ABSTRACT
GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.
Subject(s)
Ethanol/administration & dosage , Hippocampus/metabolism , Protein Subunits , Receptors, GABA-A/metabolism , Reward , Animals , Behavior, Addictive/etiology , Behavior, Addictive/metabolism , Behavior, Animal/drug effects , Behavior, Animal/physiology , Dose-Response Relationship, Drug , Drug Antagonism , Female , GABA Agonists/administration & dosage , GABA Antagonists/administration & dosage , GABA-A Receptor Agonists , GABA-A Receptor Antagonists , Gene Expression/drug effects , Genetic Predisposition to Disease , Hippocampus/drug effects , Microinjections , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Oocytes/drug effects , Oocytes/metabolism , Patch-Clamp Techniques , RNA/administration & dosage , RNA/metabolism , Rats , Rats, Inbred Strains , Receptors, GABA-A/genetics , Saccharin/administration & dosage , Self Administration , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism , XenopusABSTRACT
Bromine atoms are believed to play a central role in the depletion of surface-level ozone in the Arctic at polar sunrise. Br2, BrCl, and HOBr have been hypothesized as bromine atom precursors, and there is evidence for chlorine atom precursors as well, but these species have not been measured directly. We report here measurements of Br2, BrCl, and Cl2 made using atmospheric pressure chemical ionization-mass spectrometry at Alert, Nunavut, Canada. In addition to Br2 at mixing ratios up to approximately 25 parts per trillion, BrCl was found at levels as high as approximately 35 parts per trillion. Molecular chlorine was not observed, implying that BrCl is the dominant source of chlorine atoms during polar sunrise, consistent with recent modeling studies. Similar formation of bromine compounds and tropospheric ozone destruction may also occur at mid-latitudes but may not be as apparent owing to more efficient mixing in the boundary layer.
ABSTRACT
Experiments were performed using probe-word recognition methodology in which participants read sentences that were presented 1 word at a time and were then shown a probe word and had to make a speeded response indicating whether the word had occurred in the sentence. One experiment showed that response times to probe words increased with the size of the set of candidate probes. The other experiments showed that the effects caused by name repetition in circumstances in which the repeated name was co-referential also occurred when the repeated name was not co-referential and when the order of words in a sentence was scrambled. The results suggest that responses in the task can be based on probe-list memory, a mental representation created to keep track of those words that the participant believes are likely to be probed, and that the use of the task to make inferences about language comprehension should be accompanied by controls ruling out such strategies.
