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S.3.3 Behavioral mechanisms of nicotine abuse: Search for novel pharmacotherapies to treat nicotine dependence
Symposia
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a role in the dynamics of drug-taking behaviour during the maintenance phase of drug dependence and for a role in certain motivational effects induced by repeated drug (self-)administration, which may be involved in craving and relapse. Different brain opioid systems have been concerned in addictive behaviour: opioid systems in the VTA have been implicated in the modulatory role of endogenous opioids in drug reinforcement, whereas opioid systems in limbic areas may be involved in the dynamics of drug-taking behaviour and in craving and relapse. References [1] Gerrits, M.A.EM., Wiegant, V.M. and Van Ree, J.M., 1999. Endogenous opioids implicated in the dynamics of experimental drug addicition: an in vivo autoradiographic analysis. Neuroseienee 89, 1219-1227. [2] Van Ree, J.M., Gerrits, M.A. and Vanderschurer), L.J., 1999. Opioids, reward and addiction: An encounter of biology, psychology, and medicine. Pharmaeol. Rev. 51,341-396.
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Behavioral mechanisms of nicotine abuse: Search for novel pharmacotherapies to treat nicotine dependence
A.Y. Bespalov, E.S. Zakharova, I.M. Sukhanov, E.E. Zvartau*. Department of Psychopharmacology,
Valdman Institute of Pharmacology, Paolov State Medical University, 6/8 Leo Tolstoy St., St. Petersburg 197089, Russia Abuse potential of nicotine (NIC) is strongly linked to central nicotinic receptors and, accordingly, central nicotinic receptor antagonists such as mecamylamine (MA) prevent acquisition of NIC-conditioned place preference, block NIC self-administration under different schedules of reinforcement, antagonize discriminative stimulus effects of NIC and attenuate both development and expression of NIC-induced sensitization. Yet, MA shows somewhat limited ability to precipitate withdrawal syndrome in NICdependent subjects. These findings are quite important as they indicate that: a) giving nicotinic receptor antagonists to NIC-dependent subjects is not likely to worsen NIC withdrawal syndrome, and b) NIC withdrawal syndrome in this regard is different from that for other abused drugs such opiates. Nicotinic receptor antagonists may also reduce seeking behavior (craving) for NIC in the same way as they do in subjects selfadministering cocaine. Non-competitive nicotinic receptor antagonists are likely to avoid problems usually seen with competitive antagonists as increasing the agonist dose would be less likely to reverse the blockade (this may
be critical for human addicts who could increase the NIC/eigarette load to overcome the receptor blockade). Indeed, MA was shown to enhance acutely human NIC self-administration behavior, a finding which is fully consistent with the extinction explanation (i.e., responding bursts during the early extinction; Rose et al., 2003). Thus, the overall aim may be to present noncompetitive nicotinic receptor antagonists in order to produce pharmacological extinction of NIC-maintained behavior. Furthermore, compared to other drugs of abuse, NIC-seeking and taking behavior appears to be under much stronger control of environmental factors. Experimental evidence also indicates a significant role of NIC-associated stimuli in maintaining NIC self-administration behavior (Caggiula et al., 2002). Recent evidence also suggests that non-contingent administration of NIC may be as effective as response-contingent regimens in maintaining operant performance (Donny et al., 2003). Experimental data indicate that noneontingent NIC may enhance responding maintained by non-drug primary reinforcement and may facilitate responding with conditioned reinforcement. However, at this moment, it is not clear whether attentionenhancing properties of NIC contribute to these effects. Since associative mechanisms seem to play a critical role in maintaining NIC seeking- and taking behavior, novel pharmacotherapies may focus on attenuating the effects elicited by NIC-eonditioned stimuli. Taken together with the earlier data, antagonists acting at NMDA and mGluR5 may be particularly useful in this regard. Supported in part by the NIH Fogarty International Research Collaboration Award #1R03TW00714. References [1] Caggiula AR, Donny EC, Chaudlin N, Perkins KA, Evans-Martin FF, Sved AF (2002) Importance of nonpharmaeologieal factors in nicotine selfadministration. Physiol Behav 77: 683-7. [2] Donny EC, Chaudhri N, Caggiula AR, EvansMartin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noneontingent nicotine: implications for nicotine self-administration and reinforcement. Psyehopharmaeology (Berlin) 169: 68-76. [3] Rose JE, Behrn FM, Westman EC, Bates JE (2003) Mecamylamine acutely increases hunaan intravenous nicotine self-administration. Pharmaeol Bioehem Behav 76: 307-13.
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a role in the dynamics of drug-taking behaviour during the maintenance phase of drug dependence and for a role in certain motivational effects induced by repeated drug (self-)administration, which may be involved in craving and relapse. Different brain opioid systems have been concerned in addictive behaviour: opioid systems in the VTA have been implicated in the modulatory role of endogenous opioids in drug reinforcement, whereas opioid systems in limbic areas may be involved in the dynamics of drug-taking behaviour and in craving and relapse. References [1] Gerrits, M.A.EM., Wiegant, V.M. and Van Ree, J.M., 1999. Endogenous opioids implicated in the dynamics of experimental drug addicition: an in vivo autoradiographic analysis. Neuroseienee 89, 1219-1227. [2] Van Ree, J.M., Gerrits, M.A. and Vanderschurer), L.J., 1999. Opioids, reward and addiction: An encounter of biology, psychology, and medicine. Pharmaeol. Rev. 51,341-396.
•
Behavioral mechanisms of nicotine abuse: Search for novel pharmacotherapies to treat nicotine dependence
A.Y. Bespalov, E.S. Zakharova, I.M. Sukhanov, E.E. Zvartau*. Department of Psychopharmacology,
Valdman Institute of Pharmacology, Paolov State Medical University, 6/8 Leo Tolstoy St., St. Petersburg 197089, Russia Abuse potential of nicotine (NIC) is strongly linked to central nicotinic receptors and, accordingly, central nicotinic receptor antagonists such as mecamylamine (MA) prevent acquisition of NIC-conditioned place preference, block NIC self-administration under different schedules of reinforcement, antagonize discriminative stimulus effects of NIC and attenuate both development and expression of NIC-induced sensitization. Yet, MA shows somewhat limited ability to precipitate withdrawal syndrome in NICdependent subjects. These findings are quite important as they indicate that: a) giving nicotinic receptor antagonists to NIC-dependent subjects is not likely to worsen NIC withdrawal syndrome, and b) NIC withdrawal syndrome in this regard is different from that for other abused drugs such opiates. Nicotinic receptor antagonists may also reduce seeking behavior (craving) for NIC in the same way as they do in subjects selfadministering cocaine. Non-competitive nicotinic receptor antagonists are likely to avoid problems usually seen with competitive antagonists as increasing the agonist dose would be less likely to reverse the blockade (this may
be critical for human addicts who could increase the NIC/eigarette load to overcome the receptor blockade). Indeed, MA was shown to enhance acutely human NIC self-administration behavior, a finding which is fully consistent with the extinction explanation (i.e., responding bursts during the early extinction; Rose et al., 2003). Thus, the overall aim may be to present noncompetitive nicotinic receptor antagonists in order to produce pharmacological extinction of NIC-maintained behavior. Furthermore, compared to other drugs of abuse, NIC-seeking and taking behavior appears to be under much stronger control of environmental factors. Experimental evidence also indicates a significant role of NIC-associated stimuli in maintaining NIC self-administration behavior (Caggiula et al., 2002). Recent evidence also suggests that non-contingent administration of NIC may be as effective as response-contingent regimens in maintaining operant performance (Donny et al., 2003). Experimental data indicate that noneontingent NIC may enhance responding maintained by non-drug primary reinforcement and may facilitate responding with conditioned reinforcement. However, at this moment, it is not clear whether attentionenhancing properties of NIC contribute to these effects. Since associative mechanisms seem to play a critical role in maintaining NIC seeking- and taking behavior, novel pharmacotherapies may focus on attenuating the effects elicited by NIC-eonditioned stimuli. Taken together with the earlier data, antagonists acting at NMDA and mGluR5 may be particularly useful in this regard. Supported in part by the NIH Fogarty International Research Collaboration Award #1R03TW00714. References [1] Caggiula AR, Donny EC, Chaudlin N, Perkins KA, Evans-Martin FF, Sved AF (2002) Importance of nonpharmaeologieal factors in nicotine selfadministration. Physiol Behav 77: 683-7. [2] Donny EC, Chaudhri N, Caggiula AR, EvansMartin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noneontingent nicotine: implications for nicotine self-administration and reinforcement. Psyehopharmaeology (Berlin) 169: 68-76. [3] Rose JE, Behrn FM, Westman EC, Bates JE (2003) Mecamylamine acutely increases hunaan intravenous nicotine self-administration. Pharmaeol Bioehem Behav 76: 307-13.