The effect of telmisartan, an angiotensin receptor blocker, on alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens.

Alcohol use disorder remains a major health problem. The mesocorticolimbic dopaminergic system, including the nucleus accumbens region and multiple neural circuits, is involved in its complex underlying mechanism. For instance, alcohol intake stimulates the central and peripheral renin-angiotensin system and increases angiotensin II levels, which predominantly affect angiotensin 1 receptors both in the periphery and in the brain. In this study, we aimed to investigate the effects of the intracerebroventricularly-administered angiotensin 1 receptor blocker telmisartan on the alcohol consumption of male Sardinian alcohol-preferring (sP) rats and on the alcohol-induced dopamine levels in the nucleus accumbens region in Wistar rats. Acute intracerebroventricular administration of telmisartan (100 nM) reduced the alcohol intake for 24 hours without affecting food and water consumption in sP rats. Acute intracerebroventricular injection of the opioid receptor antagonist naloxone (75 nM), tested as a reference compound, also reduced the alcohol consumption in sP rats; however, naloxone's effect lasted only for 30 minutes. In microdialysis experiments, telmisartan administered intracerebroventricularly did not change dopamine levels in the nucleus accumbens that had been induced by acute intraperitoneal alcohol administration in Wistar rats. According to these results, further studies are needed to elucidate the role of the renin-angiotensin system on alcohol use disorder pathophysiology.

Differences in Neurodegeneration Between Kainic Acid-Injected GAERS and Wistar Rats.

AIM: To compare neurodegenerative changes using the Fluoro-Jade B staining, following status epilepticus induced by intraamygdaloid injection of kainic acid in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control Wistar rats. MATERIAL AND METHODS: A single unilateral intra-amygdaloid kainic acid (750 ng) was administered in adult male GAERS and Wistar rats to induce status epilepticus. We recorded electroencephalogram (EEG) and behavioral changes throughout the experiments. After 1 week of the kainic acid injection, rats were sacrificed, and the brains were removed. We obtained 20λm sections and processed them for Fluoro-Jade B and Nissl staining, which were evaluated semi-quantitatively. RESULTS: Following kainic acid injections, status epilepticus developed in all rats. In GAERS rats, motor seizures were considerably delayed, with no statistically significant difference in the number of seizures. However, statistically significant differences were observed in the Fluoro-Jade B staining in GAERS rats between contralateral and ipsilateral sides of the CA3, CA1, somatosensory cortex, entorhinal cortex, piriform cortex, reticular nucleus, putamen, and claustrum. In Wistar rats, the CA3, CA1, somatosensory cortex, entorhinal cortex, piriform cortex, reticular nucleus, amygdala, and laterodorsal nucleus exhibited significant differences. Comparing GAERS and Wistar rats, a statistically significant difference was observed for both sides of CA1. In both groups, the staining was prominent ipsilaterally, except for the claustrum in GAERS rats. However, the motor cortex remained unaffected in both groups. Neurodegenerative changes were not associated with the severity of seizures in both groups following the intra-amygdaloid kainic acid administration. CONCLUSION: This study demonstrates that CA1 is the only region exhibiting a statistically significant difference between Wistar and GAERS rats.

Localized cortical injections of ethosuximide suppress spike-and-wave activity and reduce the resistance to kindling in genetic absence epilepsy rats (GAERS).

Models of genetic absence epilepsy are resistant to secondary generalization of focal limbic seizures. This correlates with the postnatal development of spike-and-wave discharges (SWDs), a hallmark of absence seizures arising from a cortical focus in the perioral region of somatosensory cortex. Ethosuximide injected at this site suppresses SWDs. The effect of this suppression on kindling in "Genetic Absence Epilepsy Rats from Strasbourg" (GAERS), has been compared for postnatal 30 day (PN30) rats having immature SWDs and adult (>4 months) rats having mature SWDs. Non-epileptic Wistar and GAERS rats were implanted with a basolateral amygdaloid stimulation electrode, bilateral injection cannulas into the cortical perioral focus, and cortical recording electrodes. Following recovery cortical injections of ethosuximide or saline were made and after 30min rats were given 36 stimulations or until Racine's stage 5 seizures were produced. All Wistar rats (PN30 and adult) treated with saline or ethosuximide reached stage 5. Of GAERS given saline, 33% (PN30) and 43% (adults) were resistant to kindling; after ethosuximide pups behaved like Wistars, but adults showed a delay in kindling relative to Wistars. These findings imply that mechanisms underlying kindling resistance are related but not limited to SWD activity in animals with genetic absence epilepsy.