Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

Formalizing planning and information search in naturalistic decision-making.

Decisions made by mammals and birds are often temporally extended. They require planning and sampling of decision-relevant information. Our understanding of such decision-making remains in its infancy compared with simpler, forced-choice paradigms. However, recent advances in algorithms supporting planning and information search provide a lens through which we can explain neural and behavioral data in these tasks. We review these advances to obtain a clearer understanding for why planning and curiosity originated in certain species but not others; how activity in the medial temporal lobe, prefrontal and cingulate cortices may support these behaviors; and how planning and information search may complement each other as means to improve future action selection.

The successor representation in human reinforcement learning.

Theories of reward learning in neuroscience have focused on two families of algorithms thought to capture deliberative versus habitual choice. 'Model-based' algorithms compute the value of candidate actions from scratch, whereas 'model-free' algorithms make choice more efficient but less flexible by storing pre-computed action values. We examine an intermediate algorithmic family, the successor representation, which balances flexibility and efficiency by storing partially computed action values: predictions about future events. These pre-computation strategies differ in how they update their choices following changes in a task. The successor representation's reliance on stored predictions about future states predicts a unique signature of insensitivity to changes in the task's sequence of events, but flexible adjustment following changes to rewards. We provide evidence for such differential sensitivity in two behavioural studies with humans. These results suggest that the successor representation is a computational substrate for semi-flexible choice in humans, introducing a subtler, more cognitive notion of habit.

Valence-dependent influence of serotonin depletion on model-based choice strategy.

Human decision-making arises from both reflective and reflexive mechanisms, which underpin goal-directed and habitual behavioural control. Computationally, these two systems of behavioural control have been described by different learning algorithms, model-based and model-free learning, respectively. Here, we investigated the effect of diminished serotonin (5-hydroxytryptamine) neurotransmission using dietary tryptophan depletion (TD) in healthy volunteers on the performance of a two-stage decision-making task, which allows discrimination between model-free and model-based behavioural strategies. A novel version of the task was used, which not only examined choice balance for monetary reward but also for punishment (monetary loss). TD impaired goal-directed (model-based) behaviour in the reward condition, but promoted it under punishment. This effect on appetitive and aversive goal-directed behaviour is likely mediated by alteration of the average reward representation produced by TD, which is consistent with previous studies. Overall, the major implication of this study is that serotonin differentially affects goal-directed learning as a function of affective valence. These findings are relevant for a further understanding of psychiatric disorders associated with breakdown of goal-directed behavioural control such as obsessive-compulsive disorders or addictions.

Motivation and value influences in the relative balance of goal-directed and habitual behaviours in obsessive-compulsive disorder.

Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted.

Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI.

BACKGROUND: The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. METHODS: Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome. RESULTS: K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). CONCLUSIONS: This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.

Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review.

BACKGROUND: Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma. METHODS: We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy. RESULTS: Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2-8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules <1.5 cm to correlate positively with PREFS (P=0.070) but not PRS (P=0.49). Chemotherapy at first relapse was not associated with PREFS or PRS. CONCLUSION: Approximately half of the patients with recurrent osteosarcoma presenting as a single pulmonary metastasis more than 1 year after diagnosis were long-term survivors. Metastasectomy was the primary treatment; chemotherapy did not add benefit.

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.

Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer.

BACKGROUND: Little information is available about the diagnosis and management of acute methotrexate (MTX)-induced encephalopathy. METHODS: We reviewed clinical and magnetic resonance imaging (MRI) [including diffusion-weighted imaging (DWI)] characteristics of this complication in pediatric cancer patients treated from 2000 to 2006. RESULTS: Six of 754 (0.8%) patients with leukemia or lymphoma and 2 of 44 (4.5%) with bone sarcoma experienced acute encephalopathy within 2 weeks (median, 7.5 days) after receiving high-dose i.v. and/or intrathecal MTX. The signs and symptoms varied at presentation and during episodes: hemiparesis (eight patients, alternating from side to side in four), dysphasia (six), confusion/emotionality (six), headache (three), choreoathetosis (two), and seizure (two). All patients recovered after 1-7 days (median, 5.5 days). DWI revealed restricted diffusion in anatomic brain regions associated with the symptoms; changes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging were consistently less marked. After recovery, DWI findings were normal but T2 and/or FLAIR imaging usually showed residual abnormalities. CONCLUSIONS: Acute MTX toxicity often manifests as fluctuating neurologic symptoms with alternating hemispheric involvement. Restricted diffusion on DWI is a reliable early sign of acute MTX encephalopathy and resolves as clinical status improves, despite the persistence of subtle abnormalities on MRI.

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies.

Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3beta inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3beta inhibitors could represent an adjunct therapy for this disease.

Tumor size as a predictor of outcome in pediatric non-metastatic osteosarcoma of the extremity.

BACKGROUND: Better predictors of outcome would allow improved risk-adapted therapy for pediatric nonmetastatic osteosarcoma of the extremity. We investigated the predictive value of MR imaging-based measures of absolute and relative tumor size and volume at the time of diagnosis. We also assessed the relation of tumor size to age and histologic response. METHODS: We retrospectively abstracted demographic, treatment history, and outcome information of patients treated on a single institutional protocol. A single pediatric oncologic radiologist manually measured each primary lesion and the affected native bone in three dimensions on MR images obtained at the time of diagnosis. Eight parameters of tumor size were analyzed for their value in predicting overall survival (OS) and event-free survival (EFS). RESULTS: The median age of the 42 patients was 13.5 years (range: 5.9-18.7 years); 50% were female and 74% were Caucasian. Absolute tumor volume was an important predictor of OS (P < 0.05); absolute tumor depth (analyzed as a continuous variable) was a significant predictor of OS (P = 0.018) and EFS (P = 0.036). Relative measures of tumor size were not found to predict outcome. No relation was seen between tumor size and histologic response. CONCLUSIONS: Absolute tumor size at the time of diagnosis is significantly predictive of OS and EFS. If validated in a larger study, this indicator should be used in the design of risk-adapted treatment protocols for osteosarcoma.

Long term potentiation varies with layer in rat visual cortex.

Long term potentiation (LTP) in various layers of rat visual cortex was studied in 90 cells with visually identified, whole-cell recordings. LTP was induced in layer II/III, layer V or layer VI with theta burst stimulation (TBS), but was not observed in layer IV. In the presence of a NMDA antagonist, D-AP5, in the bath solution, potentiation was blocked in layer II/III, some depression was seen in layer V, and potentiation still remained in layer VI. After addition of a specific mGluR1 antagonist, LY367385, to the bath solution, LTP was reduced in layer II/III and layer V, and was blocked in layer VI. After a specific mGluR5 antagonist, MPEP was applied in the bath solution, LTP was enhanced in layer VI, and blocked in layer V. We conclude that: (1) LTP in layer VI is different from other layers, depending on mGluR1, but not NMDA receptors. (2) In layer II/III, LTP is NMDA-dependent and is not blocked by group I mGluR antagonists. (3) LTP in layer V is both NMDA receptor and mGluR5 receptor-dependent. (4) LTP was not induced in layer IV with TBS.

Activation of Group III mGluRs increases the activity of neurons in area 17 of the cat.

Activation of Group III metabotropic glutamate receptors (mGluRs) by L(+)-2-amino-4-phosphonobutyric acid (L-AP4) has different effects on in vitro slice preparations of visual cortex (Jin & Daw, 1998) as compared with in vivo recordings from somatosensory cortex (Wan & Cahusac, 1995). To investigate the role of Group III mGluRs in the cat visual cortex, in vivo recordings were made of neurons in area 17 of the visual cortex of kittens and adult cats at different ages and the effect of iontophoretic application of L-AP4 (100 mM) was examined. Application of L-AP4 resulted in an increase of the spontaneous activity and visual response of neurons to visual stimulation, the former more than the latter. The effect of L-AP4 was greatest at 3-5 weeks of age with the effect on the visual response declining more rapidly than the effect on spontaneous activity. Consistent with work in rat cortex (Jin & Daw, 1998), the effect of L-AP4 was significantly greater in upper and lower layers than in middle layers. Whole-cell in vitro recordings from slices of rat visual cortex indicated that L-AP4 (50 mM) did not increase the number of spikes elicited by increasing levels of current injections. These results confirm that L-AP4 increases activity in vivo and reasons for the discrepancy with the in vitro results are discussed.

A schedule of recombinant Mpl ligand highly effective at preventing lethal myelosuppression in mice given carboplatin and radiation.

OBJECTIVE: To determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression. METHODS: First, we determined whether recombinant Mpl ligand (Mpl-L) has a priming effect on thrombopoiesis in normal mice. Mice were given pegylated recombinant murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF) intravenously as a single injection or as two injections separated by intervals of 1 to 10 days. Second, we examined the scheduling of PEG-rmMGDF that would most effectively reduce thrombocytopenia in mice given a lethal myelosuppressive regimen (80 mg/kg carboplatin + 750 R Cs-137 total-body irradiation). RESULTS: In normal mice, peak platelet count with a 4-day to 8-day interval between PEG-rmMGDF injections was significantly higher than that with single injection. This priming effect was optimal with a 4-day interval between injections. In the lethal myelosuppression model, all mice given intravenous PEG-rmMGDF as a single injection on day 0 or as two injections (on days -4 and 0 or on days 0 and 4) survived; PEG-rmMGDF on day 0 was given immediately after the myelosuppressive regimen. In contrast, all mice given a single intravenous PEG-rmMGDF injection on day -4 or day 4 died. Two PEG-rmMGDF injections given on days -4 and 0 enhanced hematopoietic recovery more than did a single injection on day 0 or two injections on days 0 and 4. CONCLUSION: Mpl-L administration immediately after lethal carboplatin and radiation prevents death and enhances hematopoietic recovery in mice; this protective effect is further enhanced by a priming Mpl-L dose given 4 days before the myelosuppressive regimen.

Developmental changes and ocular dominance plasticity in the visual cortex.

There is a shift in ocular dominance of cells recorded in the visual cortex which occurs after closure of one eye during a critical period lasting from eye opening to puberty. Three criteria distinguish factors that are crucially related to ocular dominance plasticity: 1) the factor should be more concentrated or active at the peak of the critical period; 2) dark rearing, which makes the cortex less plastic early in the critical period and more plastic late in the critical period, should have a similar effect on the factor, and 3) antagonists or inhibitors of the factor should block ocular dominance plasticity. The second criterion can be used to distinguish activity-related factors that may simply increase or decrease with development from factors that are more specifically related to plasticity. Two factors currently fulfill these criteria, namely N-methyl-D-asparate (NMDA) receptors and protein kinase A (PKA). PKA and NMDA receptors are linked through calcium, since calcium influx through the NMDA receptor increases the production of cyclic AMP by calcium-sensitive adenylate cyclase, which in turn activates PKA. PKA is specifically involved, since protein kinase G and protein kinase C antagonists do not inhibit ocular dominance plasticity. However, NMDA agonists and PKA activators by themselves are not known to bring back plasticity. Thus there may be two or more pathways for ocular dominance plasticity acting in parallel with each other: for example, metabotropic glutamate receptors may act in parallel with NMDA receptors to change calcium levels within the cell.

Effect of the group I metabotropic glutamate agonist DHPG on the visual cortex.

Metabotropic glutamate receptors have a variety of effects in visual cortex that depend on the age of the animal, the layer of the cortex, and the group of the receptor. Here we describe these effects for group I receptors, using both in vivo and in vitro preparations. The metabotropic group I glutamate receptor agonist 3,5 dihydroxyphenylglycine (DHPG) potentiates the responses to N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in slices of rat visual cortex. It also increases, initially, the visual response in the cat visual cortex. Both these effects are largest at 3-4 wk of age and decline to insignificance by 10 wk of age. Both are also largest in lower layers of cortex, which explains why the facilitatory effects found with the general metabotropic glutamate agonist 1S,3R aminocyclopentane-1,3-dicarboxylic acid (ACPD) are observed only in lower layers. Prolonged application of DHPG in the cat visual cortex, after the initial excitatory effect, produces depression. We also found that DHPG facilitates the NMDA response in fast-spiking cells, which are inhibitory, providing a partial explanation for this. Thus there are multiple effects of group I metabotropic glutamate receptors, which vary with layer and age in visual cortex.

Circulating concentrations of IGF-I and IGFBP-3 are not predictive of incidence or clinical behavior of pediatric osteosarcoma.

BACKGROUND: Preclinical studies suggest a role of insulin-like growth factor-1 (IGF-1) in the proliferation of osteosarcoma cells in vivo. The purpose of this study is to address the relationship between serum levels of IGF-1 and its binding protein (IGFBP-3), and the clinical behavior and outcome of osteosarcoma in children, and to compare those levels present in osteosarcoma patients with a normal population. PROCEDURE: Serum IGF-1 and IGFBP-3 levels were determined by ELISA in 37 patients with osteosarcoma treated on the same treatment regimen (OS-91 protocol), and who had available serum samples from diagnosis. IGF-1 and IGFBP-3 levels were compared with those previously established in the normal population, matched for age and gender, and were correlated with the presence of metastatic disease, histologic response to preoperative chemotherapy, and event-free survival. RESULTS: In osteosarcoma patients the median IGF-1 level was 275 ng/ml (range, 105-613) and the median IGFBP-3 level was 3.4 mg/L (range, 2.3-5.1). IGF-1 levels differed from those in the normal population (P = 0.029); although we anticipated higher IGF-1 levels than normal children, 68% of observed standardized scores were less than 0. Furthermore, IGF-1 or IGFBP-3 levels failed to correlate with the presence of metastatic disease (P = 0.12 and P = 0.12, respectively), histologic response (Rosen-Huvos grades 3/4 vs. grades 1/2) (P = 0.95 and P = 0.71, respectively), or event-free survival (P = 0.52 and P = 0.41, respectively). There was a strong association observed between IGF-1 and IGFBP-3 levels (P < 0.001). CONCLUSIONS: In this retrospective study of 37 patients, we found that circulating levels of IGF-1 and IGFBP-3 are not predictive of the development or clinical characteristics of pediatric osteosarcoma. However, further studies on a larger patient population should be performed in order to investigate this relationship.

Metastatic osteosarcoma to the liver after treatment for synovial sarcoma: a case report.

Metastatic osteosarcoma most commonly affects the lungs and other bones. Hepatic metastasis at the time of diagnosis is extremely rare. A 14-year-old boy with synovial sarcoma of the left popliteal fossa was treated with surgical resection, radiotherapy for microscopic residual disease, and 1 year of chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin). Approximately 10 years after the initial diagnosis, a secondary osteosarcoma developed in the left proximal tibia. Computed tomography at presentation showed bilateral pulmonary metastases and large ossified nodules in the liver that demonstrated abnormal avidity on 99mTc MDP bone scan indicating hepatic metastasis. Despite chemotherapy (cisplatin, ifosfamide, high-dose methotrexate, and dacarbazine), the patient died of progressive disease 4 months after the diagnosis of the second cancer. Hepatic metastasis was found at the time of diagnosis of a secondary osteosarcoma and manifested as ossified nodules. The risk of radiation-induced osteosarcoma should always be considered in decisions about treatment for soft-tissue sarcoma.

A fast and simple screening test to search for specific inhibitors of the plasma membrane calcium pump.

No specific inhibitors of the plasma membrane Ca(2+) pump have been found to date, limiting research on the particular contribution of this pump to the Ca(2+) homeostasis of animal cells. The search for Ca(2+) pump inhibitors may have been hampered by the lack of an efficient screening method to measure pump activity that would provide an alternative to the lengthy and costly adenosine triphosphatase or Ca(2+)-flux measurements. We propose here a novel screening method in which Ca(2+) pump inhibition is translated into easily measurable cell dehydration. Intact human red cells, suspended in Ca(2+)-containing, low-K(+) buffers were exposed to sequential additions of (1) ionophore A23187 (t = 0) to load the cells with Ca(2+); (2) CoCl(2) (t = 1 minute) to block ionophore-mediated Ca(2+) transport and to allow complete extrusion of the Ca(2+) load by the pump in less than 5 minutes; and (3) NaSCN (t = 6 minutes) to accelerate cell dehydration via Ca(2+)-sensitive K(+) channels when the Ca(2+) load is retained as a result of Ca(2+) pump inhibition. Samples were taken at 10 to 25 minutes after ionophore addition and delivered into hypotonic media containing about 45 mmol/L NaCl. Non-dehydrated cells-with normal, uninhibited pumps-instantly underwent lysis, whereas dehydrated cells-with inhibited pumps-resisted lysis, resulting in translucent or opaque samples, respectively, which were quantifiable by light-absorption measurements. Vanadate was used as a test substance to assess the effect of putative pump inhibitors. This method offers a cost-efficient and easily automated alternative for testing large numbers of natural or synthetic agents.

Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex.

Visual experience during a critical period early in postnatal development can change connections within mammalian visual cortex. In a kitten at the peak of the critical period (approximately P28-42), brief monocular deprivation can lead to complete dominance by the open eye, an ocular dominance shift. This process is driven by activity from the eyes, and depends on N-methyl-D-aspartate (NMDA) receptor activation. The components of the intracellular signaling cascade underlying these changes have not all been identified. Here we show that inhibition of protein kinase A (PKA) by Rp-8-Cl-cAMPS blocks ocular dominance shifts that occur following monocular deprivation early in the critical period. Inhibition of protein kinase G by Rp-8-Br-PET-cGMPS had no effect, indicating a specificity for the PKA pathway. Enhancement of PKA activity late in the critical period with Sp-8-Cl-cAMPS did not increase plasticity. PKA is a necessary component of the pathway leading to cortical plasticity during the critical period.