Modified natural cycle versus controlled ovarian hyperstimulation IVF: a cost-effectiveness evaluation of three simulated treatment scenarios.

STUDY QUESTION: Can modified natural cycle IVF or ICSI (MNC) be a cost-effective alternative for controlled ovarian hyperstimulation IVF or ICSI (COH)? SUMMARY ANSWER: The comparison of simulated scenarios indicates that a strategy of three to six cycles of MNC with minimized medication is a cost-effective alternative for one cycle of COH with strict application of single embryo transfer (SET). WHAT IS KNOWN ALREADY: MNC is cheaper per cycle than COH but also less effective in terms of live birth rate (LBR). However, strict application of SET in COH cycles reduces effectiveness and up to three MNC cycles can be performed at the same costs as one COH cycle. STUDY DESIGN, SIZE, DURATION: The cost-effectiveness of MNC versus COH was evaluated in three simulated treatment scenarios: three cycles of MNC versus one cycle of COH with SET or double embryo transfer (DET) and subsequent transfer of cryopreserved embryos (Scenario 1); six cycles of MNC versus one cycle of COH with strictly SET and subsequent transfer of cryopreserved embryos (Scenario 2); six cycles of MNC with minimized medication (hCG ovulation trigger only) versus one cycle of COH with SET or DET and subsequent transfer of cryopreserved embryos (Scenario 3). We used baseline data obtained from two retrospective cohorts of consecutive patients (2005-2008) undergoing MNC in the University Medical Center Groningen (n = 499, maximum six cycles per patient) or their first COH cycle with subsequent transfer of cryopreserved embryos in the Academic Medical Center Amsterdam (n = 392). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 1994 MNC cycles (958 MNC-IVF and 1036 MNC-ICSI) and 392 fresh COH cycles (one per patient, 196 COH-IVF and 196 COH-ICSI) with subsequent transfer of cryopreserved embryos (n = 72 and n = 94 in MNC and COH cycles, respectively) in ovulatory, subfertile women <36 years of age served as baseline for the three simulated scenarios. To compare the scenarios, the incremental cost-effectiveness ratio (ICER) was calculated, defined as the ratio of the difference in IVF costs up to 6 weeks postpartum to the difference in LBR. Live birth was the primary outcome measure and was defined as the birth of at least one living child after a gestation of ≥25 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: In the baseline data, MNC was not cost-effective, as COH dominated MNC with a higher cumulative LBR (27.0 versus 24.0%) and lower cost per patient (€3694 versus €5254). The simulations showed that in scenario 1 three instead of six cycles lowered the costs of MNC to below the level of COH (€3390 versus €3694, respectively), but also lowered the LBR per patient (from 24.0 to 16.2%, respectively); Scenario 2: COH with strict SET was less effective than six cycles MNC (LBR 17.5 versus 24.0%, respectively), but also less expensive per patient (€2908) than MNC (€5254); Scenario 3: improved the cost-effectiveness of MNC but COH still dominated MNC when medication was minimized in terms of costs, i.e. €855 difference in favor of COH and 3% difference in LBR in favor of COH (ICER: €855/-3.0%). LIMITATIONS, REASONS FOR CAUTION: Owing to the retrospective nature of the study, the analyses required some assumptions, for example regarding the costs of pregnancy and delivery, which had to be based on the literature rather than on individual data. Furthermore, costs of IVF treatment were based on tariffs and not on actual costs. Although this may limit the external generalizability of the results, the limitations will influence both treatments equally, and would therefore not bias the comparison of MNC versus COH. WIDER IMPLICATIONS OF THE FINDINGS: The combined results suggest that MNC with minimized medication might be a cost-effective alternative for COH with strict SET. The scenarios reflect realistic alternatives for daily clinical practice. A preference for MNC depends on the willingness to trade off effectiveness in terms of LBR against the benefits of a milder stimulation regimen, including a very low rate of multiple pregnancies and hyperstimulation syndrome and ensuing lower costs per live birth. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from Merck Serono and Ferring Pharmaceuticals. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Stochastic parametrizations and model uncertainty in the Lorenz '96 system.

Simple chaotic systems are useful tools for testing methods for use in numerical weather simulations owing to their transparency and computational cheapness. The Lorenz system was used here; the full system was defined as 'truth', whereas a truncated version was used as a testbed for parametrization schemes. Several stochastic parametrization schemes were investigated, including additive and multiplicative noise. The forecasts were started from perfect initial conditions, eliminating initial condition uncertainty. The stochastically generated ensembles were compared with perturbed parameter ensembles and deterministic schemes. The stochastic parametrizations showed an improvement in weather and climate forecasting skill over deterministic parametrizations. Including a temporal autocorrelation resulted in a significant improvement over white noise, challenging the standard idea that a parametrization should only represent sub-gridscale variability. The skill of the ensemble at representing model uncertainty was tested; the stochastic ensembles gave better estimates of model uncertainty than the perturbed parameter ensembles. The forecasting skill of the parametrizations was found to be linked to their ability to reproduce the climatology of the full model. This is important in a seamless prediction system, allowing the reliability of short-term forecasts to provide a quantitative constraint on the accuracy of climate predictions from the same system.

Analysis of biomarker expression in severe endometriosis and determination of possibilities for targeted intraoperative imaging.

OBJECTIVE: To evaluate the expression of biomarkers in endometriotic tissue in order to determine the most promising molecules for targeted intraoperative imaging. METHODS: Tissue samples were obtained from 18 patients with endometriosis. The intensity and pattern of expression of the following biomarkers were assessed by immunohistochemistry: C-X-C chemokine receptor type 4 (CXCR4), epithelial cell adhesion molecule (EpCAM), estrogen receptor (ER), folate receptor α (FR-α), hypoxia-inducible factor 1-α (HIF-1α), progesterone receptor (PR), and vascular endothelial growth factor A (VEGF-A). The Target Selection Criteria scoring system was used to select the most promising biomarkers for intraoperative imaging. RESULTS: Expression of CXCR4, EpCAM, ER, PR, and VEGF-A was scored as strong in endometriotic epithelium. Expression of FR-α was detected in 94.4% of samples, whereas HIF-1α was expressed in just 5.6% of samples. Of note, CXCR4, ER, and VEGF-A were also expressed in surrounding healthy tissue, thus reducing the target-to-background ratio. CONCLUSION: Of the 7 biomarkers assessed in the present study, EpCAM, FR-α, and VEGF-A seem the most promising for targeted intraoperative imaging of endometriosis.

Parenthood in survivors of Hodgkin lymphoma: an EORTC-GELA general population case-control study.

PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.

Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study.

PURPOSE: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. PATIENTS AND METHODS: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. RESULTS: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF. CONCLUSION: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.

The European Society of Human Reproduction and Embryology guideline for the diagnosis and treatment of endometriosis: an electronic guideline implementability appraisal.

BACKGROUND: Clinical guidelines are intended to improve healthcare. However, even if guidelines are excellent, their implementation is not assured. In subfertility care, the European Society of Human Reproduction and Embryology (ESHRE) guidelines have been inventoried, and their methodological quality has been assessed. To improve the impact of the ESHRE guidelines and to improve European subfertility care, it is important to optimise the implementability of guidelines. We therefore investigated the implementation barriers of the ESHRE guideline with the best methodological quality and evaluated the used instrument for usability and feasibility. METHODS: We reviewed the ESHRE guideline for the diagnosis and treatment of endometriosis to assess its implementability. We used an electronic version of the guideline implementability appraisal (eGLIA) instrument. This eGLIA tool consists of 31 questions grouped into 10 dimensions. Seven items address the guideline as a whole, and 24 items assess the individual recommendations in the guideline. The eGLIA instrument identifies factors that influence the implementability of the guideline recommendations. These factors can be divided into facilitators that promote implementation and barriers that oppose implementation. A panel of 10 experts from three European countries appraised all 36 recommendations of the guideline. They discussed discrepancies in a teleconference and completed a questionnaire to evaluate the ease of use and overall utility of the eGLIA instrument. RESULTS: Two of the 36 guideline recommendations were straightforward to implement. Five recommendations were considered simply statements because they contained no actions. The remaining 29 recommendations were implementable with some adjustments. We found facilitators of the guideline implementability in the quality of decidability, presentation and formatting, apparent validity, and novelty or innovation of the recommendations. Vaguely defined actions, lack of facilities, immeasurable outcomes, and inflexibility within the recommendations formed barriers to implementation. The eGLIA instrument was generally useful and easy to use. However, assessment with the eGLIA instrument is very time-consuming. CONCLUSIONS: The ESHRE guideline for the diagnosis and treatment of endometriosis could be improved to facilitate its implementation in daily practice. The eGLIA instrument is a helpful tool for identifying obstacles to implementation of a guideline. However, we recommend a concise version of this instrument.

[IVF in a modified natural cycle]. / Ivf in de gemodificeerde natuurlijke cyclus.

In vitro fertilisation (IVF) usually involves controlled ovarian stimulation (COS). There is now increasing emphasis on methods that make IVF safer and more patient-friendly. Modified natural cycle (MNC)-IVF is an example of this. In MNC-IVF spontaneous ovulation is prevented with a minimal amount of hormones and spontaneous monofollicular growth is supported. As a result, there is no risk of ovarian hyperstimulation syndrome, and the risk of a multiple pregnancy is low. There is a 9.1% chance of a pregnancy after one MNC-cycle and the cumulative pregnancy rate after a maximum of 6 MNC-IVF cycles is 33.4%. The cumulative results of a maximum of 6 MNC-IVF cycles are comparable to those of the first COS-IVF treatment cycle including transfer of cryopreserved embryos produced as a result of the treatment (33.4% versus 37.7%). The risk of a twin pregnancy following MNC-IVF is 0.1%, and 18.3% following COS-IVF. This means that MNC-IVF is a good alternative for COS-IVF.

Fertility preservation after chemotherapy for Hodgkin lymphoma.

Treatment for Hodgkin lymphoma can negatively affect fertility. This review summarizes data on fertility after chemotherapy in adult patients. Alkylating chemotherapy, especially if containing procarbazine and/or cyclophosphamide, is most harmful to gonadal functioning. Alkylating regimens cause prolonged azoospermia in 90-100% of men and ovarian failure in 5-25% of women under the age of 30. Non-alkylating chemotherapy, like ABVD, is much less harmful: one-third of male patients develop transient azoospermia, and almost no female patients experience ovarian failure. Age is an important factor for women: females over 30 years have a much higher risk of acute ovarian failure. However, with long-term follow-up the cumulative risk of menopause before the age of 40 becomes the same irrespective of treatment age. In males, semen cryopreservation before start of treatment should be offered to all (post)pubertal patients. For females with a partner, IVF followed by embryo cryopreservation is a widely available method, but this necessitates postponement of lymphoma therapy for at least a month. Oocyte cryopreservation and ovarian tissue cryopreservation are experimental techniques showing great promise. GnRH-analogues are being investigated as possible means to preserve fertility in women, but effectiveness has not yet been proven conclusively.

Perinatal outcome in singletons after modified natural cycle IVF and standard IVF with ovarian stimulation.

OBJECTIVE: Singletons born after IVF treatment are at risk for adverse pregnancy outcome, the cause of which is unknown. The aim of the present study was to investigate the influence of ovarian stimulation on perinatal outcome. STUDY DESIGN: In this single-centre retrospective study, perinatal outcome of singleton pregnancies resulting from IVF treatment with (n=106) and without ovarian stimulation (n=84) were compared. For IVF without ovarian stimulation, a modified natural cycle protocol was used. RESULTS: No differences were found in pregnancy duration, proportion of prematurity and proportion of low birth weight. Mean birth weight of modified natural cycle vs standard IVF singletons was 3485 (+/-527) vs 3218 (+/-670)g; P=0.003. After adjustment for prognostic factors by linear regression analysis, the difference in birth weight remaining was 134 g; P=0.045. CONCLUSIONS: Birth weights of modified natural cycle IVF singletons found in this study are higher than standard IVF singletons, suggesting that ovarian stimulation may be a causative factor in the occurrence of low birth weight in standard IVF.

Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization.

OBJECTIVE: To study the implantation potential of unselected embryos derived from modified natural cycle IVF according to their morphological characteristics. DESIGN: Cohort study. SETTING: Academic department of reproductive medicine. PATIENT(S): A series of 449 single embryo transfers derived from modified natural cycle IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ongoing implantation rate according to embryo characteristics. RESULT(S): The best implantation was found in embryos with 4 and 8 cells on day 2 and 3 respectively,

Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma. PATIENTS AND METHODS: Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression. RESULTS: The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome. CONCLUSION: Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.

Early cessation of triptorelin in in vitro fertilization: a double-blind, randomized study.

OBJECTIVE: To compare the efficacy of two early cessation protocols of triptorelin treatment in controlled ovarian hyperstimulation with the conventional long protocol in in vitro fertilization/intracytoplasmic sperm injection. DESIGN: A double-blind, randomized, multicenter study. SETTING: Three Dutch hospitals. PATIENT(S): One hundred seventy-eight women randomized to one of three treatment groups at the start of stimulation. INTERVENTION(S): Midluteally started triptorelin administration was continued until the first day of hMG treatment (group S), or up to and including the fourth day of hMG treatment (group M) or the day of hCG injection (group L). MAIN OUTCOME MEASURE(S): Occurrence of a premature LH surge. RESULT(S): One premature LH surge was observed in group M but not in groups S and L. Both early cessation protocols (S and M) are at least as effective as the long protocol (L) with regard to the number of oocytes (11.1 and 10.3 vs. 9.3), number of embryos (7.3 and 6.5 vs. 5.5), and ongoing pregnancy rate (28% and 24% vs. 21%). CONCLUSION(S): Early cessation of triptorelin on day 1 of hMG treatment in a midluteally started IVF protocol is as effective as the traditional long protocol in preventing a premature LH surge and results in similar fertility effects.

A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse.

Fragile X Syndrome is the most common form of inherited mental retardation. It is also known for having a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always caused by inactivation of the X-linked FMR1 gene. A single knockout mouse model, fmr1-tm1Cgr, exists. In this report we further characterize the cognitive and behavioral phenotype of the fmr1-tm1Cgr Fragile X mouse through the use of F1 hybrid mice derived from two inbred strains (FVB/NJ and C57BL/6J). Use of F1 hybrids allows focus on the effects of the fmr1-tm1Cgr allele with reduced influence from recessive alleles present in the parental inbred strains. We find that the cognitive phenotype of fmr1-tm1Cgr mice, including measures of working memory and learning set formation that are known to be seriously impacted in humans with Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any fmr1-tm1Cgr cognitive deficit is surprisingly mild or absent. There is, however, clear support presented for a robust audiogenic seizure phenotype in all strains tested, as well as increased entries into the center of an open field. Finally, a molecular examination of the fmr1-tm1Cgr mouse shows that, contrary to common belief, it is not a molecular null. Implications of this finding for interpretation of the phenotype are discussed.

Neuronal activity in the nucleus accumbens is necessary for performance-related increases in cortical acetylcholine release.

In vivo microdialysis was used to determine the necessity of neuronal activity in the nucleus accumbens (NAC) for task-induced increases in cortical acetylcholine (ACh) efflux. Rats were trained in a behavioral task in which they were required to perform a defined number of licks of a citric acid solution in order to gain access to a palatable, cheese-flavored food. Upon reaching a consistent level of performance, rats were implanted with microdialysis cannula in the medial prefrontal cortex (mPFC) and either the ipsilateral shell of the NAC or in the dorsal striatum (STR; control site). Dialysis samples from the mPFC were analyzed for ACh concentrations and samples from the NAC were analyzed for dopamine (DA) concentrations. Performance in the task was associated with increases in both ACh efflux in the cortex (150-200%) and DA efflux in the NAC (50-75%). These increases were blocked by administration of tetrodotoxin (TTX; 1.0 microM) via reverse dialysis into the NAC. Administration of TTX into the dorsal STR control site was ineffective in blocking performance-associated increases in cortical ACh. The D2 antagonist sulpiride (10 or 100 microM) administered into the NAC via reverse dialysis was ineffective in blocking increases in cortical ACh efflux. The present data reveal that neuronal activity in the NAC is necessary for behaviorally induced increases in cortical ACh efflux and that this activation does not require increases in D2 receptor activity.

Differential cortical acetylcholine release in rats performing a sustained attention task versus behavioral control tasks that do not explicitly tax attention.

The present study used microdialysis techniques to compare acetylcholine release in the frontoparietal cortex of rats performing in a task requiring sustained attention with that of rats performing in two control procedures. The two control procedures were a fixed-interval 9-s schedule of reinforcement assessing primarily the effects of operant responding and comparable reward rates, and an operant procedure designed to test the effects of lever extension to prompt responding. These two control procedures involved comparable sensory-motor and motivational variables to those of the sustained attention task, but did not explicitly tax attentional processes. Performance of the sustained attention task was associated with a significant increase in cortical acetylcholine efflux, reaching a maximum of nearly 140%. Performance of the two control procedures was associated with significantly smaller (approximately 50%) increases in cortical acetylcholine release. This robust dissociation between attentional and control performance-associated increases in cortical acetylcholine release resulted, in part, from the elimination of the pre-task transfer of the animals into the operant chambers and the associated increases in acetylcholine release observed in previous studies. The present results support the hypothesis that demands on attentional performance, as opposed to the frequency of lever pressing, reward delivery and other task-related variables, selectively activate the basal forebrain corticopetal cholinergic system.

Dissociations between the effects of intra-accumbens administration of amphetamine and exposure to a novel environment on accumbens dopamine and cortical acetylcholine release.

Previous research has demonstrated an interaction between the effects of amphetamine and exposure to a novel environment on the activity of neurons in the nucleus accumbens. Given a model in which these accumbens efferents gate the excitability of basal forebrain cholinergic corticopetal neurons, the administration of intra-accumbens amphetamine was hypothesized to potentiate the increase in cortical acetylcholine produced by introduction to a novel environment. Dual probe microdialysis revealed no synergistic interactions between exposure to a novel environment and amphetamine on nucleus accumbens dopamine or cortical acetylcholine efflux. This finding indicates that exposure to a novel environment failed to recruit the telencephalic activation of the nucleus accumbens presumably necessary to reveal modulatory effects of accumbens dopaminergic transmission on cortical acetylcholine release.

Amphetamine-stimulated cortical acetylcholine release: role of the basal forebrain.

Systemic administration of amphetamine results in increases in the release of acetylcholine in the cortex. Basal forebrain mediation of this effect was examined in three experiments using microdialysis in freely-moving rats. Experiment 1 examined whether dopamine receptor activity within the basal forebrain was necessary for amphetamine-induced increase in cortical acetylcholine by examining whether intra-basalis perfusion of dopamine antagonists attenuates this increase. Systemic administration of 2.0 mg/kg amphetamine increased dopamine efflux within the basal forebrain nearly 700% above basal levels. However, the increase in cortical acetylcholine efflux following amphetamine administration was unaffected by intra-basalis perfusions of high concentrations of D1- (100 microM SCH 23390) or D2-like (100 microM sulpiride) dopamine receptor antagonists. Experiments 2 and 3 determined whether glutamatergic or GABAergic local modulation of the excitability of the basal forebrain cholinergic neurons influences the ability of systemic amphetamine to increase cortical acetylcholine efflux. In Experiment 2, perfusion of kynurenate (1.0 mM), a non-selective glutamate receptor antagonist, into the basal forebrain attenuated the increase in cortical acetylcholine produced by amphetamine. Experiment 3 revealed that positive modulation of GABAergic transmission by bilateral intra-basalis infusion of the benzodiazepine receptor agonist chlordiazepoxide (40 microg/hemisphere) also attenuated the amphetamine-stimulated increase in cortical acetylcholine efflux. These data suggest that amphetamine increases cortical acetylcholine release via a complex neuronal network rather than simply increasing basal forebrain D1 or D2 receptor activity.

Olfactory conditioning facilitates diet transition in human infants.

We evaluated whether Pavlovian conditioning methods could be used to increase the ingestion of non-preferred solutions by formula-fed human infants. In baseline measures, 5-7 month old infants sucked less frequently and consumed less water than regular formula. During a 3-day olfactory conditioning period, parents placed a small scented disk, the conditioned stimulus, on the rim of their infants' formula bottle at every feeding. Following this training, infants' responses to water were tested when their water bottles had a disk scented with the training odor, a novel odor, or no odor. Infants tested with the training odor sucked more frequently and consumed significantly more water than they had at baseline. Infants tested with no odor or a novel odor consumed water at or below baseline levels. These data demonstrate that olfactory conditioning can be used to enhance ingestion in infants and suggest that such methods may be useful for infants experiencing difficulty when making transitions from one diet to another.

Systemic and intra-accumbens administration of amphetamine differentially affects cortical acetylcholine release.

The present experiments tested the hypothesis that the amphetamine-induced increase in dopamine release in the nucleus accumbens represents a necessary and sufficient component of the ability of systemically administered amphetamine to stimulate cortical acetylcholine release. The effects of systemic or intra-accumbens administration of amphetamine on accumbens dopamine release and cortical acetylcholine release were assessed simultaneously in awake animals equipped with dialysis probes inserted into the shell of the nucleus accumbens and the medial prefrontal cortex. Additionally, the ability of intra-accumbens administration of dopamine D(1) and D(2) receptor antagonists to attenuate the effects of systemic amphetamine on cortical acetylcholine was tested. The effects of all treatments were assessed in interaction with a stimulus-induced activation of cortical acetylcholine release to account for the possibility that the demonstration of the trans-synaptic effects of accumbens dopamine requires pre-activation of basal forebrain circuits. Systemic amphetamine resulted in increases in basal cortical acetylcholine and accumbens dopamine efflux. Intra-accumbens administration of amphetamine substantially increased accumbens dopamine efflux, but did not significantly affect cortical acetylcholine efflux. Furthermore, intra-accumbens administration of sulpiride or SCH 23390 did not attenuate the systemic amphetamine-induced increase in cortical acetylcholine efflux. Collectively, the present data suggest that increases in accumbens dopamine release are neither sufficient nor necessary for the effects of systemically administered amphetamine on cortical acetylcholine release. The systemic amphetamine-induced increase in cortical acetylcholine may be mediated via multiple, parallel pathways and may not be attributable to a single afferent pathway of the basal forebrain.

The acquisition of an appetite.

Unlike older animals, weanling-age rats do not seek water to drink when they are dehydrated, despite the fact that a physiological sensitivity to dehydration is present very soon after birth. We demonstrate here that the appetitive behaviors needed to approach and obtain water become linked to dehydration only as a result of specific postnatal learning experience. Preventing early experience with dehydration retards the developmental emergence of dehydration-induced, water-oriented behavior in young rats. But a single pairing of water with dehydration can establish an appetitive response. These findings reveal a critical role of early learning in the development of goal-oriented behavior. Such a learning process is potentially characteristic of other behavioral systems, from the most basic appetites to complex motives.