tetragastrin and Substance-Withdrawal-Syndrome

Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

Topics: Adult; Alprazolam; Animals; Anti-Anxiety Agents; Benzodiazepines; Cell Line; Drug Tolerance; gamma-Aminobutyric Acid; Humans; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Neurotransmitter Agents; Panic Disorder; Purines; Rats; Rats, Sprague-Dawley; Receptors, GABA; Receptors, GABA-A; Substance Withdrawal Syndrome; Tetragastrin

Effects of GB-115, an anxiolytic L-triptophan-containing dipeptide, based on the endogenous tetrapeptide cholecystokinin, were evaluated during and after withdrawal of its long-term administration to rats in comparison with diazepam. It was shown using the "elevated plus-maze" test (EPM) that GB-115 retained its anxiolytic properties after i/p injections at a daily dose of 0.1 mg/kg fo r 30-days. Discontinuation of dipeptide administration 24h and 48 hours after the onset of the experiment did not lead to behavioral (increased anxiety, aggression) and convulsive (decreased corazol sensitivity) manifestations of withdrawal syndrome. In contrast, the withdrawal ofdiazepam (4.0 mg/kg/day, ip, 30 days) induced the anxiogenic response in EPM, reduction of the aggression threshold, and enhancement of convulsive readiness. Significant differences between GB-115 and diazepam effects on the levels of dopamine, norepinephrine, and their metabolites after chronic administration and withdrawal were restricted to striatum.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Corpus Striatum; Diazepam; Dipeptides; Dopamine; Drug Tolerance; Male; Norepinephrine; Rats; Substance Withdrawal Syndrome; Tetragastrin; Time

The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Animals, Outbred Strains; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Benzodiazepines; Brain Chemistry; Diazepam; Dipeptides; Disease Models, Animal; Dopamine; Exploratory Behavior; Male; Maze Learning; Rats; Substance Withdrawal Syndrome; Tetragastrin; Tranquilizing Agents

The aim of present study was to reveal the role of cholecystokinin (CCK) in the jumping behaviour induced by the opioid antagonist naloxone (30 mg/kg) after the acute administration of morphine (200 mg/kg) in mice. Treatment with caerulein (0.01-1 microg/kg), a nonselective agonist of CCK receptors, induced a large reduction of jumping frequency without parallel suppression of locomotor activity. The CCK(B) receptor agonist CCK tetrapeptide (CCK-4. 0.125-32 mg/kg) caused the same effect, but it happened at much higher doses (above 0.5 mg/kg). Devazepide (1 microg/kg), a preferential CCK(A) receptor antagonist, completely reversed the action of caerulein (0.1 gmg/kg) and CCK-4 (2 mg/kg). A preferential CCK(B) receptor antagonists LY 288,513 at a high dose (4 mg/kg) blocked the action of CCK-4, but not that of caerulein. Acetorphan (16-128 mg/kg), an inhibitor of enkephalin metabolism, did not block naloxone-precipitated jumping behaviour. However, the combination of subthreshold doses of caerulein (0.001 microg/kg) and CCK-4 (0.25 mg/kg) with acetorphan (64 mg/kg) potently antagonized the behaviour induced by naloxone. In conclusion, the antagonism of CCK agonists against naloxone-precipitated jumping behaviour is apparently mediated via the CCK(A) receptor subtype. The stimulation of CCK(A) receptors seems to increase the release of endogenous enkephalins.

Topics: Animals; Ceruletide; Devazepide; Dose-Response Relationship, Drug; Hormone Antagonists; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Pyrazoles; Receptors, Cholecystokinin; Substance Withdrawal Syndrome; Tetragastrin; Thiorphan