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Blockade of δ-opioid receptors in the nucleus accumbens prevents ethanol-induced stimulation of dopamine release
European Journal of Pharmacology, 230 (1993) 239-241
239
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 0385R
Rapid communication
Blockade of 3-opioid receptors in the nucleus accumbens prevents ethanol-induced stimulation of dopamine release Elio Acquas, Marco Meloni and G a e t a n o Di Chiara Department of Toxicology, Unit,ersity of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy Received 9 December 1992, accepted 11 December 1992
Naltrindole, a specific 6-opioid antagonist, infused by reverse dialysis in the nucleus accumbens of freely moving rats completely prevented the increase in extracellular dopamine concentrations elicited in the nucleus accumbens by ethanol (1.0 g/kg i.p.) as well as by the 6-opioid receptor agonist [D-AlaZ]deltorphin II (50/xM), also perfused by reverse dialysis, but not by cocaine (15 mg/kg s.c.). The results provide in vivo evidence for a critical role of 6-opioid receptors in the dopamine-releasing properties of ethanol in vivo. 6-Opioid receptors; Dopamine; Ethanol
Biochemical (Di Chiara and Imperato, 1988) and pharmacological (Koob, 1992) evidence indicates that mesolimbic dopamine plays a critical role in the positive reinforcing properties of ethanol. On the other hand, phermacological evidence suggests that opioid transmission is involved in the reinforcing properties of ethanol (Koob, 1992). Since dopamine via D~ receptors, positively interacts with 3-opioid receptors in the nucleus accumbens (Longoni et al., 1990), we postulated that these receptors could play a role in the dopamine releasing properties of ethanol in that area (Di Chiara and Imperato, 1988). In order to investigate this issue, we studied the effect of naltrindole, a specific antagonist of 6-opioid receptors (Portoghese et al., 1988), on the release of dopamine in the nucleus accumbens, as estimated by brain microdialysis in freely moving rats. Male Sprague-Dawley rats (250-300 g, Charles River, Calco, Como Italy) were implanted with transcerebral dialysis probes (HOSPAL) in the nucleus accumbens according to the technique already described by us (Acquas and Di Chiara, 1992). The next day the rats were placed in hemispheric bowls, perfused with Ringer through the dialysis tube and dopamine and metabolites monitored by HPLC with electrochemical detection (Acquas and Di Chiara,
Correspondence to: G. Di Chiara, Department of Toxicology, University of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy. Tel. (39) 70/303.819 or 300.437, fax (39) 70/300.740.
1992). When stable values of dopamine and metabolites were obtained, normal Ringer was substituted with Ringer containing naltrindole HC1 (1.0 txM) (obtained by Research Biochemicals Incorporated, Natick, MA, USA) and perfusion with this Ringer was continued for 1 h; then normal Ringer was reintroduced and after another hour ethanol (1.0 g/kg) was given i.p. as a 18% v / v solution in saline; in other experiments cocaine (15 mg/kg s.c.) was given in place of ethanol. In some experiments, [D-Ala2]deltorphin II, (obtained by Peninsula Laboratories INC., Belmont, CA, USA), an agonist of &opioid receptors (Erspamer et al., 1990), was included in the perfusion Ringer at a concentration of 50 /xM in control rats or in rats perfused with naltrindole 1 h earlier. As shown in table 1, perfusion of the nucleus accumbens with naltrindole (1.0/xM) while did not affect basal dopamine output, completely prevented the increase in dopamine output elicited by ethanol and [D-AIa2]deltorphin II but had no effect on that elicited by cocaine (15 mg/kg s.c.). Lower concentrations of naltrindole (0.5 txM) were less effective than 1.0 tzM, but still significantly reduced the effect of ethanol on dopamine output (not shown). Therefore, naltrindole at concentrations that antagonize the effect of a 3-opioid receptor agonist, also prevents the ability of ethanol but not of cocaine to increase extracellular dopamine concentrations. These results provide in vivo evidence for a role of &opioid receptors of the nucleus accumbens in the dopamine releasing properties of ethanol. The mechanisms un-
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241 derlying this i n t e r a c t i o n might be a facilitatory influence of 6-opioid receptors o n i m p u l s e - d e p e n d e n t d o p a m i n e release; the 6 - m e d i a t e d facilitation might in t u r n result from e t h a n o l - i n d u c e d s t i m u l a t i o n of the release of a 6-active opioid p e p t i d e in the n u c l e u s accumbens. T h e s e results might provide a basis for the r e p o r t e d ability of opioid r e c e p t o r a n t a g o n i s t s to disrupt e t h a n o l s e l f - a d m i n i s t r a t i o n (Koob, 1992).
References Acquas, E. and G. Di Chiara, 1992, Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence, J. Neuroehem. 58, 1620.
Di Chiara, G. and A. Imperato, 1988, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Nat. Acad. Sci. U.S.A. 85, 5274. Erspamer, V., P. Melchiorri, G. Falconieri-Erspamer, L. Negri, R. Corsi, C. Severini, D. Barra, M. Simmaco, G. Kreil, 1989, Deltorphins: a family of naturally occurring peptides with high affinity for delta opioid binding sites, Proc. Nat. Acad. Sci. U.S.A. 86, 461. Longoni R., L. Spina, A. Mulas, E. Carboni, L. Garau, P. Melchiorri and G. Di Chiara, 1990, [D-Ala2] Deltorphin II: Dl-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens, J. Neurosci. 11 (6) 1565. Koob G.F., 1992, Neural mechanisms of drug reinforcement, in: The Neurobiology of Drug and Alcohol Addiction, eds. P. Kalivas and H.H. Samson, Ann. N.Y. Acad. Sci. 654, 171. Portoghese P.S., M. Sultana and A.E. Takemori, 1988, Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist, Eur. J. Pharmacol. 146, 185.
239
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 0385R
Rapid communication
Blockade of 3-opioid receptors in the nucleus accumbens prevents ethanol-induced stimulation of dopamine release Elio Acquas, Marco Meloni and G a e t a n o Di Chiara Department of Toxicology, Unit,ersity of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy Received 9 December 1992, accepted 11 December 1992
Naltrindole, a specific 6-opioid antagonist, infused by reverse dialysis in the nucleus accumbens of freely moving rats completely prevented the increase in extracellular dopamine concentrations elicited in the nucleus accumbens by ethanol (1.0 g/kg i.p.) as well as by the 6-opioid receptor agonist [D-AlaZ]deltorphin II (50/xM), also perfused by reverse dialysis, but not by cocaine (15 mg/kg s.c.). The results provide in vivo evidence for a critical role of 6-opioid receptors in the dopamine-releasing properties of ethanol in vivo. 6-Opioid receptors; Dopamine; Ethanol
Biochemical (Di Chiara and Imperato, 1988) and pharmacological (Koob, 1992) evidence indicates that mesolimbic dopamine plays a critical role in the positive reinforcing properties of ethanol. On the other hand, phermacological evidence suggests that opioid transmission is involved in the reinforcing properties of ethanol (Koob, 1992). Since dopamine via D~ receptors, positively interacts with 3-opioid receptors in the nucleus accumbens (Longoni et al., 1990), we postulated that these receptors could play a role in the dopamine releasing properties of ethanol in that area (Di Chiara and Imperato, 1988). In order to investigate this issue, we studied the effect of naltrindole, a specific antagonist of 6-opioid receptors (Portoghese et al., 1988), on the release of dopamine in the nucleus accumbens, as estimated by brain microdialysis in freely moving rats. Male Sprague-Dawley rats (250-300 g, Charles River, Calco, Como Italy) were implanted with transcerebral dialysis probes (HOSPAL) in the nucleus accumbens according to the technique already described by us (Acquas and Di Chiara, 1992). The next day the rats were placed in hemispheric bowls, perfused with Ringer through the dialysis tube and dopamine and metabolites monitored by HPLC with electrochemical detection (Acquas and Di Chiara,
Correspondence to: G. Di Chiara, Department of Toxicology, University of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy. Tel. (39) 70/303.819 or 300.437, fax (39) 70/300.740.
1992). When stable values of dopamine and metabolites were obtained, normal Ringer was substituted with Ringer containing naltrindole HC1 (1.0 txM) (obtained by Research Biochemicals Incorporated, Natick, MA, USA) and perfusion with this Ringer was continued for 1 h; then normal Ringer was reintroduced and after another hour ethanol (1.0 g/kg) was given i.p. as a 18% v / v solution in saline; in other experiments cocaine (15 mg/kg s.c.) was given in place of ethanol. In some experiments, [D-Ala2]deltorphin II, (obtained by Peninsula Laboratories INC., Belmont, CA, USA), an agonist of &opioid receptors (Erspamer et al., 1990), was included in the perfusion Ringer at a concentration of 50 /xM in control rats or in rats perfused with naltrindole 1 h earlier. As shown in table 1, perfusion of the nucleus accumbens with naltrindole (1.0/xM) while did not affect basal dopamine output, completely prevented the increase in dopamine output elicited by ethanol and [D-AIa2]deltorphin II but had no effect on that elicited by cocaine (15 mg/kg s.c.). Lower concentrations of naltrindole (0.5 txM) were less effective than 1.0 tzM, but still significantly reduced the effect of ethanol on dopamine output (not shown). Therefore, naltrindole at concentrations that antagonize the effect of a 3-opioid receptor agonist, also prevents the ability of ethanol but not of cocaine to increase extracellular dopamine concentrations. These results provide in vivo evidence for a role of &opioid receptors of the nucleus accumbens in the dopamine releasing properties of ethanol. The mechanisms un-
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241 derlying this i n t e r a c t i o n might be a facilitatory influence of 6-opioid receptors o n i m p u l s e - d e p e n d e n t d o p a m i n e release; the 6 - m e d i a t e d facilitation might in t u r n result from e t h a n o l - i n d u c e d s t i m u l a t i o n of the release of a 6-active opioid p e p t i d e in the n u c l e u s accumbens. T h e s e results might provide a basis for the r e p o r t e d ability of opioid r e c e p t o r a n t a g o n i s t s to disrupt e t h a n o l s e l f - a d m i n i s t r a t i o n (Koob, 1992).
References Acquas, E. and G. Di Chiara, 1992, Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence, J. Neuroehem. 58, 1620.
Di Chiara, G. and A. Imperato, 1988, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Nat. Acad. Sci. U.S.A. 85, 5274. Erspamer, V., P. Melchiorri, G. Falconieri-Erspamer, L. Negri, R. Corsi, C. Severini, D. Barra, M. Simmaco, G. Kreil, 1989, Deltorphins: a family of naturally occurring peptides with high affinity for delta opioid binding sites, Proc. Nat. Acad. Sci. U.S.A. 86, 461. Longoni R., L. Spina, A. Mulas, E. Carboni, L. Garau, P. Melchiorri and G. Di Chiara, 1990, [D-Ala2] Deltorphin II: Dl-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens, J. Neurosci. 11 (6) 1565. Koob G.F., 1992, Neural mechanisms of drug reinforcement, in: The Neurobiology of Drug and Alcohol Addiction, eds. P. Kalivas and H.H. Samson, Ann. N.Y. Acad. Sci. 654, 171. Portoghese P.S., M. Sultana and A.E. Takemori, 1988, Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist, Eur. J. Pharmacol. 146, 185.