dizocilpine-maleate and gaboxadol

Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA(A) receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA(A), N-methyl-D-aspartate (NMDA), σ₁, or 5-HT₃ receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.. The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA(A) receptors might contribute to its discriminative stimulus effects.. Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.. Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA(A) receptors, such as extrasynaptic GABA(A), NMDA, σ₁, and 5-HT₃ receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA₂ values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.. While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABA(A) receptors, they indicate a primary and possibly exclusive role of synaptic GABA(A) receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA(A) receptors.

Topics: Animals; Conditioning, Operant; Data Interpretation, Statistical; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Flumazenil; Flunitrazepam; GABA Modulators; Gonadal Steroid Hormones; Hypnotics and Sedatives; Isoxazoles; Macaca mulatta; Male; Midazolam; Pregnanolone; Receptors, GABA-A; Reinforcement Schedule

The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA(A) receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.

Topics: Adenylyl Cyclases; Analysis of Variance; Animals; Ataxia; Behavior, Animal; Blotting, Western; Calcium; Central Nervous System Depressants; Cyclic AMP-Dependent Protein Kinases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Activation; Ethanol; Excitatory Amino Acid Antagonists; Food Preferences; GABA Agonists; Isoxazoles; Ketamine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pentobarbital; Phosphorylation; Psychomotor Performance; Quinine; Reaction Time; Reflex; Saccharin; Sleep