- Browse by Author
Browsing by Author "Windisch, Kyle Allyson"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Achieving pharmacologically relevant IV alcohol self-administration in the rat(2012-09-27) Windisch, Kyle Allyson; Czachowski, Cristine L.; Grahame, Nicholas J.; Kosobud, Ann E. K.Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be quite separate temporally from time of intake) and the more temporally “relevant” effects (primarily olfactory and taste) that bridge the time from intake to the onset of the pharmacological effects. Dissociating these effects is essential to untangling the neurologic underpinnings of alcohol abuse and dependence. Intravenous self-administration of ethanol allows for controlled and precise dosing, bypasses first order absorption kinetics allowing for a faster onset of pharmacologic effects, and eliminates the confounding “non-pharmacological” effects associated with oral consumption. Intravenous self-administration of ethanol has been reliably demonstrated in both mouse and human experimental models; however, consistent intravenous self-administration of pharmacologically relevant levels of ethanol remains elusive in the rat. Previous work has demonstrated reliable elevated intravenous ethanol self administration using a compound reinforcer of oral sucrose and intravenous ethanol. The present study sought to elucidate the role of each component of this reinforcer complex using a multiple schedule study design. Male P rats had free access to both food and water during all intravenous self-administration sessions and all testing was performed in conjunction with the onset of the dark cycle. Once animals achieved stable operant responding on both levers for an orally delivered 1% sucrose solution (1S) on a FR4 schedule, surgery was conducted to implant an indwelling jugular catheter. Animals were habituated to the attachment of infusion apparatus and received twice daily sessions for four days to condition each lever to its associated schedule. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5 minute components. During one component only oral 1S was presented, while in the second component a compound reinforcer of oral 1S + IV 20% ethanol was presented (25 mg/kg/injection). Both levers were extended into the chamber during the session, with the active lever/schedule alternating as the session progressed across components. Average ethanol intake was 0.47 ± 0.04 g/kg. A significant increase in sucrose only reinforcers and sucrose lever error responding was found suggesting that sucrose not ethanol is responsible for driving overall responding. The current findings suggest that the existing intravenous ethanol self-administration methodology remains aversive in the rat.Item Role of group II metabotropic glutamate receptor subtype 2 (MGluR2) in appetitive and consummatory aspects of ethanol reinforcement(2014-12) Windisch, Kyle Allyson; Czachowski, Cristine; Lapish, Christopher; Neal-Beliveau, Bethany S.; Chester, Julia A.Background: Group II metabotropic glutamate receptors (mGluR2/3) are predominately presynaptically located Gi/o coupled receptors that are highly expressed in the cortex, nucleus accumbens, amygdala, and hippocampus. Previous studies suggest that group II mGluRs are involved in regulating ethanol (EtOH) consumption and seeking following extinction (Backstrom and Hyytia, 2005; Kufahl, et al., 2011). The sipper tube model, which allows for procedural separation of seeking and consumption, was used to further clarify the role of mGluR2/3 in EtOH-seeking and consumption. The non-selective group II mGluR agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator (PAM) BINA were used to determine the relative contribution of mGlu2 and mGlu3 receptors on EtOH seeking and consumption. Following characterization of the agonist and PAM on EtOH reinforcement, a microinjection study was performed examining the effect of blockade of nucleus accumbens core mGluR2/3 on systemic agonist induced suppression of EtOH-seeking. Methods: For the systemic agonist/PAM experiments, separate groups of male Wistar rats [n=8-9 group; LY37 (0-2.0 mg/kg) and BINA (0-20 mg/kg)] were trained to complete a response requirement (RR) of 10 lever presses that resulted in access to 10% EtOH or 2% sucrose (in separate groups) for a 20-minute drinking period. For consummatory testing, animals received weekly drug injections with a RR1. The RR was then increased over sessions to a RR20. For appetitive testing, animals received weekly drug injections followed by a non-reinforced extinction session. To determine effects of blockade of NAc core mGluR2/3 receptors on agonist-induced suppression of EtOH-seeking, a separate group of male Wistar rats (n=15) was trained to complete a RR10 for access to 10% EtOH. Animals were surgically implanted with bilateral guide cannulae terminating 1mm above the NAc core. Following recovery, animals received four sets of microinjections in a balanced design (systemic vehicle + core vehicle, systemic LY37 + core vehicle, systemic LY37 + core LY34, and systemic vehicle + core LY34). A final non-balanced microinjection of LY37 was then performed. Results and Conclusions: Systemic administration of the mGluR2/3 agonist LY37 significantly reduced EtOH- and sucrose- seeking with no systematic effect on locomotion. Systemic administration of the selective mGluR2 PAM BINA had no significant effect on either seeking or consumption. These findings suggest that modulation of glutamatergic neurotransmission by a systemic mGluR2/3 agonist, but not allosteric modulation of mGluR2, significantly reduces reinforcer seeking. Intra- accumbens core administration of LY37 significantly reduced EtOH-seeking, suggesting a role of NAc core mGluR2/3 modulation in EtOH-seeking during maintenance drinking. Systemic administration of LY37 was also found to significantly reduce sucrose consumption and body weight 24-hours following systemic administration, meriting further examination of the role of mGluR2/3 receptors on feeding behavior.