments and possesses antioxidant properties, thus after further preclinical and clinical studies this compound may provide an interesting approach in pharmacotherapy, as well as prophylactics of AD.

Calcium channel antagonists attenuate cross-sensitization to the rewarding and/or locomotor effects of nicotine, morphine and MK-801

The present study focused on the evaluation of behavioural cross‐sensitization, particularly in locomotor activities and conditioned rewarding effects, between nicotine and morphine, cocaine, amphetamine or MK‐801. Nicotine (0.5 mg kg−1)‐experienced mice manifested an enhanced locomotor response to morphine (5 mg kg−1) or MK‐801 (0.3 mg kg−1). No cross‐sensitization was observed between nicotine and amphetamine (2 mg kg−1) or cocaine (15 mg kg−1). Additionally, the L‐type voltage‐dependent calcium‐channel antagonists, nimodipine and verapamil, but not diltiazem, at a dose of 20 mg kg−1 injected before morphine or MK‐801 challenge, blocked the expression of this cross‐sensitization. In the second test, an enhancement of morphine place conditioning in rats pre‐exposed to nicotine (0.5 mg kg−1, injected daily for 5 days) was demonstrated. After two conditioning sessions, morphine (5 mg kg−1) induced a clear place preference only in animals that had previously received nicotine injections. The administration of nimodipine (10 and 20 mg kg−1), verapamil (10 and 20 mg kg−1) and diltiazem (10 and 20 mg kg−1) prior to nicotine dose‐dependently prevented this sensitization to the rewarding effect of morphine produced by prior injections of nicotine. These findings support the hypothesis that similar neural calcium‐dependent mechanisms are involved in the appetitive effects of nicotine and morphine and in the sensitized locomotor stimulant effects of nicotine and morphine or MK‐801.

On the mechanism of cross-tolerance between morphine- and nicotine-induced antinociception: involvement of calcium channels.

The present study focused on the evaluation of a mechanism of nicotine-induced antinociception and cross-tolerance to antinociceptive effects between nicotine and morphine in mice. The results indicate that, at a dose of 3 mg/kg, nicotine produced a significant antinociception in the hot-plate test. Additionally, the L-type voltage-dependent calcium channel antagonists, nimodipine, verapamil and diltiazem (5, 10 and 20 mg/kg), as well as an opioid receptor antagonist naloxone (0.5 and 1 mg/kg), dose-dependently attenuated this nicotine-induced antinociception. In a second series of experiments, mice were treated with morphine (25 and 50 mg/kg) once daily, for 3 days. On the 4th day, the antinociceptive response of morphine (10 mg/kg) and nicotine (3 mg/kg) was measured. Tolerance to the effects of both drugs was observed only in mice pretreated with the highest dose of morphine. Furthermore, the administration of nimodipine, diltiazem, flunarizine (10 and 20 mg/kg), but not of verapamil (10 and 20 mg/kg) nor mecamylamine (1 and 2 mg/kg) prior to morphine injections, prevented this cross-tolerance to the antinociceptive effects of morphine and nicotine. These findings support the hypothesis that similar opioid- and calcium-dependent mechanisms are involved in morphine- and nicotine-induced antinociception and in the development of cross-tolerance between these drugs.

Calcium-dependent mechanisms of the reinstatement of nicotine-conditioned place preference by drug priming in rats.

Reinstatement of drug-seeking behaviour in animals is relevant to relapse to drug taking in humans. We used the conditioned place preference version of the reinstatement model to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.), a cannabinoid receptor agonist WIN55,212-2 (0.5 mg/kg, i.p.), ethanol (0.5 g/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). The priming injections of nicotine, WIN55,212-2 and ethanol, but not of d-amphetamine renewed a preference for the compartment previously paired with nicotine. Finally, we examined the influence of the calcium channel antagonists, nimodipine (5 and 10 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine place conditioning induced by WIN55,212-2 and ethanol. It was shown that the calcium channel blockers attenuated the reinstatement of nicotine-conditioned response induced by both drugs. As reinstatement of drug-seeking is a factor for the development of dependence, the L-type calcium channel antagonists may be useful in the relapse-prevention phase of addiction treatment, including cannabinoid, ethanol, and/or nicotine dependence.

Cannabinoid receptor ligands suppress memory-related effects of nicotine in the elevated plus maze test in mice.

The purpose of the experiments was to examine the memory-related effects of nicotine using the mouse elevated plus maze. It has been shown that the acute doses of nicotine (0.1 and 0.5 mg/kg) significantly decreased the time of transfer latency (TL2) on the retention trial, indicating that nicotine improved memory processes. Similarly, acute doses of the CB1 cannabinoid receptor antagonist AM 251 (0.5, 1, 1.5 and 3 mg/kg) significantly decreased TL2 values. WIN55,212-2, a non-selective CB cannabinoid receptor agonist, at any dose tested (0.25, 0.5 and 1 mg/kg), did not provoke any effect in this model. Moreover, the acute injection of both WIN55,212-2 (0.25 and 0.5 mg/kg) and AM 251 (0.25 mg/kg), prior to injections of nicotine (0.1 and 0.5 mg/kg), significantly prevented nicotine-induced memory improvement. The results of this study provide clear evidence that the endogenous cannabinoid system participates in the responses induced by nicotine on memory-related behaviour in mice.

Effects of imperatorin on nicotine-induced anxiety- and memory-related responses and oxidative stress in mice.

The purpose of the reported experiments was to examine the effects of imperatorin [9-[(3-methylbut-2-en-1-yl)oxy]-7H-furo[3,2-g]chromen-7-one] on anxiety and memory-related responses induced by nicotine in mice and their relation to the level of nicotine-induced oxidative stress in brain as well as in the hippocampus and the prefrontal cortex. Male Swiss mice were tested for anxiety in the elevated plus maze test (EPM), and for cognition using passive avoidance (PA) procedures. Imperatorin, purified by high-speed counter-current chromatography from methanol extract of fruits of Angelica officinalis, acutely administered at the doses of 10 and 20mg/kg impaired the anxiogenic effect of nicotine (0.1mg/kg, s.c.). Furthermore, acute injections of subthreshold dose of imperatorin (1mg/kg, i.p.) improved processes of memory acquisition when co-administered with nicotine used at non-active dose of 0.05 mg/kg, s.c. Additionally, repeated administration of imperatorin (1mg/kg, i.p., twice daily, for 6 days) improved different stages of memory processes (both acquisition and consolidation) when injected in combination with non-active dose of nicotine (0.05 mg/kg, s.c.) in the PA task. Oxidative stress was assessed by determination of antioxidant enzymes (glutathione peroxidases (GPx), superoxide dismutase (SOD), glutathione reductase (GR)) activities as well as of malondialdehyde (MDA) concentration in the whole brain, the hippocampus and the prefrontal cortex after repeated administration of imperatorin (1mg/kg, 6 days) and single nicotine injection (0.05 mg/kgs.c.) on the seventh day. The results of our research suggest strong behavioural interaction between imperatorin and nicotine at the level of anxiety- and cognitive-like processes. Furthermore, imperatorin inhibited nicotine-induced changes in examined indicators of oxidative stress, especially in the hippocampus and the cortex.

Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze in mice

In this study, we investigated the effects of acute administration of nicotine on memory-related behavior in mice using the elevated plus maze test. In this test, the time necessary for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. Our results revealed that nicotine (0.035 and 0.175 mg/kg, base, sc) shortened the transfer latency relative to the saline-treated group. Moreover, we investigated the effects of bupropion (10, 20 and 40 mg/kg, ip) and L-type voltage-dependent calcium channel antagonists (nimodipine, flunarizine, verapamil, diltiazem - 5, 10 and 20 mg/kg, ip) on memory-related behavior. At all tested doses, bupropion, did not significantly affect transfer latency. However, flunarizine and verapamil (both at 10 mg/kg) resulted in a slight decrease in transfer latency, whereas nimodipine (10 mg/kg) increased transfer latency. Interestingly, both bupropion (20 mg/kg) and calcium channel blockers (5 mg/kg) attenuated the improvement of memory induced by nicotine. Our findings indicate that the cholinergic nicotinic system may play an important role in memory consolidation, and that neural calcium-dependent mechanisms can be involved in the modulation of memory-related responses induced by nicotine. The results of these studies have revealed neuronal mechanisms that are important for nicotinic modulation of cognition and will be useful for the treatments of human disorders in which cholinergic pathways have been implicated, such as psychiatric disorders and addiction.

Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test.

The purpose of the current experiments was to examine the anxiety-related effects of repeated amphetamine and nicotine administration using the mouse elevated plus maze (EPM). d-amphetamine was administered daily for 8 days (2 mg/kg, i.p.). On the 9th day, mice were challenged with amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.), and were tested 30 min after this last injection. Additionally, a distinct group of mice was pretreated with nicotine (0.1 mg/kg, s.c., 6 days). These mice were subjected to nicotine (0.1 mg/kg, s.c.) or amphetamine (2 mg/kg, i.p.) challenge on the seventh day to see if full crossover effects developed after the pretreatment of both psychostimulant drugs. Moreover, the L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5 and 10 mg/kg, i.p.) and diltiazem (5 and 10 mg/kg, i.p.) were injected prior to each injection of chronic d-amphetamine or nicotine. We observed cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine that was blunted by a pretreatment with calcium channel blockers. Overall our findings imply that similar neural calcium-dependent mechanisms are involved in the anxiety-related responses to chronic amphetamine and nicotine injections. As anxiety seems to be an important factor for the development of psychostimulant dependence, the L-type VDCC antagonists can offer an interesting approach for the pharmacotherapy of addiction, including amphetamine and/or nicotine dependence.