Addiction and Behavior
Oral Presentations
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GABA-A RECEPTOR ANTAGONISM MIMICS THE EFFECT OF PROGESTERONE WITHDRAWAL ON FORCED SWIM TEST IMMOBILITY.
Ethan Beckley, Ethan H. Beckley, Deborah A. FinnKeywords: Depression, Neurosteroids, Gaba-A Receptor Abstract:Withdrawal of the steroid progesterone (PRO) increases immobility in the Forced Swim Test (FST) in female mice. Inhibiting PRO metabolism decreased concentrations of the GABAergic neurosteroid allopregnanolone (ALLO) and increased FST immobility, suggesting that PRO withdrawal may increase FST immobility through downstream ALLO withdrawal. We assessed the role of the PRO and GABA A receptors during PRO withdrawal-induced FST immobility by testing the effects of the PRO receptor antagonist mifepristone (MIF) and the GABA A receptor antagonist picrotoxin (PTX) on FST immobility among mice treated chronically with PRO . Neither 20 mg/kg MIF nor 2 mg/kg PTX increased FST immobility, alone or in combination, when coadministered with PRO (5 mg/kg) for 3 days following 5 days of PRO injections. An additional experiment determined that coadministration of PRO with 2-6 mg/kg PTX did not increase FST immobility. Following pharmacokinetic analysis of exogenously administered PRO and its metabolism to ALLO , we determined that 2 mg/kg PTX administered 60 min following PRO increased FST immobility (F3,37=3.9, p<.05). These data support the hypothesis that PRO withdrawal increases FST immobility by decreasing ALLO modulation of GABA A receptors. These findings may have relevance for premenstrual syndrome and postpartum depression, which are temporally linked to rapid PRO withdrawal.
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Are opioid-sensitive neurons in the rostral ventromedial medulla inhibitory interneurons?
Cleary Daniel, D.R. Cleary, M.J. Neubert and M.M. HeinricherKeywords: Off Cells, On Cells, Nucleus Raphe Magnus, Disinhibition, Descending Control, Pain Modulation Abstract:μ-Opioid agonists frequently activate output neurons in the brain via disinhibition, that is, they inhibit “secondary cells” which results in disinhibition of the “primary cells.” Secondary cells are generally presumed to be inhibitory interneurons that serve only to regulate the activity of the output neurons. However, studies of the opioid-sensitive neurons in the rostral ventromedial medulla, a region with a well-documented role in nociceptive modulation, indicate that the opioid-inhibited neurons in this region, “on-cells,” have a distinct functional role that parallels and opposes the output of “off-cells,” a subset of RVM neurons that are activated following opioid administration.
Our aim was to analyze the relative timing of on- and off-cell reflex-related firing in the rostral ventromedial medulla to determine whether on-cells are likely to function as inhibitory interneurons in this region. On- and off-cells display complementary firing patterns during noxious-evoked withdrawal: off-cells stop firing and on-cells show a burst of activity. If on-cells are inhibitory interneurons mediating the off-cell pause, the on-cells should begin their reflex-related discharge before the off-cells cease firing. However, we found off-cells typically ceased firing before on-cells began reflex-related firing, with a mean 481 (±69) ms lag between the final off-cell spike and the first on-cell spike. This data suggests that on-cells do not mediate the off-cell pause and points instead to presynaptic mechanisms in opioid-mediated disinhibition of medullary output neurons.
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Dopamine D4 receptors regulate approach-avoidance behavior, behavioral inhibition and the response to methylphenidate
Thomas Keck, K. L. Suchland, C. C. Jimenez, D. K. GrandyKeywords: Methlyphenidate, Dopamine Receptor D4 Abstract:Alleles of the human dopamine D4 receptor (D4R) gene have reproducibly been associated with attention deficit hyperactivity disorder (ADHD) and behavioral phenotypes associated with altered novelty seeking. Methylphenidate (MPD), a psychostimulant related to amphetamine, elevates extracellular dopamine levels and is the most widely prescribed treatment for ADHD . All psychostimulants have abuse potential and induce behavioral sensitization, a condition marked by a progressive increase in the efficacy of a given drug following its repeated administration; human and animal experimental evidence indicates that behavioral sensitization plays an important role in the development of drug-seeking behavior.
The purpose of the present study was to test the hypotheses that (1) D4R signaling contributes to impulsivity and approach-avoidance behaviors (2) that these behaviors can be modulated by MPD (3) and signaling mediated by D4R contributes to behavioral sensitization to MPD . To test these hypotheses, we used D4R -deficient (D4R
/) mice, backcrossed for 20 generations to wild-type, inbred C57Bl/6J mice.Compared to wild-type littermates, drug-naive N20 D4R
/mice exhibit altered impulsivity and approach-avoidance behavior. MPD treatment significantly influenced these behaviors in a genotype-dependent manner. Behavioral sensitization to 5mg/kg MPD was significantly greater in D4R/mice. These findings support our hypothesis that dopamine D4R -mediated signaling contributes significantly to impulsivity and approach-avoidance behavior as well as the extent to which behavioral sensitization develops in response to repeated, low-dose psychostimulant exposure.
Poster Presentations
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Massed and Spaced Extinction of Ethanol Conditioned Place Preference
Charlene Voorhees, Christopher CunninghamKeywords: Extinction, Cpp Abstract:Drug-associated stimuli in the environment may induce compulsive drug seeking through Pavlovian conditioning processes. It is important to understand the temporal parameters that best facilitate extinction of associations in behavioral therapies for drug addiction. The conditioned place preference (CPP) procedure is an animal model of drug seeking. These experiments investigated the effects of trial spacing on extinction of CPP . DBA/2J mice were conditioned with 2 g/kg ethanol paired with tactile floor cues. In Experiment 1, the Spaced group was exposed to six choice tests 24 hrs apart. The Massed group was exposed to six choice tests 15 min apart on final day of the 6-day cycle. Both groups were tested 24 hrs later. Following three cycles, the Massed group did not show CPP while the Spaced group expressed significant CPP . Experiment 1 indicates that massed sessions promote better extinction learning than spaced. Experiment 2 replicated Experiment 1 with the added control of overall context exposure. The Massed group had 5 days exposure paper floors (to match the Spaced group’s daily exposure to the apparatus) and six massed test sessions on the final day. The Spaced group had six tests 24 hrs apart, and five exposures 15 min apart on paper on the last day. After three cycles, the Massed and Spaced groups showed the same magnitude of CPP , indicating no difference in extinction. These experiments suggest that under certain conditions massed extinction treatment can produce faster extinction than spaced, and may offer insight on the spacing of cue exposure therapy. Supported by AA07468 , AA07702, ARCS Foundation.