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P.4.08 Inhibition of anandamide hydrolysis antagonizes nicotine effects on neurons in the nucleus accumbens shell in the rat
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Addiction: towards new drug targets
P.4.08 Inhibition of anandamide hydrolysis antagonizes nicotine effects on neurons in the nucleus accumbens shell in the rat A. Luchicchi1 ° , G. Pillolla1 , S. Lecca1 , M. Pistis1 . University of Cagliari, Neuroscience, Cagliari, Italy
1
The nucleus accumbens (NAc) is a brain area crucially involved in the modulation of goal-directed behaviour. Among sub-regions of the NAc, the shell (shNAc) responds to primary reinforcing or motivational properties of drugs of abuse and natural stimuli. It is now wellestablished that different addicting drugs, such as nicotine, cocaine and ethanol increase the release of dopamine (DA) in the shNAc [1]. A common feature of different drugs of abuse is also the depression of excitability of GABAergic medium spiny neurons (MSNs) in the NAc, which occurs mostly via DA-mediated but also DA-independent mechanisms. In recent years it was hypothesized that the endocannabinoid (ECb) system is an important modulator of the effects of addicting drugs, including nicotine, in the NAc. For example, studies have discovered that the cannabinoid type-1 (CB1) receptor antagonist SR141716-A (SR, rimonabant) inhibits the efflux of DA induced by drugs of abuse in the NAc [2] and antagonizes motivational properties of nicotine. Consistently, it is under clinical investigation as an anti-craving medication in tobacco dependence. For this reason, in this study, we evaluated the possibility that the ECb system might have an active role in the modulation of nicotine effects in shNAc MSNs. To this aim we used in vivo single unit elecrophysiological recordings in urethane anaesthetized rats from MSNs in the shNAc. Since these neurons do not fire spontaneously in anesthetized animals, they were identified by stimulation of the basolateral amygdala (BLA), one of the major excitatory afferents to the shNAc. As expected, nicotine (0.2 mg/kg i.v.) persistently inhibited the excitability of shNAc MSNs (61%±12 of baseline level; one-way ANOVA, P < 0.05), as measured by their response to threshold BLA stimulation. SR (0.5 mg/kg i.v. 4 min before nicotine) failed to revert nicotine-induced inhibition of MSNs (64±13%, two-way ANOVA, P > 0.05 vs. nicotine). Next, rats were pretreated with URB597, a potent inhibitor of fatty acid amide hydrolase (FAAH), the major hydrolyzing enzyme for the endocannabinoid anandamide. This dose of URB597 persistently (>6h) enhances anandamide levels in the brain. Surprisingly, following URB597 administration, nicotine exerted excitatory actions instead (123±12%, two-way ANOVA, P<0.01 vs. nicotine). The effects of URB597 were abolished by SR (0.5 mg/kg i.v.) (67±25%, two-way ANOVA, P > 0.05 vs. nicotine), indicating that
they occurred through stimulation of CB1 receptors by increased levels of anandamide. Our results suggest that, contrary to our expectation, elevation of anandamide levels by URB597, but not blockade of CB1 receptor by SR, fully antagonizes the inhibitory effects of nicotine in the NAc. These effects may occur through blockade of nicotine-induced increase in DA release in the NAc. These data add to the mounting evidence that modulation of the ECb system, and in particular FAAH inhibition, may represent a novel therapeutic target in the treatment of tobacco addiction. Reference(s) [1] Di Chiara, G., Imperato, A., 1988, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278. [2] Cheer, J.F., Wassum, K.M., Sombers, L.A., Heien, M.L., Ariansen, J.L., Aragona, B.J., Phillips, P.E., Wightman, R.M., 2007, Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. J Neurosci 27: 791–795. P.4.09 NMDA receptors and beta-adrenergic receptors as molecular targets for the prevention of relapse to drug-seeking A.L. Milton1 ° , B.J. Everitt1 . 1 University of Cambridge, Department of Experimental Psychology, Cambridge, United Kingdom Addiction is a chronic, relapsing disorder, which is typically well-established when individuals present for treatment. As addiction has been hypothesised to reflect the aberrant engagement of pavlovian and instrumental learning processes [1], recent work has attempted to disrupt the reconsolidation of the memories underlying drug-seeking behaviour. Memory reconsolidation is the hypothesised process by which memories become labile and susceptible to disruption following retrieval. Both beta-adrenergic receptors and NMDA receptors have been shown to be necessary for the reconsolidation of the pavlovian CS-drug memory underlying conditioned reinforcement and new, flexible drug-seeking [2,3] but it has not been established whether antagonism at these receptors is sufficient to prevent relapse to drug-seeking when the instrumental response is well-learned. Rats were trained to self-administer cocaine through chronic, indwelling catheters by making an instrumental response that delivered both the drug, and a pavlovian light CS. Following extensive instrumental training, the animals underwent a brief memory reactivation session
Addiction: towards new drug targets
P.4.08 Inhibition of anandamide hydrolysis antagonizes nicotine effects on neurons in the nucleus accumbens shell in the rat A. Luchicchi1 ° , G. Pillolla1 , S. Lecca1 , M. Pistis1 . University of Cagliari, Neuroscience, Cagliari, Italy
1
The nucleus accumbens (NAc) is a brain area crucially involved in the modulation of goal-directed behaviour. Among sub-regions of the NAc, the shell (shNAc) responds to primary reinforcing or motivational properties of drugs of abuse and natural stimuli. It is now wellestablished that different addicting drugs, such as nicotine, cocaine and ethanol increase the release of dopamine (DA) in the shNAc [1]. A common feature of different drugs of abuse is also the depression of excitability of GABAergic medium spiny neurons (MSNs) in the NAc, which occurs mostly via DA-mediated but also DA-independent mechanisms. In recent years it was hypothesized that the endocannabinoid (ECb) system is an important modulator of the effects of addicting drugs, including nicotine, in the NAc. For example, studies have discovered that the cannabinoid type-1 (CB1) receptor antagonist SR141716-A (SR, rimonabant) inhibits the efflux of DA induced by drugs of abuse in the NAc [2] and antagonizes motivational properties of nicotine. Consistently, it is under clinical investigation as an anti-craving medication in tobacco dependence. For this reason, in this study, we evaluated the possibility that the ECb system might have an active role in the modulation of nicotine effects in shNAc MSNs. To this aim we used in vivo single unit elecrophysiological recordings in urethane anaesthetized rats from MSNs in the shNAc. Since these neurons do not fire spontaneously in anesthetized animals, they were identified by stimulation of the basolateral amygdala (BLA), one of the major excitatory afferents to the shNAc. As expected, nicotine (0.2 mg/kg i.v.) persistently inhibited the excitability of shNAc MSNs (61%±12 of baseline level; one-way ANOVA, P < 0.05), as measured by their response to threshold BLA stimulation. SR (0.5 mg/kg i.v. 4 min before nicotine) failed to revert nicotine-induced inhibition of MSNs (64±13%, two-way ANOVA, P > 0.05 vs. nicotine). Next, rats were pretreated with URB597, a potent inhibitor of fatty acid amide hydrolase (FAAH), the major hydrolyzing enzyme for the endocannabinoid anandamide. This dose of URB597 persistently (>6h) enhances anandamide levels in the brain. Surprisingly, following URB597 administration, nicotine exerted excitatory actions instead (123±12%, two-way ANOVA, P<0.01 vs. nicotine). The effects of URB597 were abolished by SR (0.5 mg/kg i.v.) (67±25%, two-way ANOVA, P > 0.05 vs. nicotine), indicating that
they occurred through stimulation of CB1 receptors by increased levels of anandamide. Our results suggest that, contrary to our expectation, elevation of anandamide levels by URB597, but not blockade of CB1 receptor by SR, fully antagonizes the inhibitory effects of nicotine in the NAc. These effects may occur through blockade of nicotine-induced increase in DA release in the NAc. These data add to the mounting evidence that modulation of the ECb system, and in particular FAAH inhibition, may represent a novel therapeutic target in the treatment of tobacco addiction. Reference(s) [1] Di Chiara, G., Imperato, A., 1988, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278. [2] Cheer, J.F., Wassum, K.M., Sombers, L.A., Heien, M.L., Ariansen, J.L., Aragona, B.J., Phillips, P.E., Wightman, R.M., 2007, Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. J Neurosci 27: 791–795. P.4.09 NMDA receptors and beta-adrenergic receptors as molecular targets for the prevention of relapse to drug-seeking A.L. Milton1 ° , B.J. Everitt1 . 1 University of Cambridge, Department of Experimental Psychology, Cambridge, United Kingdom Addiction is a chronic, relapsing disorder, which is typically well-established when individuals present for treatment. As addiction has been hypothesised to reflect the aberrant engagement of pavlovian and instrumental learning processes [1], recent work has attempted to disrupt the reconsolidation of the memories underlying drug-seeking behaviour. Memory reconsolidation is the hypothesised process by which memories become labile and susceptible to disruption following retrieval. Both beta-adrenergic receptors and NMDA receptors have been shown to be necessary for the reconsolidation of the pavlovian CS-drug memory underlying conditioned reinforcement and new, flexible drug-seeking [2,3] but it has not been established whether antagonism at these receptors is sufficient to prevent relapse to drug-seeking when the instrumental response is well-learned. Rats were trained to self-administer cocaine through chronic, indwelling catheters by making an instrumental response that delivered both the drug, and a pavlovian light CS. Following extensive instrumental training, the animals underwent a brief memory reactivation session