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A role for the mesolimbic dopaminergic system in the pathophysiology of depression has become increasingly evident. Specifically, brain-derived neurotrophic factor (BDNF) has been shown to be elevated in the nucleus accumbens of depressed patients and to positively contribute to depression-like behaviour in rodents. The dopamine D1–D2 receptor heteromer exhibits significant expression in NAc and has also been shown to enhance BDNF expression and signalling in this region. We therefore examined the effects of D1–D2 heteromer stimulation in rats by SKF 83959, or its inactivation by a selective heteromer-disrupting TAT-D1 peptide on depression- and anxiety-like behaviours in non-stressed animals and in animals exposed to chronic unpredictable stress. SKF 83959 treatment significantly enhanced the latency to immobility in the forced swim test, increased the latency to drink condensed milk and reduced total milk consumption in the novelty-induced hypophagia test, and additionally reduced the total time spent in the open arms in the elevated plus maze test. These pro-depressant and anxiogenic effects of SKF 83959 were consistently abolished or attenuated by TAT-D1 peptide pre-treatment, signifying the behaviours were mediated by the D1–D2 heteromer. More importantly, in animals exposed to chronic unpredictable stress (CUS), TAT-D1 peptide treatment alone induced significant and rapid anxiolytic and antidepressant-like effects in two tests for CUS-induced anhedonia-like reactivity and in the novelty-suppressed feeding test. Together these findings indicate a positive role for the D1–D2 heteromer in mediating depression- and anxiety-like behaviours and suggest its possible value as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

A role for the dopamine D1–D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1–D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioral model widely used to study the neuroadaptations associated with psychostimulant addiction. D1–D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5 day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1–D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5 day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1–D2 receptor heteromer exerts a tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1–D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants. [ABSTRACT FROM AUTHOR]

Cocaine-induced increases in dopamine signaling in nucleus accumbens (NAc) play a significant role in cocaine seeking behavior. The majority of cocaine addiction research has focused on neuroanatomically segregated dopamine D1 and D2 receptor-expressing neurons, yet an involvement for those NAc neurons coexpressing D1 and D2 receptors in cocaine addiction has never been explored. In situ proximity ligation assay, confocal fluorescence resonance energy transfer and coimmunoprecipitation were used to show native D1 and D2 receptors formed a heteromeric complex in D1/D2 receptor-coexpressing neurons in rat and non-human primate NAc. D1–D2 heteromer expression was lower in NAc of adolescent rats compared to their adult counterparts. Functional disruption of the dopamine D1–D2 receptor heteromer, using a peptide targeting the site of interaction between the D1 and D2 receptor, induced conditioned place preference and increased NAc expression of ∆FosB. D1–D2 heteromer disruption also resulted in the promotion, exacerbation and acceleration of the locomotor activating and incentive motivational effects of cocaine in the self-administration paradigm. These findings support a model for tonic inhibition of basal and cocaine-induced reward processes by the D1–D2 heteromer thus highlighting its potential value as a novel target for drug discovery in cocaine addiction. Given that adolescents show increased drug abuse susceptibility, an involvement for reduced D1–D2 heteromer function in the heightened sensitivity to the rewarding effects of cocaine in adolescence is also implicated. [ABSTRACT FROM AUTHOR]

Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404Glu and 405Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmuno-precipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-pro-tein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment. [ABSTRACT FROM AUTHOR]

Abstract: The descriptive study attempts to find house factors associated with earthquake deaths due to the earthquake that struck central Taiwan. Isoseismic area was selected for study to compare building damage and mortality. The rate of houses collapsing increased with intensity of earthquake, inferior constructing, and construction time. According to the ranking by mortality and statistics of death toll in various houses, the poor seismic resistant capacity of mud-brick residence is found to be the major factor that caused great loss of lives. There is 47.6% of the deaths occurred in mud-brick houses though present only 3.8% of all houses. While the reinforced steel concrete buildings had very low damage rate in the major earthquake. Asphyxia and internal hemorrhage were the major cause of deaths in house collapses. These results suggest that improvements in anti-seismic constructing and rescue team efforts could decrease the effect of disaster. [Copyright &y& Elsevier]

Examines the factors associated with deaths resulting from the great Chi-Chi Earthquake that occurred on September 21, 1999 in Taiwan. Consideration of the vertical peak ground acceleration of ground motion intenjsity as the most appropriate index for the evaluation of building collapse and mortality; Relation between increase in mortality and increase in earthquake intensity; Occurrence of the greatest number of collapsed buildings and human deaths between the Chelungpu Fault and Shuantun Fault.