Psychopharmacology

, Volume 190, Issue 1, pp 65–72

Nucleus accumbens PKA inhibition blocks acquisition but enhances expression of amphetamine-produced conditioned activity in rats

  • Todor V. Gerdjikov
  • Andrew C. Giles
  • Shelley N. Swain
  • Richard J. Beninger
Original Investigation

Abstract

Rationale

The nucleus accumbens (NAc) plays a central role in dopamine-produced reward-related learning. In previous studies, the cyclic adenosine monophosphate-dependent protein kinase (PKA) inhibitor Rp-Cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (Rp-cAMPS) blocked the acquisition but not expression of NAc reward-related learning for natural rewards and the acquisition of psychostimulant drug conditioning.

Objectives

The current study assessed the role of PKA in the expression of NAc amphetamine (amph)-produced conditioning using conditioned activity (CA).

Materials and methods

After 5 days of habituation, a test environment was paired with bilateral NAc injections of amph (0.0 or 25.0 μg) and the PKA inhibitor Rp-cAMPS (0.0, 5.0, 10.0, or 20.0 μg) over three 60-min conditioning sessions separated by 48 h. To test for effects on expression, some groups received vehicle or amph alone before conditioning sessions and were injected with 0.0, 0.25, 5.0, or 20.0 μg of Rp-cAMPS before the single 60-min test session.

Results

Amph produced acute increases in locomotion and robust CA. Rp-cAMPS impaired the acquisition of amph-produced CA but not its expression; in fact, it enhanced expression.

Conclusions

Results show that PKA inhibition blocks the acquisition but not the expression of amph-produced conditioning.

Keywords

Addiction Acquisition Amphetamine Expression Locomotion Learning PKA Psychostimulant Reward 

References

  1. Ahmed SH, Stinus L, Cador M (1998) Amphetamine-induced conditioned activity is insensitive to perturbations known to affect Pavlovian conditioned responses in rats. Behav Neurosci 112:1167–1176PubMedCrossRefGoogle Scholar
  2. Anagnostaras SG, Schallert T, Robinson TE (2002) Memory processes governing amphetamine-induced psychomotor sensitization. Neuropsychopharmacology 26:703–715PubMedCrossRefGoogle Scholar
  3. Arnsten AF, Ramos BP, Birnbaum SG, Taylor JR (2005) Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Trends Mol Med 11:121–128PubMedCrossRefGoogle Scholar
  4. Baldwin AE, Sadeghian K, Holahan MR, Kelley AE (2002) Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens. Neurobiol Learn Mem 77:44–62PubMedCrossRefGoogle Scholar
  5. Beninger R (1983) The role of dopamine in locomotor activity and learning. Brain Res Rev 6:173–196CrossRefGoogle Scholar
  6. Beninger RJ, Gerdjikov T (2004) The role of signaling molecules in reward-related incentive learning. Neurotox Res 6:91–104PubMedCrossRefGoogle Scholar
  7. Beninger RJ, Hahn BL (1983) Pimozide blocks establishment but not expression of amphetamine-produced environment-specific conditioning. Science 220:1304–1306PubMedCrossRefGoogle Scholar
  8. Beninger RJ, Gerdjikov TV (2005) Dopamine-glutamate interactions in reward-related incentive learning. In Schmidt WJ, Reith ME (eds) Dopamine and glutamate in psychiatric diseases. Humana Press, Totowa, NJ, 315–350Google Scholar
  9. Beninger RJ, Cooper TA, Mazurski EJ (1985) Automating the measurement of locomotor activity. Neurobehav Toxicol Teratol 7:79–85PubMedGoogle Scholar
  10. Beninger RJ, Mazurski EJ, Hoffman DC (1991) Receptor subtype-specific dopaminergic agents and unconditioned behavior. Pol J Pharmacol Pharm 43:507–528PubMedGoogle Scholar
  11. Beninger RJ, Nakonechny PL, Savina I (2003) cAMP-dependent protein kinase and reward-related learning: intra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats. Psychopharmacology (Berl) 170:23–32CrossRefGoogle Scholar
  12. Brown EE, Fibiger HC (1993) Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference. Psychopharmacology (Berl) 113:123–130CrossRefGoogle Scholar
  13. Carr GD, White NM (1986) Anatomical disossiation of amphetamine’s rewarding and aversive effects: an intracranial microinjection study. Psychopharmacology 89:340–346PubMedCrossRefGoogle Scholar
  14. Cervo L, Mukherjee S, Bertaglia A, Samanin R (1997) Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning. Brain Res 775:30–36PubMedCrossRefGoogle Scholar
  15. Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114PubMedCrossRefGoogle Scholar
  16. Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW (1999) Associative processes in addiction and reward: the role of amygdala-ventral striatal subsystems. Ann N Y Acad Sci 877:412–438PubMedCrossRefGoogle Scholar
  17. Fuchs RA, Evans KA, Parker MC, See RE (2004) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 176:459–465CrossRefGoogle Scholar
  18. Gerdjikov TV, Beninger RJ (2005) Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats. Eur J Neurosci 22:697–705PubMedCrossRefGoogle Scholar
  19. Gerdjikov TV, Ross GM, Beninger RJ (2004) Place preference induced by nucleus accumbens amphetamine is impaired by antagonists of ERK or p38 MAP kinases in rats. Behav Neurosci 118:740–750PubMedCrossRefGoogle Scholar
  20. Harris GC, Wimmer M, Byrne R, Aston-Jones G (2004) Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine. Neuroscience 129:841–847PubMedCrossRefGoogle Scholar
  21. Ikemoto S, Qin M, Liu ZH (2005) The functional divide for primary reinforcement of D-amphetamine lies between the medial and lateral ventral striatum: is the division of the accumbens core, shell, and olfactory tubercle valid? J Neurosci 25:5061–5065PubMedCrossRefGoogle Scholar
  22. Jentsch JD, Olausson P, Nestler EJ, Taylor JR (2002) Stimulation of protein kinase A activity in the rat amygdala enhances reward-related learning. Biol Psychiatry 52:111–118PubMedCrossRefGoogle Scholar
  23. Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179PubMedCrossRefGoogle Scholar
  24. Keppel G, Wickens TD (2004) Design and analysis: a researcher’s handbook. Prentice Hall, Englewood Cliffs, NJGoogle Scholar
  25. Lynch WJ, Taylor JR (2005) Persistent changes in motivation to self-administer cocaine following modulation of cyclic AMP-dependent protein kinase A (PKA) activity in the nucleus accumbens. Eur J Neurosci 22:1214–1220PubMedCrossRefGoogle Scholar
  26. Martin-Iverson MT, Fawcett SL (1996) Pavlovian conditioning of psychomotor stimulant-induced behaviours: has convenience led us astray? Behav Pharmacol 7:24–41PubMedGoogle Scholar
  27. Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873–884PubMedCrossRefGoogle Scholar
  28. Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, Nabeshima T (2004) Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mol Pharmacol 65:1293–1301PubMedCrossRefGoogle Scholar
  29. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449PubMedCrossRefGoogle Scholar
  30. Parkinson JA, Olmstead MC, Burns LH, Robbins TW, Everitt BJ (1999) Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J Neurosci 19:2401–2411PubMedGoogle Scholar
  31. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, AcademicGoogle Scholar
  32. Phillips GD, Setzu E, Hitchcott PK (2003) Facilitation of appetitive pavlovian conditioning by d-amphetamine in the shell, but not the core, of the nucleus accumbens. Behav Neurosci 117:675–684PubMedCrossRefGoogle Scholar
  33. Schultz W (2002) Getting formal with dopamine and reward. Neuron 36:241–263PubMedCrossRefGoogle Scholar
  34. Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ (1998) Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J Neurosci 18:1848–1859PubMedGoogle Scholar
  35. Sellings LH, Clarke PB (2003) Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial shell and core. J Neurosci 23:6295–6303PubMedGoogle Scholar
  36. Setlow B, Holland PC, Gallagher M (2002) Disconnection of the basolateral amygdala complex and nucleus accumbens impairs appetitive Pavlovian second-order conditioned responses. Behav Neurosci 116:267–275PubMedCrossRefGoogle Scholar
  37. Sutton MA, Beninger RJ (1999) Psychopharmacology of conditioned reward; evidence for a rewarding signal at D1-like dopamine receptors. Psychopharmacology 144:95–110PubMedCrossRefGoogle Scholar
  38. Sutton MA, McGibney K, Beninger RJ (2000) Conditioned locomotion in rats following amphetamine infusion into the nucleus accumbens: blockade by coincident inhibition of protein kinase A. Behav Pharmacol 11:365–376PubMedGoogle Scholar
  39. Swain SN, Beninger RJ (2004) PKA inhibition in nucleus accumbens attenuates establishment but not expression of amphetamine-produced conditioned activity. Program no. 210.6. 2004 Abstract Viewer/Itinerary Planner. Society for Neuroscience, Washington, DCGoogle Scholar
  40. Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701–8709PubMedGoogle Scholar
  41. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492PubMedCrossRefGoogle Scholar
  42. Zahm D (2000) An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci Biobehav Rev 24:85–105PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Todor V. Gerdjikov
    • 1
  • Andrew C. Giles
    • 1
  • Shelley N. Swain
    • 1
  • Richard J. Beninger
    • 1
    • 2
  1. 1.Department of PsychologyQueen’s UniversityKingstonCanada
  2. 2.Department of PsychiatryQueen’s UniversityKingstonCanada

Personalised recommendations