dizocilpine-maleate and 1-(3-chlorophenyl)biguanide

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.

Topics: Animals; Biguanides; Central Nervous System Depressants; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; GABA Modulators; Male; Midazolam; Morphine; Narcotics; Phencyclidine; Pregnanolone; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Agonists

The present study examined the effect of ethanol (0.25-1.0 g/kg, I.P.) alone and in combination with drugs affecting different ligand-gated ion channels on a horizontal locomotor activity of male Wistar rats. None of the drugs given alone affected the locomotor activity. Similarly, combining ethanol either with nicotine (0.1 or 0.6 mg/kg, S.C.) or the competitive NMDA receptor antagonist, CGP 40116 (0.5 mg/kg, I.P.) did not result in any significant changes in ambulation. On the other hand, a significant hyperadditive interaction between ethanol (0.5 or 1.0 g/kg) and the uncompetitive NMDA receptor antagonist, dizocilpine (0.1 mg/kg, I.P.) was found. Thus, a combined administration of ethanol and dizocilpine produced a marked stimulation of the locomotor activity. Combining 1.0 g/kg ethanol with the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (5.0 mg/kg, I.P.) tended to produce locomotor stimulation. Our results suggest the existence of interaction between ethanol and the NMDA receptor complex in mediation of locomotor stimulation. Alternatively, a common neurotransmitter system (other than glutamatergic) mediate central stimulatory effects of ethanol and dizocilpine. A possible role of dopamine in this interaction is being discussed.

Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Biguanides; Central Nervous System Depressants; Dizocilpine Maleate; Drug Interactions; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Nicotine; Nicotinic Agonists; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate