Activation of exchange protein activated by cAMP in the rat basolateral amygdala impairs reconsolidation of a memory associated with self-administered cocaine.

The intracellular mechanisms underlying memory reconsolidation critically involve cAMP signaling. These events were originally attributed to PKA activation by cAMP, but the identification of Exchange Protein Activated by cAMP (Epac), as a distinct mediator of cAMP signaling, suggests that cAMP-regulated processes that subserve memory reconsolidation are more complex. Here we investigated how activation of Epac with 8-pCPT-cAMP (8-CPT) impacts reconsolidation of a memory that had been associated with cocaine self-administration. Rats were trained to lever press for cocaine on an FR-1 schedule, in which each cocaine delivery was paired with a tone+light cue. Lever pressing was then extinguished in the absence of cue presentations and cocaine delivery. Following the last day of extinction, rats were put in a novel context, in which the conditioned cue was presented to reactivate the cocaine-associated memory. Immediate bilateral infusions of 8-CPT into the basolateral amygdala (BLA) following reactivation disrupted subsequent cue-induced reinstatement in a dose-dependent manner, and modestly reduced responding for conditioned reinforcement. When 8-CPT infusions were delayed for 3 hours after the cue reactivation session or were given after a cue extinction session, no effect on cue-induced reinstatement was observed. Co-administration of 8-CPT and the PKA activator 6-Bnz-cAMP (10 nmol/side) rescued memory reconsolidation while 6-Bnz alone had no effect, suggesting an antagonizing interaction between the two cAMP signaling substrates. Taken together, these studies suggest that activation of Epac represents a parallel cAMP-dependent pathway that can inhibit reconsolidation of cocaine-cue memories and reduce the ability of the cue to produce reinstatement of cocaine-seeking behavior.

Chronic nicotine attenuates phencyclidine-induced impulsivity in a mouse serial reaction time task.

Schizophrenia is a disorder characterized by positive, negative, and cognitive symptoms. While positive symptoms can be effectively treated with typical antipsychotic medication, which generally affects the dopaminergic system, negative and cognitive symptoms, including attentional deficits and impulsive behavior, are less sensitive to standard treatments. It has further been well documented that schizophrenic patients use tobacco products at a rate much higher than the general population, and this persists despite treatment. It has been argued this behavior may be a form of self-medication, to alleviate some symptoms of schizophrenia. It has further been posited that prefrontal glutamatergic hypofunction may underlie some aspects of schizophrenia, and in accordance with this model, systemic phencyclidine has been used to model the disease. We employed a modified 5-choice serial reaction time test, a paradigm that is often used to investigate many of the treatment-resistant symptoms of schizophrenia including impulsivity, selective attention, and sustained attention/cognitive vigilance, to determine the medicinal effects of nicotine. We demonstrate that chronic oral, but not acute injections of nicotine can selectively attenuate phencyclidine-induced increases in impulsivity without affecting other measures of attention. This suggests that nicotine use by schizophrenics may provide some relief of distinct symptoms that involve impulsive behaviors.

Repeated nicotine exposure during adolescence alters reward-related learning in male and female rats.

RATIONALE: Repeated nicotine exposure causes neuroadaptations in limbic cortico-striatal circuits involved in learning and motivation. Such alterations are relevant to addiction because they are suggested to mediate the ability of smoking-associated stimuli to control behavior and to enhance nicotine-seeking and -taking behaviors. Female smokers report higher cue reactivity relative to their male counter parts, yet little is known about putative gender-specific effects of adolescent nicotine exposure on reward-related learning. Prior repeated nicotine exposure in adult male rats enhances Pavlovian approach behavior and conditioned reinforcement. OBJECTIVE: Given that smoking is typically initiated during adolescence, here we assessed the extent to which adolescent nicotine exposure impacts Pavlovian approach and conditioned reinforcement in male and female rats. METHODS: Rats were injected with nicotine on postnatal days 31-45 prior to training on Pavlovian approach behavior starting on day 51. They were trained to associate a conditioned stimulus (CS), illumination of a magazine light, and tone, with an unconditioned stimulus (US), the delivery of water, for 10-daily sessions, and then were tested on the acquisition of responding with conditioned reinforcement. RESULTS: Adolescent nicotine exposure selectively increased approach to the magazine during the CS in males but decreased approach to the magazine during the CS in female rats. Vehicle-exposed female rats, however, showed greater magazine approach during the CS than did male control rats. Prior nicotine exposure also enhanced conditioned reinforcement in both male and female rats. CONCLUSIONS: Repeated exposure to nicotine during adolescence had opposite effects on Pavlovian approach behavior in male and female rats but enhanced acquisition of a new response with conditioned reinforcement. Novel information on how nicotine exposure influences reward-related learning during adolescence may increase our understanding of neurobiological mechanisms involved in the initiation of smoking behavior.

Low prefrontal PSA-NCAM confers risk for alcoholism-related behavior.

The factors underlying vulnerability to alcoholism are largely unknown. We identified in rodents an innate endophenotype predicting individual risk for alcohol-related behaviors that was associated with decreased expression of the neuroplasticity-related polysialylated neural cell adhesion molecule (PSA-NCAM). Depletion of PSA-NCAM in the ventromedial prefrontal cortex was sufficient to render mice unable to extinguish alcohol seeking, indicating a causal role of naturally occurring variation. These data suggest a mechanism of aberrant prefrontal neuroplasticity that underlies enhanced propensity for inflexible addiction-related behavior.

Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A.

Drug addiction is a chronic disorder associated with recurrent craving and relapse often precipitated by the presence of drug-associated stimuli. Pharmacological and behavioral treatments that disrupt drug-associated stimulus memories could be beneficial in the treatment of addictive disorders. Memory restabilization (or reconsolidation) following retrieval of drug-paired stimuli depends upon the amygdala. Here we assessed whether amygdalar PKA is required for the reconsolidation of an appetitive, cocaine-paired stimulus. Rats were trained to lever press for intravenous cocaine infusions paired with a light/tone conditioned stimulus. After 12 d of acquisition, rats either underwent lever extinction (8-12 d) followed by light/tone reactivation and subsequent cue-induced and cocaine-induced (15 mg/kg, i.p.) reinstatement testing or were subsequently tested to assess the ability of the light/tone stimulus to serve as a conditioned reinforcer in the acquisition of a new instrumental response (nose poking). Bilateral intra-amygdalar infusions of the PKA inhibitor Rp-cAMPS (18 microg per side) given immediately following light/tone stimulus reactivation decreased subsequent cue-induced reinstatement and responding with a conditioned reinforcer, while having no effect on cocaine-induced reinstatement. Intra-amygdalar infusions of Rp-cAMPS made 3 h following reactivation or immediately following no stimulus reactivation had no effect on subsequent cue-induced reinstatement. These data show that memory reconsolidation for a cocaine-paired stimulus is retrieval dependent and time limited and critically depends upon amygdalar PKA.

The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats.

Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressant-like behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained-release alginate implant, produced an antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.

Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression.

BACKGROUND: Elevated phosphorylation of neurotrophin-regulated transcription factors, such as cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), in the hippocampus has been proposed as a common mediator of antidepressant (ADT) efficacy in otherwise naive rodents. The intracellular factors by which ADTs and glucocorticoids, causal factors in depression, regulate depression-like behavior remain unclear, but extracellular signal-regulated kinase 1/2 (ERK1/2), upstream of CREB, is a likely candidate. METHODS: We explored the long-term consequences of glucocorticoid exposure and subsequent ADT treatment in a novel model of chronic depression. Motivated behaviors, immobility during tail suspension, and ERK1/2, known to be required for behavioral response to ADTs, were quantified. RESULTS: Chronic corticosterone (CORT) increased immobility, decreased responding in an operant conditioning task of motivation, and selectively reduced phosphorylated ERK1/2 (pERK1/2) in the dentate gyrus. Behavioral and biochemical measures were restored to baseline by amitriptyline (AMI) treatment. Corticosterone regulated pERK1/2 on a time course that paralleled increases in heat shock proteins associated with depression and decreased tyrosine kinase receptor B (trkB) phosphorylation. Chronic AMI also produced regionally dissociable effects on pERK1/2 in CA1/CA3, amygdala, and striatum, but not prefrontal cortex. CONCLUSIONS: Antidepressant efficacy in a motivational task and behavioral despair assay are associated with altered limbic pERK1/2, including restored pERK1/2 in the dentate gyrus after stress-related insult.

Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability.

Cyclin-dependent kinase 5 (Cdk5) regulates dopamine neurotransmission and has been suggested to serve as a homeostatic target of chronic psychostimulant exposure. To study the role of Cdk5 in the modulation of the cellular and behavioral effects of psychoactive drugs of abuse, we developed Cre/loxP conditional knock-out systems that allow temporal and spatial control of Cdk5 expression in the adult brain. Here, we report the generation of Cdk5 conditional knock-out (cKO) mice using the alphaCaMKII promoter-driven Cre transgenic line (CaMKII-Cre). In this model system, loss of Cdk5 in the adult forebrain increased the psychomotor-activating effects of cocaine. Additionally, these CaMKII-Cre Cdk5 cKO mice show enhanced incentive motivation for food as assessed by instrumental responding on a progressive ratio schedule of reinforcement. Behavioral changes were accompanied by increased excitability of medium spiny neurons in the nucleus accumbens (NAc) in Cdk5 cKO mice. To study NAc-specific effects of Cdk5, another model system was used in which recombinant adeno-associated viruses expressing Cre recombinase caused restricted loss of Cdk5 in NAc neurons. Targeted knock-out of Cdk5 in the NAc facilitated cocaine-induced locomotor sensitization and conditioned place preference for cocaine. These results suggest that Cdk5 acts as a negative regulator of neuronal excitability in the NAc and that Cdk5 may govern the behavioral effects of cocaine and motivation for reinforcement.

Role of calcineurin in nicotine-mediated locomotor sensitization.

Calcineurin is a serine/threonine phosphatase that contributes to the effects of nicotine on calcium signaling in cultured cortical neurons; however, the role of calcineurin in behavioral responses to nicotine in vivo has not been examined. We therefore determined whether calcineurin blockade could alter nicotine-mediated locomotor sensitization in Sprague Dawley rats using systemic or brain region-specific administration of the calcineurin inhibitors cyclosporine or FK506. Systemic cyclosporine administration decreased calcineurin activity in the brain, attenuated nicotine-mediated locomotor sensitization, and blocked the effects of nicotine on DARPP32 (dopamine- and cAMP-regulated phosphoprotein-32) activation in the striatum. Direct infusion of calcineurin inhibitors cyclosporine or FK506 into the ventral tegmental area (VTA) also attenuated nicotine-mediated locomotor sensitization, whereas infusion of rapamycin, which binds to FK-binding protein but does not inhibit calcineurin, did not affect sensitization. Together, the data suggest that activation of calcineurin, particularly in the VTA, is a novel signaling event important for nicotine-mediated behavior and intracellular signaling.

Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats.

RATIONALE: Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction. OBJECTIVE: Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats. MATERIALS AND METHODS: Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845. RESULTS: Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats. CONCLUSION: These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation.

Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor deltaFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of deltaFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of deltaFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by deltaFosB, and provide evidence that drug-induced alterations in gene expression via induction of deltaFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A.

Reconsolidation-the stabilization of a memory after retrieval-is hypothesized to be a critical and distinct component of memory processing, the disruption of which results in memory impairment. In the rat, we found that activation of amygdalar protein kinase A (PKA) was sufficient to enhance memory only when it was retrieved; in contrast, PKA inhibition impaired reconsolidation. This study demonstrates both a selective enhancement and an impairment of memory reconsolidation dependent on amygdalar PKA.

beta2-Subunit-containing nicotinic acetylcholine receptors are involved in nicotine-induced increases in conditioned reinforcement but not progressive ratio responding for food in C57BL/6 mice.

RATIONALE: Nicotine administration potentiates conditioned reinforcement in rats, an effect that persists for weeks after chronic exposure. Little is known regarding the nicotinic receptor subtypes that may mediate this effect. OBJECTIVE: The purpose of this study was to determine whether beta2-subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) are necessary for lasting effects of nicotine on conditioned and primary reinforcement in mice. METHODS: Beta2 knockout (beta2KO) and wild-type (WT) mice received 14 days of nicotine exposure (NIC, 200 microg/ml in 2% saccharin) or saccharin alone (SAC) in their drinking water. Five days later, mice received paired presentations of a conditioned stimulus (CS) with water unconditioned stimulus (US) or explicitly unpaired presentations of the CS and US during Pavlovian discriminative approach training. Training was followed by two conditioned reinforcement tests. Mice were subsequently tested for food-reinforced responding in the absence of explicit cues followed by a progressive ratio test. RESULTS: During conditioned reinforcement testing, only mice in the paired condition showed increased responding in the CS-reinforced aperture over inactive apertures. WT-NIC mice showed enhanced conditioned reinforcement compared to WT-SAC animals. beta2KO-SAC mice showed elevated conditioned reinforcement compared to WT-SAC subjects, but beta2KO-NIC and beta2KO-SAC mice did not differ in responding with conditioned reinforcement. Prior nicotine exposure did not alter food-reinforced responding but resulted in elevated break points for food in both genotypes. CONCLUSION: These data show that nicotine exposure enhances conditioned reinforcement in mice and indicate that beta2*nAChRs are necessary for nicotine-dependent enhancement of incentive aspects of motivation but not motivation for primary reinforcement measured by progressive ratio responding.

Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat.

Thalamic projections to prefrontal cortex are important for executive aspects of attention. Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex. Although it is known that attention can be improved when nicotine is infused directly into the midlayer of the prefrontal cortex in the rat, the effects of hypocretin on attention are not known. The overlap in thalamocortical synapses excited by hypocretin and nicotine and the lack of direct postsynaptic effects prompted us to compare their effects on a sustained and divided attention task in the rat. Similar to nicotine, infusions of hypocretin-2 peptide into the prefrontal cortex significantly improved accuracy under high attentional demand without effects on other performance measures. We show for the first time that hypocretin can improve attentional processes relevant to executive functions of the prefrontal cortex.

Protein kinase A as a therapeutic target for memory disorders: rationale and challenges.

cAMP-dependent protein kinase A (PKA) signaling has a key role in memory processes and has been identified as a potential therapeutic target for memory disorders. The activation of PKA signaling is crucial for the consolidation of long-term memories dependent on the hippocampus and/or the amygdala, By contrast, initial studies indicate that cAMP-PKA activation might impair the working memory and executive functions of the prefrontal cortex. Furthermore, PKA activation in the nucleus accumbens might increase sensitivity to addiction. These complexities must be heeded when designing medications aimed at altering PKA activity. PKA might be most practical as a therapeutic target in disorders with global alterations in cAMP-PKA activity due to genetic or environmental factors.

Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones.

We have previously shown that following extended access to cocaine, females, but not males, show marked increases in motivation to obtain cocaine, and we have hypothesized that such changes may contribute to long-term compulsive aspects of addiction that result in a persistent vulnerability to relapse. Here, we investigate the effects of extended cocaine access on short-term motivational changes in both male and female rats. An additional goal was to determine whether estrogen modulates motivation to self-administer cocaine in female rats following extended access to cocaine. A discrete trial procedure was used that allowed rats 24-h access to cocaine infusions (1.5 mg/kg) that were available in discrete trials (four, 10-min trials/h) for 7 consecutive days. Motivation to obtain cocaine was assessed by responding under a progressive ratio schedule, and preference for sucrose (1%) vs water was assessed using a two-bottle, 24-h test. Each was assessed prior to and immediately following discrete trial cocaine self-administration. Results showed that following discrete trial cocaine self-administration, both males and females showed a decrease in preference for sucrose, but only females showed a reduction in levels of responding for cocaine under the progressive ratio schedule, suggesting a sex difference in motivation that was specific to cocaine. Subsequent studies with ovariectomized rats showed that estrogen replacement blocked the decrease in motivation to obtain cocaine infusions. Together, these findings suggest that there is a dissociation between sex and the short- vs long-term alteration in motivation to use cocaine. The mechanisms that may underlie these observed sex differences, including the role of estrogen, are discussed.

Repeated nicotine exposure enhances responding with conditioned reinforcement.

RATIONALE: Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes. OBJECTIVE: This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion. METHODS: Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 microg per side) prior to the conditioned reinforcement test. RESULTS: Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine. CONCLUSIONS: These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.

Nicotine enhances responding with conditioned reinforcement.

RATIONALE: The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes. OBJECTIVE: In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects. METHODS: After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25-350 micro g/kg SC; -5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 micro g/kg SC; -20 min) alone, or in combination with nicotine (350 micro g/kg SC; -5 min), on conditioned reinforcement was also examined. RESULTS: Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 micro g/kg SC; -5 min) was selectively blocked by mecamylamine (300 micro g/kg). CONCLUSIONS: These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.

Repeated nicotine exposure enhances reward-related learning in the rat.

Repeated exposure to addictive drugs causes neuroadaptive changes in cortico-limbic-striatal circuits that may underlie alterations in incentive-motivational processes and reward-related learning. Such drug-induced alterations may be relevant to drug addiction because enhanced incentive motivation and increased control over behavior by drug-associated stimuli may contribute to aspects of compulsive drug-seeking and drug-taking behaviors. This study investigated the consequences of repeated nicotine treatment on the acquisition and performance of Pavlovian discriminative approach behavior, a measure of reward-related learning, in male rats. Water-restricted rats were trained to associate a compound conditioned stimulus (tone+light) with the availability of water (the unconditioned stimulus) in 15 consecutive daily sessions. In separate experiments, rats were repeatedly treated with nicotine (0.35 mg/kg, s.c.) either (1) prior to the onset of training, (2) after each daily training session was completed (ie postsession injections), or (3) received nicotine both before the onset of training as well as after each daily training session. In this study, all nicotine treatment schedules increased Pavlovian discriminative approach behavior and, thus, prior repeated exposure to nicotine, repeated postsession nicotine injections, or both, facilitated reward-related learning.

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

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.