جستجوی مقالات مرتبط با کلیدواژه "ناحیه تگمنتوم شکمی" در نشریات گروه "پزشکی"

Extensive evidence shows that morphine impairs cognitive functions. On the other hand, ghrelin is a gastrointestinal hormone that affects learning and memory process. The purpose of the current study was to evaluate the effect of intra-ventral tegmental area (VTA) injection of ghrelin on morphine-induced amnesia in male rats. In this experimental study, 104 male Wistar rats (220-250 g) were randomly divided into 13 groups (n=8 for all groups) including: saline, morphine treated groups (0.5-7.5 mg/kg), ghrelin treatd groups (0-3 nmol/μl) plus morphine (7.5 mg/kg) or saline. Memory was measured in a step-through type inhibitory avoidance apparatus. All groups received intra-ventral tegmental area (intra-VTA) injection of saline or ghrelin immediately after training. After 5 mins saline or morphine was injected subcutaneously. Testing phase was done 24 hrs after training. Data were analyzed using one-way and two-way ANOVA analysis followed by Tukey’s multiple comparison test. The results showed that post-training administration of morphine significantly reduced step-through latency compared with the saline group (p<0.001). Intra-VTA injection of ghrelin also reduced morphine-induced amnesia (7.5 mg/kg) (p< 0.001). Ghrelin plus saline administration had no significant effect on memory retrieval (p>0.05). The results indicate that intra-VTA injction of ghrelin prevents the disrupting effects of morphine on avoidance memory.
Key words: Ghrelin, Inhibitory avoidance learning, Male rat, Morphine, Ventral tegmentum area
Funding: This study was funded by University of Arak.                             
Conflict of interest: None declared.
Ethical approval: The Ethics Committee of Arak University of Medical Sciences approved the study. (1397.139).
How to cite this article: Nazari-serenjeh F, Darbandi N, Yadegary A, Momeni HR. The Effect of Intra-ventral Tegmental Area Injection of Ghrelin on Morphine-Induced Amnesia in Male Rats: An Experimental Study. J Rafsanjan Univ Med Sci 2019; 18 (2): 147-60. [Farsi]

Ventral Tegmental Area (VTA), as a major source of dopaminergic (DA) neurons, has crucial roles in the vital and pathologic conditions, such as drug dependence and depression. The receptors on the VTA-DA neurons with different density and diversity have modulatory effects on their target tissues, such as the cerebral cortex. The aim of the present study was to study the effect of GABA-A receptor blockade on the VTA-DA neuronal firing pattern.
Male Wistar rats (~200 gr) were randomly allocated in 8 groups with equal substitutive numbers (control, sham, and treatments). The VTA-DA neuronal firing patterns (simple-tonic or burst firing) were acquisitioned under urethane anesthesia and stereotaxic approach. Bicuculline as a GABA-A receptor antagonist were infused microiontophoretically intracerebroventricularly (5, 25, 50, 500, 1000, and 2500 ngr) and peri-injection neuronal firing were captured for burst firing detection.
The simple-tonic spiking of the VTA-DA neurons in the pre-injection period was about 5.78 spikes/sec overall with stable firing. Bicuculline microinjection dose-dependently modulated burst firing pattern. The abovementioned amounts of Bicuculline induced 5.2, 10.4, 23.4, 28.8, 35.9, 36.17 percent of neurons to fire burst with duration of 5.2, 8.7, 24.45, 29.87, 40.56, and 50.34 minutes, respectively. The post injection simple-tonic firing rates were also dose-dependently elevated from 8 to 358 percent of the pre-injection levels.
The results showed that GABA-A receptors on the VTA-DA neurons can have regulatory roles on their firing patterns. The external GABAergic afferents or internal interneurons that mediate GABA modulation on the VTA-DA neurons can interfere in the efferent functions of the VTA-DA neurons.

Chronic high doses of morphine inhibit cell proliferation and induce cell death. One of the centers in reward pathway is the ventral tegmental area (VTA). Stimulation of opioid receptors in the reward circuit in the brain by morphine could be enabling a factor induce apoptosis in some brain regions، and expression of death receptors increases on the cell surface. This study was designed to evaluate the effect of morphine on changes in apoptotic factors (Bax/Bcl-2، PARP and caspase-3) in the VTA during the acquisition of morphine-induced conditioned place preference (CPP) and extinction period.

In this study، in behavioral experiments، the CPP paradigm was done on 64 adult male albino Wistar rats. In saline-control and three doses of morphine (0. 5، 5، 10 mg/kg) experimental groups in acquisition، in addition with effective dose of morphine (5 mg/kg) evaluate extinction period (8 days). Then، in the molecular section the changes in apoptotic proteins assess with western blot technique.

We found that apoptotic factors increase in all three experimental groups in response to morphine. However، the most response was significantly occurred at the dose of 5 mg/kg morphine. Additionally، there is no change has been seen in the apoptotic factors during the extinction period.

It seems that morphine in all doses cause apoptosis، but quite contrary، by increasing the dose of morphine، the number of receptors involved in apoptosis increases and morphine’s neuroprotective effects are appeared.

Several Studies have identified that the mesocorticolimbic dopaminergic pathway consisting of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) plays an important role in morphine dependence and withdrawal signs. Orexin projection and its receptors have been found in the brain regions including VTA that involved in the expression of morphine withdrawal signs. The aim of this study was to evaluate the effects of orexin receptor-1 (OX1R) agonist and antagonist microinjection into the VTA on withdrawal signs in morphine dependent rats. This experimental study was carried out on 24 male Wistar rats (weighing 250-300 g) in 2012 that were divided in 4 groups. They were rendered morphine dependent by subcutaneous injection of morphine sulfate at intervals of 12 h for 10 days. On day 11، intra-VTA microinjection of orexin receptor-1 agonist (orexin-A) and antagonist (SB-334867) was performed (2h after last morphine injection and before naloxan injection) and naloxone precipitated withdrawal sings were evaluated for 30 min. In the vehicle group، normal salin was microinjected into the VTA. Data were analyzed using t-test and ANOVA. Intra-VTA SB-334867 microinjection significantly decreased the jumping sign (P< 0. 01). Orexin-A microinjection significantly increased the wet-dog shakes sign (P< 0. 05). With regard to the results، OX1R in the VTA has a little effect on expression of withdrawal signs in morphine dependent rats.

Nitric oxide synthesis has been detected in ventral tegmental area, which is a key brain region that seems to mediate behavioral effect of morphine and nicotine. In the present study, the effects of L-arginine, a nitric oxide precursor, in the ventral tegmental area in nicotine’s effect on morphine-induced amnesia has been investigated. This study was done experimentally on 250 male rats. Rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride, plus xylazine and then placed in a stereotaxic apparatus. Two stainless-steel cannuale were placed in the ventral tegmental area. The behavioral testing was started in inhibitory avoidance task, and the step-through latency for entering into the dark compartment was measured for the assessment of memory retention. One-side analysis of variance (ANOVA) and Tukey test were used to evaluate the statistical significance between experimental groups. A difference of p<0.05 was considered statistically significant. Post-training injection of morphine (5 and 7.5mg/kg) decreased the memory retrieval. Injection of nicotine or L-arginine before test by itself has no effect on memory retrieval. On the other hand, pre-test administration of morphine (7.5mg/kg), nicotine (0.5 and 1mg/kg), L-arginine or ineffective doses of L-arginine plus non-effective dose of nicotine restored memory impairment induced by post-training injection of morphine. The finding of the study indicate that nitric oxide system of the ventral tegmental area may play an important role in the improving effect of nicotine on the morphine-induced amnesia.

The mesolimbic dopaminergic system that projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is critical for initiation of opioid reinforcement and reward-related effects of drugs of abuse. In the present study, the effects of reversible inactivation of VTA on firing rate of nucleus accumbens neurons and on acquisition and expression of morphine-induced conditioned place preference (CPP) were investigated in rats. Adult male Wistar rats were used in these experiments. In behavioral study, the reversible inactivation of VTA was done through bilateral intra-VTA microinjection of 2% lidocaine during the acquisition and expression of morphine (5 mg/kg; s.c.)-induced CPP and in electrophysiology section, it was done through unilateral intra-VTA microinjection of 2% lidocaine during single unit recording from the NAc neurons. Conditioning score and locomotor activity were recorded by Ethovision software. Firing rate of neurons was recorded by single unit recording technique. The results showed that bilateral intra-VTA administration of lidocaine significantly decreases the acquisition (P<0.01) and expression (P<0.05) of morphine-induced CPP compared to their respective saline-microinjected groups. Moreover, intra-VTA administration of lidocaine had no effect on locomotor activity in these experiments. Also, unilateral intra-VTA administration of lidocaine significantly increased the firing rate of nucleus accumbens neurons. Our results further support the idea that VTA may play an important role in the acquisition and expression of morphine-induced CPP.