Loss of dopamine D2 receptors induces atrophy in the temporal and parietal cortices and the caudal thalamus of ethanol-consuming mice.

BACKGROUND: The need of an animal model of alcoholism becomes apparent when we consider the genetic diversity of the human populations, an example being dopamine D2 receptor (DRD2) expression levels. Research suggests that low DRD2 availability is associated with alcohol abuse, while higher DRD2 levels may be protective against alcoholism. This study aims to establish whether (i) the ethanol-consuming mouse is a suitable model of alcohol-induced brain atrophy and (ii) DRD2 protect the brain against alcohol toxicity. METHODS: Adult Drd2+/+ and Drd2-/- mice drank either water or 20% ethanol solution for 6 months. At the end of the treatment period, the mice underwent magnetic resonance (MR) imaging under anesthesia. MR images were registered to a common space, and regions of interest were manually segmented. RESULTS: We found that chronic ethanol intake induced a decrease in the volume of the temporal and parietal cortices as well as the caudal thalamus in Drd2-/- mice. CONCLUSIONS: The result suggests that (i) normal DRD2 expression has a protective role against alcohol-induced brain atrophy and (ii) in the absence of Drd2 expression, prolonged ethanol intake reproduces a distinct feature of human brain pathology in alcoholism, the atrophy of the temporal and parietal cortices.

Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C.

Classically, 17beta-estradiol (E2) is thought to control homeostatic functions such as reproduction, stress responses, feeding, sleep cycles, temperature regulation, and motivated behaviors through transcriptional events. Although it is increasingly evident that E2 can also rapidly activate kinase pathways to have multiple downstream actions in CNS neurons, the receptor(s) and the signal transduction pathways involved have not been identified. We discovered that E2 can alter mu-opioid and GABA neurotransmission rapidly through nontranscriptional events in hypothalamic GABA, proopiomelanocortin (POMC), and dopamine neurons. Therefore, we examined the effects of E2 in these neurons using whole-cell recording techniques in ovariectomized female guinea pigs. E2 reduced rapidly the potency of the GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E2-BSA and selective estrogen receptor modulators, including a new diphenylacrylamide compound, STX, that does not bind to intracellular estrogen receptors alpha or beta, suggesting that E2 acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a Galpha(q)-mediated activation of phospholipase C, leading to the upregulation of protein kinase Cdelta and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKCdelta and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E2 in GABA, POMC, and dopamine neurons. Therefore, this unique Gq-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.