Original article| Volume 52, ISSUE 2, P111-118, July 15, 2002

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Stimulation of protein kinase a activity in the rat amygdala enhances reward-related learning

  • J.David Jentsch
    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Peter Olausson
    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Eric J Nestler
    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Jane R Taylor
    Address reprint requests to Jane R. Taylor, Ph.D., Department of Psychiatry, Yale University School of Medicine, CMHC, 34 Park Street, 3rd Floor Research Laboratories, New Haven CT 06508, USA
    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
    Search for articles by this author


      Background: Drug addiction in humans is associated with abnormal metabolic activity within the amygdala and heightened control of behavior by drugs and drug-related (conditioned) stimuli. Drug-induced neuroadaptations, including activation of cAMP (cyclic adenosine monophosphate)-dependent protein kinase A (PKA), within the amygdala may contribute to the synaptic plasticity and reward-related learning that underlies pathologic behavior in addicted individuals.
      Methods: In this study, we tested the hypothesis that stimulation of PKA activity within the rat amygdala would facilitate the acquisition of Pavlovian approach behavior, a measure of reward-related learning.
      Results: Intraamygdala infusions of Sp-cAMPS (which activates PKA) produced concentration-dependent enhancements of the acquisition of approach to a conditioned stimulus that predicted water availability; intraamygdala infusions of cholera toxin (which elevates cAMP levels) produced a similar effect. Conversely, intraamygdala infusions of Rp-cAMPS, an inhibitor of PKA, impaired acquisition of approach behavior.
      Conclusions: Together, these data demonstrate that stimulation of PKA activity in the amygdala can facilitate reward-related learning and suggest that neuroadaptative changes in the PKA pathway within this brain region may be a mechanism by which chronic drug abuse alters the control of behavior by drug-associated stimuli.


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        • Abel T.
        • Nguyen P.V.
        • Barad M.
        • Deuel T.A.
        • Kandel E.R.
        • Bourtchouladze R.
        Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory.
        Cell. 1997; 88: 615-626
        • Arroyo M.
        • Markou A.
        • Robbins T.W.
        • Everitt B.J.
        Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats.
        Psychopharmacology. 1998; 140: 331-344
        • Berke J.D.
        • Hyman S.E.
        Addiction, dopamine and the molecular mechanisms of memory.
        Neuron. 2000; 25: 515-532
        • Bourtchouladze R.
        • Abel T.
        • Berman N.
        • Gordon R.
        • Lapidus K.
        • Kandel E.R.
        Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA.
        Learning and Memory. 1998; 5: 365-374
        • Bourtchouladze R.
        • Frenguelli B.
        • Blendy J.
        • Cioffi D.
        • Schutz G.
        • Silva A.J.
        Deficient long-term memory in mice with a targeted mutation of the cAMP-response element-binding protein.
        Cell. 1994; 79: 59-68
        • Burns L.H.
        • Robbins T.W.
        • Everitt B.J.
        Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intraaccumbens infusions of d-amphetamine.
        Behav Brain Res. 1993; 55: 167-183
        • Childress A.R.
        • Hole A.V.
        • Ehrman R.N.
        • Robbins S.J.
        • McLellan A.T.
        • O’Brien C.P.
        Limbic activation during cue-induced cocaine craving.
        Am J Psychiatry. 1999; 156: 11-18
        • Frey U.
        • Huang Y.Y.
        • Kandel E.R.
        Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons.
        Science. 1993; 260: 1661-1664
        • Gass P.
        • Wolfer D.P.
        • Balschun D.
        • Rudolph D.
        • Frey U.
        • Lipp H.P.
        • Schutz G.
        Deficits in memory tasks of mice with CREB mutations depend on gene dosage.
        Learning Memory. 1998; 5: 274-288
        • Goosens K.A.
        • Holt W.
        • Maren S.
        A role for amygdala PKA and PKC in the acquisition of long-term conditional fear memories in rats.
        Behav Brain Res. 2000; 114: 145-152
        • Grant S.
        • London E.D.
        • Newlin D.B.
        • Villemagne V.L.
        • Liu X.
        • Contoreggi C.
        • et al.
        Activation of memory circuits during cue-elicited cocaine craving.
        Proc Nat Acad Sci USA. 1996; 93: 12040-12045
        • Harmer C.J.
        • Phillips G.D.
        Enhanced appetitive conditioning following repeated pretreatment with d-amphetamine.
        Behav Pharmacol. 1998; 9: 299-308
        • Hitchcott P.K.
        • Phillips G.D.
        Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours.
        Psychopharmacology. 1998; 140: 458-469
        • Huang Y.Y.
        • Li X.
        • Kandel E.R.
        cAMP contributes to mossy fiber LTP initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase.
        Cell. 1994; 79: 69-79
        • Huang Y.Y.
        • Kandel E.R.
        Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala.
        Neuron. 1998; 21: 169-178
        • Izquierdo L.A.
        • Barros D.M.
        • Ardenghi P.G.
        • Pereira P.
        • Rodrigues C.
        • Choi H.
        • et al.
        Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning.
        Behav Brain Res. 2000; 15: 93-98
        • Jentsch J.D.
        • Taylor J.R.
        Impulsivity resulting from frontostriatal dysfunction in drug abuse.
        Psychopharmacology. 1999; 146: 373-390
        • Kelley A.E.
        • Holahan M.R.
        Enhanced reward-related responding following cholera toxin infusion into the nucleus accumbens.
        Synapse. 1997; 26: 46-54
        • Luscher C.
        • Nicoll R.A.
        • Malenka R.C.
        • Muller D.
        Synaptic plasticity and dynamic modulation of the postsynaptic membrane.
        Nat Neurosci. 2000; 3: 545-550
        • Maren S.
        Neurobiology of Pavlovian fear conditioning.
        Annu Rev Neurosci. 2001; 24: 897-931
        • Mayford M.
        • Kandel E.R.
        Genetic approaches to memory storage.
        Trends Genet. 1999; 15: 463-470
        • McFarland K.
        • Ettenberg A.
        Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli.
        Psychopharmacology. 1997; 131: 86-92
        • McGaugh J.L.
        Time-dependent processes in memory storage.
        Science. 1966; 153: 1351-1358
        • McGaugh J.L.
        • Cahill L.
        Interaction of neuromodulatory systems in modulating memory storage.
        Behav Brain Res. 1997; 83: 31-38
        • Meil W.M.
        • See R.E.
        Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine.
        Behav Brain Res. 1997; 87: 139-148
        • Nestler E.J.
        Molecular basis of long-term plasticity underlying addiction.
        Nat Rev Neurosci. 2001; 2: 119-128
        • Nguyen P.V.
        • Kandel E.R.
        A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices.
        J Neurosci. 1996; 16: 3189-3198
        • O’Brien C.P.
        • Childress A.R.
        • Ehrman R.
        • Robbins S.J.
        Conditioning factors in drug abuse.
        J Psychopharmacol. 1998; 12: 15-22
        • Olmstead M.C.
        • Parkinson J.A.
        • Miles F.J.
        • Everitt B.J.
        • Dickinson A.
        Cocaine-seeking by rats.
        Psychopharmacology. 2000; 152: 123-131
        • Parkinson J.A.
        • Robbins T.W.
        • Everitt B.J.
        Dissociable roles of the central and basolateral amygdala in appetitive emotional learning.
        Eur J Neurosci. 2000; 12: 405-413
        • Punch L.
        • Self D.
        • Nestler E.J.
        • Taylor J.R.
        Opposite modulation of opiate withdrawal behaviors upon microinfusion of a protein kinase A inhibitor versus activator into the LC or PAG.
        J Neuroscience. 1997; 17: 8528-8535
        • Rammes G.
        • Steckler T.
        • Kresse A.
        • Schutz G.
        • Zieglgansberger W.
        • Lutz B.
        Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrain.
        Eur J Neurosci. 2000; 12: 2534-2546
        • Robbins T.W.
        • Everitt B.J.
        Drug addiction.
        Nature. 1999; 398: 567-570
        • Robinson T.E.
        • Berridge K.C.
        The neural basis of drug craving.
        Brain Res Rev. 1993; 18: 247-291
        • Schafe G.E.
        • LeDoux J.E.
        Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala.
        J Neurosci. 2000; 20: RC96
        • Shaham Y.
        • Erb S.
        • Stewart J.
        Stress-induced relapse to heroin and cocaine seeking in rats.
        Brain Res Rev. 2000; 33: 13-33
        • Stevens C.F.
        A million dollar question.
        Neuron. 1998; 20: 1-2
        • Taylor J.R.
        • Horger B.A.
        Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization.
        Psychopharmacology. 1999; 142: 31-40
        • Taylor J.R.
        • Jentsch J.D.
        Repeated intermittent administration of psychomotor stimulant drugs differentially alters the acquisition of Pavlovian appetitive approach behavior in rats.
        Biol Psychiatry. 2001; 50: 137-143
        • Terwilliger R.Z.
        • Beitner-Johnson D.
        • Sevarino K.A.
        • Crain S.M.
        • Nestler E.J.
        A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function.
        Brain Res. 1991; 548: 100-110
        • Williams S.F.
        • Colling S.B.
        • Whittington M.A.
        • Jefferys J.G.
        Epileptic focus induced by intrahippocampal cholera toxin in rat.
        Epilepsy Res. 1993; 16: 137-146