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Poster Abstracts
Conference Abstracts / Alcohol 42 (2008) 303-341
333
P104
P106
Electrophysiological properties of dopamine neurons in the ventral tegmental area of Sardinian alcohol-preferring rats 1,2 M. Melis, 1,2G. Pillolla, 3G. Colombo, 1,3A. L. Muntoni, and 1,2M. Pistis 1Centre of Excellence “Neurobiology of Addiction”, 2“B.B. Brodie” Department of Neuroscience, University of Cagliari, Italy;3C.N.R. Institute of Neuroscience, c/o “B.B. Brodie” Department of Neuroscience, University of Cagliari, Italy.
Nociceptin/Orphanin FQ reduces somatic alcohol withdrawal signs and hangover anxiety Serena Stopponi, Simone Braconi, Massimo Ubaldi, Amalia Fedeli, Roberto Ciccocioppo, Maurizio Massi, Daina Economidou, Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Macerata, Italy
Ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drug-related behaviors, including alcohol selfadministration. Sardinian alcohol-preferring (sP) or -non preferring (sNP) rats are one of the few lines of rat pairs selectively bred for their alcohol preference or aversion, respectively. In this study, we investigated the electrophysiological properties of VTA DA cells of sP and sNP rats both in vivo and in vitro. Extracellular single unit recordings in anesthetized rats revealed a difference in baseline firing activity between sP and sNP rats. More particularly, sP rats showed an increased spontaneous neuronal activity. However, no difference was found when whole-cell patch clamp recordings from VTA DA neurons were performed from the same groups of animals in vitro. Additionally, VTA DA cells of sP and sNP rats showed similar intrinsic properties, thus suggesting that changes at synaptic level might underlie and explain our in vivo observation. To this aim inhibitory and excitatory -mediated currents were studied. sP rats showed a decreased probability of GABA release when compared with sNP rats. Because endocannabinoids (eCB) activating presynaptic cannabinoid-type 1 (CB1) receptors inhibit neurotransmitter release, we studied a form of eCB-mediated short term synaptic plasticity, that is depolarization-induced suppression of inhibition (DSI). sP rats showed a reduced DSI, which can be explained by either a reduced number or functionality of CB1 receptors. Taken together, these findings support the role of eCBs and CB1 receptors in fine tuning the activity of VTA DA that may be associated to alcohol preference and seeking/drinking behaviour.
Different studies demonstrated that somatic signs of withdrawal are associated to a hyperglutamatergic state resulting from abrupt cessation of alcohol consumption. Withdrawal and hangover induced anxiety, seems instead, to be linked to an increased extrahypotalamic corticotrophin releasing factor (CRF) activity. Interestingly, the nociceptin/orphanin FQ (N/OFQ) system, by inhibiting presynaptic neurotransmission, has been shown to reduce brain glutamatergic and CRF activity. In the present investigation we evaluated the effect of intracranial (ICV) N/OFQ administration on somatic withdrawal signs and anxiety measured after chronic ethanol intoxication and acute ethanol administration, respectively. In the first experiment, ethanol dependence was induced by intagastric intubation and 10 g/kg of ethanol per day for 6 consecutive days were administered in a dietary liquid vehicle 4 times a day. After 5 days of this treatment regimen, blood alcohol levels for the ethanol-treated group reached 250-300 mg% and, severe somatic withdrawal symptoms were observed on day 6 (12 h following the last ethanol administration). N/OFQ (1.0 and 3.0 microgram/rat) given ICV three times at 6, 9 and 12 hrs after the last ethanol injection significantly reduced physical signs of withdrawal measured immediately after the last peptide injection. In the second experiment animals received a single i.p. dose of 3 g/kg of ethanol (20% w/v). After 12 hours animals were injected ICV with N/OFQ (0.0, 1.0, 2.0 microgram/rat) and tested on the elevated plus-maze. Results demonstrated that N/OFQ dose dependently reduces the anxiogenic response associated to alcohol hangover. Overall these data are consistent with the inhibitory action of N/OFQ on the brain glutamatergic and CRF neurotransmission.
P105
P107
Involvement of the Neuropeptide S system in the regulation of alcohol relapse Marsida Kallupi, Nazzareno Cannella, Daina Economidou, Laura Soverchia, Barbara Ruggeri, Roberto Ciccocioppo, Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Macerata, Italy
Chronic binge-like ethanol drinking in rats produces widespread decreases in brain biogenic monoamine neurotransmitter turnover rates reversed by ethanol drinking J.E. Smith, C. Co, S. McIntosh and C.C. Cunningham, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC, USA
Alcoholism is a chronic relapsing disorder characterized by compulsive drug-seeking and use. Stress and environmental conditioning have been recognized as the two major determinants of relapse in abstinent individuals. Recently, a new arousal promoting neuropeptide, named Neuropeptide S (NPS), that binds to its cognate Gq protein coupled receptor and identified as NPSR receptor has been deorphanized. In situ hybridization experiments showed abundant expression of NPSR receptor mRNA in brain regions (i.e., amygdala, hippocampus and lateral hypothalamus), that are known for their role in the regulation of alcohol abuse and reinstatement of alcohol seeking. In the present study we investigated the effect of NPS on ethanol self-administration and relapse. Wistar rats were trained to operantly self-administer 10% ethanol until stable baseline of responding was established. At this point, rats received intracerebroventricular (ICV) injection of NPS (0.0, 1.0 and 2.0 nmol/rat) prior to ethanol self-administration. Results showed no effect of drug treatment (P>0.05). In a subsequent series of experiments the ability of NPS to modulate reinstatement of alcoholseeking induced by environmental conditioning factors or stress was tested. Re-exposure to alcohol cues or exposure to footshock elicited a significant reinstatement of responding (p<0.01). NPS (0.0, 1.0 and 2.0 nmol/rat) given ICV prior to relapse tests remarkably increased alcoholseeking elicited by both cues or stress. Overall results demonstrated that activation of NPS receptors does not affect ethanol intake but facilitates relapse to alcohol seeking induced by environmental conditioning factors and stress. (Supported by PRIN 2006 to RC).
This experiment assessed the turnover rates (TORs) of dopamine (DA), norepinephrine (NE), serotonin (5-HT) in small brain regions as a measure of neuronal activity during rodent ethanol/sucrose (EtOH) and sucrose (SUC) consumption and in animals with a history of such consumption. Groups of five male Wistar adult rats were used, with two trained to drink EtOH solutions, two to drink SUC and one to serve as a non-drinking control. Rats were allowed to drink designated solutions during 90 minute daily session with the patterns of consumption indicative of moderate binge drinking. When stable drinking patterns were obtained, rats were implanted with jugular catheters, allowed to recover and pulse labeled intravenously with [3H]-tyrosine and [3H]tryptophan. One of each pair of the EtOH drinking and SUC drinking rats per group were exposed to the drinking session while the other two remained in their home cages as drinking history controls. The TORs of DA, NE, 5-HT were determined in 26 brain regions and an acute EtOH deprivation effect detected in the EtOH drinking history group that was accompanied by decreases in the activity of 5-HT, DA and NE innervations of the forebrain that were mostly reversed by EtOH drinking. A neuronal circuit is proposed that may mediate components of EtOH drinking and this reversal. This neurochemical deficit could set the stage for the alleviation of anhedonic stimuli with further EtOH intake that strengthen EtOH seeking behaviors through negative reinforcement [Supported in part by USPHS Grant AA11661 (JES), AA11272, AA00279 (CCC) and DA00114 (JES)].
333
P104
P106
Electrophysiological properties of dopamine neurons in the ventral tegmental area of Sardinian alcohol-preferring rats 1,2 M. Melis, 1,2G. Pillolla, 3G. Colombo, 1,3A. L. Muntoni, and 1,2M. Pistis 1Centre of Excellence “Neurobiology of Addiction”, 2“B.B. Brodie” Department of Neuroscience, University of Cagliari, Italy;3C.N.R. Institute of Neuroscience, c/o “B.B. Brodie” Department of Neuroscience, University of Cagliari, Italy.
Nociceptin/Orphanin FQ reduces somatic alcohol withdrawal signs and hangover anxiety Serena Stopponi, Simone Braconi, Massimo Ubaldi, Amalia Fedeli, Roberto Ciccocioppo, Maurizio Massi, Daina Economidou, Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Macerata, Italy
Ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drug-related behaviors, including alcohol selfadministration. Sardinian alcohol-preferring (sP) or -non preferring (sNP) rats are one of the few lines of rat pairs selectively bred for their alcohol preference or aversion, respectively. In this study, we investigated the electrophysiological properties of VTA DA cells of sP and sNP rats both in vivo and in vitro. Extracellular single unit recordings in anesthetized rats revealed a difference in baseline firing activity between sP and sNP rats. More particularly, sP rats showed an increased spontaneous neuronal activity. However, no difference was found when whole-cell patch clamp recordings from VTA DA neurons were performed from the same groups of animals in vitro. Additionally, VTA DA cells of sP and sNP rats showed similar intrinsic properties, thus suggesting that changes at synaptic level might underlie and explain our in vivo observation. To this aim inhibitory and excitatory -mediated currents were studied. sP rats showed a decreased probability of GABA release when compared with sNP rats. Because endocannabinoids (eCB) activating presynaptic cannabinoid-type 1 (CB1) receptors inhibit neurotransmitter release, we studied a form of eCB-mediated short term synaptic plasticity, that is depolarization-induced suppression of inhibition (DSI). sP rats showed a reduced DSI, which can be explained by either a reduced number or functionality of CB1 receptors. Taken together, these findings support the role of eCBs and CB1 receptors in fine tuning the activity of VTA DA that may be associated to alcohol preference and seeking/drinking behaviour.
Different studies demonstrated that somatic signs of withdrawal are associated to a hyperglutamatergic state resulting from abrupt cessation of alcohol consumption. Withdrawal and hangover induced anxiety, seems instead, to be linked to an increased extrahypotalamic corticotrophin releasing factor (CRF) activity. Interestingly, the nociceptin/orphanin FQ (N/OFQ) system, by inhibiting presynaptic neurotransmission, has been shown to reduce brain glutamatergic and CRF activity. In the present investigation we evaluated the effect of intracranial (ICV) N/OFQ administration on somatic withdrawal signs and anxiety measured after chronic ethanol intoxication and acute ethanol administration, respectively. In the first experiment, ethanol dependence was induced by intagastric intubation and 10 g/kg of ethanol per day for 6 consecutive days were administered in a dietary liquid vehicle 4 times a day. After 5 days of this treatment regimen, blood alcohol levels for the ethanol-treated group reached 250-300 mg% and, severe somatic withdrawal symptoms were observed on day 6 (12 h following the last ethanol administration). N/OFQ (1.0 and 3.0 microgram/rat) given ICV three times at 6, 9 and 12 hrs after the last ethanol injection significantly reduced physical signs of withdrawal measured immediately after the last peptide injection. In the second experiment animals received a single i.p. dose of 3 g/kg of ethanol (20% w/v). After 12 hours animals were injected ICV with N/OFQ (0.0, 1.0, 2.0 microgram/rat) and tested on the elevated plus-maze. Results demonstrated that N/OFQ dose dependently reduces the anxiogenic response associated to alcohol hangover. Overall these data are consistent with the inhibitory action of N/OFQ on the brain glutamatergic and CRF neurotransmission.
P105
P107
Involvement of the Neuropeptide S system in the regulation of alcohol relapse Marsida Kallupi, Nazzareno Cannella, Daina Economidou, Laura Soverchia, Barbara Ruggeri, Roberto Ciccocioppo, Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Macerata, Italy
Chronic binge-like ethanol drinking in rats produces widespread decreases in brain biogenic monoamine neurotransmitter turnover rates reversed by ethanol drinking J.E. Smith, C. Co, S. McIntosh and C.C. Cunningham, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC, USA
Alcoholism is a chronic relapsing disorder characterized by compulsive drug-seeking and use. Stress and environmental conditioning have been recognized as the two major determinants of relapse in abstinent individuals. Recently, a new arousal promoting neuropeptide, named Neuropeptide S (NPS), that binds to its cognate Gq protein coupled receptor and identified as NPSR receptor has been deorphanized. In situ hybridization experiments showed abundant expression of NPSR receptor mRNA in brain regions (i.e., amygdala, hippocampus and lateral hypothalamus), that are known for their role in the regulation of alcohol abuse and reinstatement of alcohol seeking. In the present study we investigated the effect of NPS on ethanol self-administration and relapse. Wistar rats were trained to operantly self-administer 10% ethanol until stable baseline of responding was established. At this point, rats received intracerebroventricular (ICV) injection of NPS (0.0, 1.0 and 2.0 nmol/rat) prior to ethanol self-administration. Results showed no effect of drug treatment (P>0.05). In a subsequent series of experiments the ability of NPS to modulate reinstatement of alcoholseeking induced by environmental conditioning factors or stress was tested. Re-exposure to alcohol cues or exposure to footshock elicited a significant reinstatement of responding (p<0.01). NPS (0.0, 1.0 and 2.0 nmol/rat) given ICV prior to relapse tests remarkably increased alcoholseeking elicited by both cues or stress. Overall results demonstrated that activation of NPS receptors does not affect ethanol intake but facilitates relapse to alcohol seeking induced by environmental conditioning factors and stress. (Supported by PRIN 2006 to RC).
This experiment assessed the turnover rates (TORs) of dopamine (DA), norepinephrine (NE), serotonin (5-HT) in small brain regions as a measure of neuronal activity during rodent ethanol/sucrose (EtOH) and sucrose (SUC) consumption and in animals with a history of such consumption. Groups of five male Wistar adult rats were used, with two trained to drink EtOH solutions, two to drink SUC and one to serve as a non-drinking control. Rats were allowed to drink designated solutions during 90 minute daily session with the patterns of consumption indicative of moderate binge drinking. When stable drinking patterns were obtained, rats were implanted with jugular catheters, allowed to recover and pulse labeled intravenously with [3H]-tyrosine and [3H]tryptophan. One of each pair of the EtOH drinking and SUC drinking rats per group were exposed to the drinking session while the other two remained in their home cages as drinking history controls. The TORs of DA, NE, 5-HT were determined in 26 brain regions and an acute EtOH deprivation effect detected in the EtOH drinking history group that was accompanied by decreases in the activity of 5-HT, DA and NE innervations of the forebrain that were mostly reversed by EtOH drinking. A neuronal circuit is proposed that may mediate components of EtOH drinking and this reversal. This neurochemical deficit could set the stage for the alleviation of anhedonic stimuli with further EtOH intake that strengthen EtOH seeking behaviors through negative reinforcement [Supported in part by USPHS Grant AA11661 (JES), AA11272, AA00279 (CCC) and DA00114 (JES)].