We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.
This study examined the impact of coping strategies employed by homeless youth upon suicidal ideation, suicide attempts on the streets, and feeling trapped/helpless. Coping strategies examined in the analysis included problem‐focused and avoidant coping, along with several coping strategies identified in previous exploratory qualitative studies. Greater risk was associated with avoidant coping, social withdrawal, use of drugs and alcohol as coping, with “belief in a better future” linked to lowered risk levels. Gender interactions emerged with respect to avoidant coping and social withdrawal, both of which served as greater contributors to risk levels among females. Several approaches to coping including problem‐focused strategies and strategies identified by youths in previous qualitative works emerged as not serving to ameliorate suicidality.
It has been hypothesized that alcohol addiction is mediated, at least in part, by specific gamma-aminobutyric acid(A) (GABA(A)) receptors within the ventral pallidum (VP). Among the potential GABA(A) receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABA(A) alpha1 receptor subtype (GABA(A1)) appears pre-eminent. In the present study, we developed beta-carboline-3-carboxylate-t-butyl ester (betaCCt), a mixed agonist-antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VP(A1) receptors in the euphoric properties of alcohol. The in vivo actions of betaCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of betaCCt (0.5-40 microg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of betaCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol-reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered betaCCt (1-40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that betaCCt reversed the locomotor sedation produced by both chlordiazepoxide (10 mg/kg) and EtOH (1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that betaCCt acted as a low-efficacy partial agonist at alpha3beta3gamma2 and alpha4beta3gamma2 receptors and as a low-efficacy inverse agonist at alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors. The present study indicates that betaCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of betaCCt are primarily mediated via the GABA(A1) receptor. betaCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.
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We extended prior research on the medical health-correlates of forgiving others by examining the relationship between self-forgiveness, other-forgiveness and health. Results derived from a cross-sectional survey of 266 healthy undergraduates showed that these dimensions of forgiveness were positively related to perceived physical health. Regression analysis revealed that self-forgiveness uniquely predicted a significant amount of variance in perceived physical health, and predicted more variance than did other-forgiveness. These results are discussed in light of the limitations of the current study and directions for future research.
Past research has indicated that chronic ethanol exposure enhances dopamine (DA) neurotransmission in several brain regions. The present study examined the effects of chronic ethanol drinking on dopamine transporter (DAT) function in the nucleus accumbens (Acb) of High-AlcoholDrinking replicate line 1 (HAD-1) rats. HAD rats were given concurrent 24-hr access to 15% ethanol and water or water alone for 8 weeks. Subsequently, DA uptake and the V max of the DAT were compared between the two groups using homogenates of the nucleus accumbens. DA uptake was measured following a 2 minute incubation at 37°C in the presence of 8 nM [ 3 H]DA. For kinetic analyses, DA uptake was assessed in the presence of 5 concentrations of [ 3 H]DA ranging from 8nM to 500nM. Analyses of the data revealed a significant increase in DA uptake in the ethanol group compared to water controls. Kinetic analyses revealed the change in DA uptake to be a consequence of an increase in the V max of transport. These findings demonstrate that chronic free-choice oral ethanol consumption in HAD-1 female rats increases DA uptake in the Acb by increasing the V max of the transporter. However, it is not known whether the ethanol-induced change in V max is caused by differences in the actual number of available transporter sites or from a difference in the velocity of operation of a similar number of transporters. Overall, the data indicate that chronic ethanol consumption by HAD-1 rats produces prolonged neuroadaptations within the mesolimbic DA system, which may be important for the understanding of the neurobiological basis of alcoholism.
The goal of this study was to determine whether acute stroke survivors demonstrate abnormal synergy patterns in their affected lower extremity. During maximum isometric contractions with subjects in a standing position, joint torques generated simultaneously at the knee and hip were measured, along with associated muscle activation patterns in eight lower limb muscles. Ten acute stroke survivors and nine age-match controls participated in the study. For all joints tested, stroke subjects demonstrated significantly less maximum isometric torque than age-matched control subjects. However, the synergistic torques generated in directions different than the direction that was being maximized were not significantly different between the two groups. According to electromyography (EMG) data, it was found that stroke subjects activated antagonistic muscle groups significantly higher than the control group subjects, suggesting that deficits in joint torque may be at least partially attributable to co-contraction of antagonistic muscles. Our findings suggest that a primary contributor to lower limb motor impairment in acute hemiparetic stroke is poor volitional torque generating capacity, which is at least partially attributable to co-contraction of antagonistic muscles. Furthermore, while we did not observe abnormal torque synergy patterns commonly found in the upper limbs, muscle activation patterns differed between groups for many of the directions tested indicating changes in the motor control strategies of acute stroke survivors.
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