The role of the hippocampus and 5-HT/GABA interaction in the central effects of benzodiazepine receptor ligands

Abstract

The effects of an intrahippocampal administering of a nonselective full (midazolam), a partial benzodiazepine (BDZ) receptor agonist (bretazenil), and a BDZ1 selective (zolpidem) receptor ligand were examined in the open field test (OFT) of neophobia and Vogel's test (VT) of conflict behavior in rats. Moreover, the influence of local injections of a noncompetitive GABA(A) receptor antagonist, picrotoxin, on the anxiolytic-like effect of serotonin (5-HT) depletion (p-chlorophenylalanine, p-CPA) in the Vogel test was studied. It was found that in the OFT only midazolam (0.1 microg/site) given to the hippocampus (HP) disinhibited rat exploratory behavior, whereas all the examined compounds inhibited animal motor activity when injected locally at 10.0 microg/site, the highest dose used in the tests. In the VT, again, only midazolam disinhibited rat conflict behavior on a dose-dependent basis. Picrotoxin administered to the HP produced a tendency to increase locomotor activity in rats, and significantly attenuated the anti-conflict action of serotonin depletion without changing the pain threshold and spontaneous drinking of the animals. p-CPA induced potent, dose-dependent and selective 5-HT and 5-hydroxyindoleacetic acid decrease in the HP after administering the dose used in the behavioral experiment. Thus, the present data provide evidence for the lack of selective anxiolytic activity of a partial non-selective agonist and a full selective agonist at the BDZ1 receptor after their administration to the HP. The model of intra-HP drug injections appeared effective in discriminating the anxiolytic spectrum of activity of new psychotropic compounds. Moreover, the obtained results indicate that the dorsal HP is one of the central sites important for GABA/5-HT interaction that modulates rat emotional behavior.

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

“…The hippocampus is also an important site for GABA and serotonin interaction, which is thought to modulate emotional behaviour. 47 In patients with PTSD structural and functional alterations of the hippocampus have consistently been demonstrated. [48][49][50][51] Benzodiazepine agonists enhance GABA A Abbreviations: BA, Brodmann area; PTSD, post-traumatic stress disorder.…”

Effect of Tandospirone on Sleep Latency in Rats Placed on a Grid Suspended Over Water

“…p-Chlorophenylalanine administration (300 mg / kg, i.p., for 2 days) resulted in a significant shortening of sleep latency in rats placed on the grid suspended over water. Nazar et al (9) reported that 5-HT contents in the hippocampus were significantly decreased after 2 days administration of p-chlorophenylalanine (300 mg / kg) compared with those of control animals. Engel et al (12) have reported that 5-HT depletion caused by p-chlorophenylalanine resulted in an anticonflict effect measured by a modified Vogel's conflict test.…”

“…On the first day, EEG and EMG were measured and then p-chlorophenylalanine (300 mg / kg) was administered daily for 2 days. After p-chlorophenylalanine treatment, a significant decrease in 5-HT contents in hippocampus was reported (9). Thereafter, on day 4, EEG and EMG were also measured.…”

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…It is well known that psychiatric disorders such as depression and schizophrenia, causing emotional and cognitive disorders, are related to an alteration of the serotonin system [32,113,153,178]; in these pathologies, some responsibility might be attributed to a disruption of 5-HT-mediated control over glutamate-and GABA-mediated transmission in the hippocampus and frontal cortex [32,113,136]. In particular schizophrenia is characterized by changes in synaptic connectivity in the hippocampus, affecting mainly glutamate transmission but also the function of GABAergic neurons [70].…”