Behavioral and Biochemical Impact of Chronic Unpredictable Mild Stress on the Acquisition of Nicotine Conditioned Place Preference in Rats.

Addiction is a chronic psychiatric disease which represents a global problem, and stress can increase drug addiction and relapse. Taking into account frequent concomitance of nicotine dependence and stress, the purpose of the present study was to assess behavioral and biochemical effects of chronic unpredictable mild stress (CUMS) exposure on nicotine reward in rats measured in the conditioned place preference (CPP) paradigm. Rats were submitted to the CUMS for 3 weeks and conditioned with nicotine (0.175 mg/kg) for 2 or 3 days. Our results revealed that only CUMS-exposed animals exhibited the CPP after 2 days of conditioning indicating that stressed rats were more sensitive to the rewarding properties of nicotine and that chronic stress exacerbates nicotine preference. Administration of metyrapone (50 mg/kg), a glucocorticosteroid antagonist, and imipramine (15 mg/kg), an antidepressant, abolished nicotine CPP in stressed rats after 2 days of conditioning. The biochemical experiments showed increased markers of oxidative stress after nicotine conditioning for 2 and 3 days, while the CUMS further potentiated pro-oxidative effects of nicotine. Moreover, metyrapone reversed oxidative changes caused by stress and nicotine, while imipramine was not able to overwhelm nicotine- and stress-induced oxidative damages; however, it could exert antioxidant effect if administered repeatedly. The results suggest that recent exposure to a stressor may augment the rewarding effects of nicotine through anhedonia- and stress-related mechanisms. Our study contributes to the understanding of behavioral and biochemical stress-induced modification of the rewarding effects of nicotine on the basis of the development of nicotine dependence.

Behavioral and Biochemical Interaction Between Nicotine and Chronic Unpredictable Mild Stress in Mice.

Nicotine, the main component of tobacco smoke, exerts influence on mood, and contributes to physical and psychological dependence. Taking into account frequent concomitance of nicotine abuse and stress, we aimed to research behavioral and biochemical effects associated with nicotine administration in combination with chronic unpredictable mild stress (CUMS). Mice were submitted to the procedure of CUMS for 4 weeks, 2 h per day. Our results revealed that CUMS-exposed animals exhibited behavioral alteration like anxiety disorders in the elevated plus maze (EPM) test, the disturbances in memory in the passive avoidance (PA) test and depressive effects in the forced swim test (FST). Moreover, nicotine (0.05-0.5 mg/kg), after an acute or subchronic administration decreased stress-induced depression- and anxiety-like effect as well as memory deficit. Administration of metyrapone (50 mg/kg), a glucocorticosteroid antagonist, alleviated the depressive effect induced by the CUMS. The biochemical experiments showed decreased values of the total antioxidant status (TAS), activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) with simultaneously increased in malondialdehyde (MDA) concentration in mice submitted to the CUMS. The same effects were observed after an acute and subchronic nicotine administration within all examined brain structures (i.e., hippocampus, cortex, and cerebellum) and in the whole brain in non-stressed and stressed mice confirming pro-oxidative effect of nicotine. Our study contributes to the understanding of behavioral and biochemical mechanisms involved in stress-induced disorders such as depression, anxiety and memory disturbances as well as dual nicotine-stress interactions on the basis of the development of nicotine dependence.

Effects of the cannabinoid receptor ligands on anxiety-related effects of d-amphetamine and nicotine in the mouse elevated plus maze test.

The purpose of the experiments was to examine the anxiety-related effects of d-amphetamine and nicotine, and the possible involvement of the endocannabinoid system. D-amphetamine (2 mg/kg, ip) was administered acutely or daily for 8 days. On the 9th day, mice were challenged with d-amphetamine (2 mg/kg, ip) or nicotine (0.1 mg/kg, sc), and were tested in the elevated plus maze. Additionally, a distinct group of mice was pretreated with an acute (0.1 mg/kg,sc) or subchronic nicotine (6 days), and subjected to nicotine (0.1 mg/kg, sc) or d-amphetamine (2 mg/kg, ip) challenge on the 7th day. The cannabinoid receptor ligands, WIN 55,212-2, a non-selective cannabinoid receptor agonist (0.25; 0.5 and 1 mg/kg, ip) and rimonabant, a CB1 cannabinoid receptor antagonist (0.25; 0.5; 1 and 2 mg/kg, ip) were injected prior to each injection of saline or acute and subchronic d-amphetamine or nicotine. We observed that acute anxiogenic and subchronic anxiolytic effects of both psychostimulants as well as the development of full cross-tolerance to their anxiogenic effects were dose-dependently blunted by ineffective doses of WIN 55,212-2 (0.25 and 0.5 mg/kg) and rimonabant (0.5 and 1 mg/kg). These results provide evidence that the endogenous cannabinoid system is involved in the anxiety-related responses to d-amphetamine and/or nicotine.

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.

[Histologic examination of some hippocampus fields after experimental ischemia]. / Histologiczne badania niektórych pól hipokampa po doswiadczalnej ischemii.

The examinations of rats hippocampus were made after ischaemia (the rats vertebral and common carotid arteries were closed for 20 minutes). Serial sections of the brains were stained with hematoxylin and eosin. 24 hours after completing the experiment a small number of cells in the field CA1 was damaged. They were dark and shrunken. 120 hours after the experiment strong damages affected large groups of pyramidal cells, especially in field CA1. The changes were asymmetrical and regarded one hemisphere of the brain only.

Morphometrical and histological alterations in the hippocampus cells affected by anoxia.

Clinical reports suggest that the hippocampus is a structure closely related to the functioning of memory and it plays a significant role in the learning process (15). It is also known that anoxia frequently induces degenerating alterations in the CNS whose characteristic features are lesion and cell necrosis. The alterations of this type appear in various fields and also in the hippocampus [2, 8, 9]. Sommer [13] was the first to report that this CNS area is very sensitive to damages during anoxia or epilepsy. Since there are different relations between the Willis' arterial circle and the system of vertebral and carotid arteries in different animals [4, 5], the effects of any vessel occlusion will vary.

Histological examinations of the influence of 6-hydroxydopamine (6-OH-DA) upon the ileum of the guinea pig.

Examinations of the influence of 6-OH-DA (6-hydroxydopamine) upon the structure of nerve cells and their axons have been conducted by many authors and in various aspects (1, 2, 8, 10). They have concerned histochemistry, fluorescence and ultrastructure of neurons and have shown that the substance evokes various changes in the perikaryons and axons of adrenergic neurons. The wall of the small intestine is innervated by external autonomyous nerves and fibres of the intramural autonomyous plexuses. External autonomyous fibres make numerous anastomoses with the neurons of the two intramural plexuses and ganglia: the myenteric one (Auerbach's) and the submucosal one (Meissner's) (6). Both ganglia run along the length of the intestine and their neurons apart from making anastomoses, send axons to the nonstrained muscles cells and glandular cells in the mucosa. As a consequence, the active phase is easily carried over along the alimentary system stimulating action of nonstrained muscles and glandular cells. 6-OH-DA exerts strong action upon the nerve cells and ends, that is why we have decided to examine the changes taking place in the ileum when the substance starts to operate.