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PubMed2006

A mechanistic account of striatal dopamine function in human cognition: psychopharmacological studies with cabergoline and haloperidol.

The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D2 agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive reinforcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia.

Adolescent↗
PubMed1987

The effect of MDMA ("Ecstasy") and its optical isomers on schedule-controlled responding in mice.

Eleven mice were trained to respond under an FR 20 schedule of reinforcement and, after learning the schedule, were administered doses of saline and the following phenylisopropylamines: (+/-)-MDMA, S(+)-MDMA, R(-)-MDMA and (+)-amphetamine. Each of the phenylisopropylamines decreased rates of operant responding in a dose-dependent manner. S(+)-MDMA (ED50 = 3.1 mg/kg) was nearly equipotent with racemic MDMA and four times more potent than R(-)-MDMA (ED50 = 4.1 and 11.6 mg/kg, respectively), but less potent than (+)-amphetamine (ED50 = 0.74 mg/kg). The present study constitutes the first enantiomeric behavioral-potency comparison for the optical isomers of MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1985

Lack of effect of Pitressin on the learning ability of Brattleboro rats with diabetes insipidus using positively reinforced operant conditioning.

Brattleboro rats with hereditary hypothalamic diabetes insipidus (BDI) received daily subcutaneous injections of vasopressin in the form of Pitressin tannate (0.5 IU/24 hr). They were initially deprived of food and then trained to work for food reward in a Skinner box to a fixed ratio of ten presses for each pellet received. Once this schedule had been learned the rats were given a discrimination task daily for seven days. The performances of these BDI rats were compared with those of rats of the parent Long Evans (LE) strain receiving daily subcutaneous injections of vehicle (arachis oil). Comparisons were also made between these two groups of treated animals and untreated BDI and LE rats studied under similar conditions. In the initial learning trial, both control and Pitressin-treated BDI rats performed significantly better, and manifested less fear initially, than the control or vehicle-injected LE rats when first placed in the Skinner box. Once the initial task had been learned there was no marked difference in the discrimination learning between control or treated BDI and LE animals. These results support the view that vasopressin is not directly involved in all types of learning behaviour, particularly those involving positively reinforced operant conditioning.

Animals↗
PubMed2003

Activity of neurons in the pedunculopontine nucleus during a food-related operant conditioned reflex.

The activity of 91 neurons in the compact and diffuse zones of the pedunculopontine nucleus of freely mobile rabbits was studied during performance of a food-related operant conditioned reflex. A total of 37.4% of the neurons recorded showed reactivity to the conditioned stimulus, which is evidence that the pedunculopontine nucleus is involved in operant learning. A significant predominance of excitatory responses to the conditioned stimulus and to food reinforcement was demonstrated. The main patterns of cell responses were identified, these reflecting the nature of the effect of the conditioned stimulus on neuron activity, the structure of the behavioral act, and the properties of the reinforcement, and demonstrating a relationship between the pedunculopontine nucleus and the processes of attention, motor learning, and reinforcement. Differences were seen in the associative reactive properties of the compact and diffuse zones of the pedunculopontine nucleus to the conditioned stimulus and reinforcement, which is evidence for the functional diversity of this formation and suggests a leading role for the cholinergic compact zone in food-related operant learning and reinforcement, the diffuse zone having a leading role in food-related classical conditioned-reflex learning.

Action Potentials↗
PubMed1980

Probability learning and aging.

The performance of 48 young (ages 18--20) and 48 old (mean age = 78) adult Ss was studied in a probability learning task which used different reinforcement procedures and material rewards. In the course of learning, the noncorrection procedure was associated with a greater tendency to choose the majority stimulus than was the correction procedure, but this difference was not maintained. All Ss chose the majority stimulus less often than did rats despite the fact that the experimental procedure was based on that used in animal experiments. An interaction effect was found between age level and sex, such that the young women and the old men chose the majority stimulus more than the young men and old women, respectively. It was suggested that the results could imply an increase in rigidity and cautiousness with age in men and a decrease in these qualities with age in women. This suggestion was shown to be consistent with findings reported by other psychologists showing sex differences in personality change associated with aging.

Adolescent↗
PubMed2000

Blockade of behavioral sensitization by MK-801: fact or artifact? A review of preclinical data.

RATIONALE: It is widely assumed that various forms of neural and behavioral plasticity, including sensitization, are strongly dependent on the activation of N-methyl-D-aspartate (NMDA)-receptors, but evidence also exists to suggest that not all forms of sensitization are unequivocally blocked by NMDA-receptor antagonism. Also, findings from studies examining the effects of NMDA-receptor blockade on forms of behavioral plasticity other than locomotor sensitization (various forms of tolerance, sensitization of catalepsy, and learning and conditioning) reinforce the view that forms of behavioral plasticity exist that are not blocked by NMDA-receptor antagonists. OBJECTIVES: Since the publication of two reviews addressing this issue in detail, this field of research has continued to be very active and controversial, and a number of further studies have been published in the meantime which are relevant to the topic. The aim of this review is to provide a summary of this literature and to consider new approaches that might make important contributions to the present discussion. RESULTS AND CONCLUSIONS: The studies reviewed herein have produced results both consistent with and in contradiction to the view that MK-801 and related drugs block behavioral plasticity, and the debate about how exactly MK-801 and related drugs interact with other drugs in sensitization experiments is still in full swing. What seems crucial for future studies relating to this subject is a careful experimental design to reduce the number of potential interpretations of the findings.

Animals↗
PubMed1978

Discriminative stimulus properties of clozapine and chlorpromazine.

Rats were trained to discriminate pairs of drug states in a two-lever operant paradigm for food reinforcement. One group learned to discriminate clozapine from vehicle, a second group learned to discriminate chlorpromazine from vehicle, and a third group learned to discriminate clozapine from chlorpromazine. The result that the clozapine versus chlorpromazine discrimination was acquired, as well as the results of substitution tests with non-training drugs, suggest that the stimulus properties of the classical neuroleptics and other psychotherapeutic agents indicate that the stimulus properties of antipsychotics are distinct from other classes of psychotropic agents, and support the hypothesis that clozapine may be a unique antipsychotic. It is suggested that the unique discrimination stimulus produced by clozapine may be related to the differential effect of the drug on the extrapyramidal versus accumbens dopamine system.

Animals↗
PubMed1984

Effects of d-amphetamine and d-fenfluramine on performance of rats in a food maze.

d-Amphetamine and d-fenfluramine caused different patterns of disruption in a learned maze performance reinforced with food. A 0.8 mg/kg dose of amphetamine increased correct and incorrect (errors) alley entrances as well as earned reinforcers consumed. Larger doses (1.6-3.2 mg/kg) decreased correct responses, increased errors, and resulted in earned reinforcers not being consumed. Metergoline pretreatment did not reverse these deficits. d-Fenfluramine (1.5 and 3.0 mg/kg) reduced correct responses dose- relatedly with a slight increase in errors after the larger dose; all earned reinforcers were consumed. Pretreatment with metergoline reversed the deficit in correct responses but not the errors. Combinations of d-amphetamine and d-fenfluramine produced greater deficits than each drug separately, with fewer correct responses and an increase in reinforcers earned but not consumed. Metergoline pretreatment before the combination did not reverse these effects but increased alley entrances scored as errors. The results indicate that the d-fenfluramine but not the d-amphetamine deficit relates to a 5-hydroxytryptamine (5-HT) mechanism. Furthermore, the enhanced effect of the combination appears to relate to drug interactions not dependent upon a 5-HT component.

Animals↗
PubMed2005

Mu-opioid-mediated inhibition of glutamate synaptic transmission in rat central amygdala neurons.

The central nucleus of the amygdala (CeA) plays an important role both in stimulus-reward learning for the reinforcing effects of drugs of abuse and in environmental condition-induced analgesia. Both of these two CeA functions involve the opioid system within the CeA. However, the pharmacological profiles of its opioid receptor system have not been fully studied and the synaptic actions of opioid receptors in the CeA are largely unknown. In this study with whole-cell voltage-clamp recordings in brain slices in vitro, we examined actions of opioid agonists on glutamate-mediated excitatory postsynaptic currents (EPSCs) in CeA neurons. Opioid peptide methionine-enkephalin (ME; 10 microM) produced a significant inhibition (38%) in the amplitude of evoked EPSCs, an action mimicked by the mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO; 1 microM, 44%). Both effects of ME and DAMGO were abolished by the mu receptor antagonist CTAP (1 microM), suggesting a mu receptor-mediated effect. Neither delta-opioid receptor agonist [D-Pen(2),D-Pen(5)]-enkephalin (1 microM) nor kappa-opioid receptor agonist U69593 (300 nM) had any effect on the glutamate EPSC. ME significantly increased the paired-pulse ratio of the evoked EPSCs and decreased the frequency of miniature EPSCs without altering the amplitude of miniature EPSCs. Furthermore, the mu-opioid inhibition of the EPSC was blocked by 4-aminopyridine (4AP; 100 microM), a voltage-dependent potassium channel blocker, and by phospholipase A(2) inhibitors AACOCF(3) (10 microM) and quinacrine (10 microM). These results indicate that only the mu-opioid receptor is functionally present on presynaptic glutamatergic terminals in normal CeA neurons, and its activation reduces the probability of glutamate release through a signaling pathway involving phospholipase A(2) and the presynaptic, 4AP-sensitive potassium channel. This study provides evidence for the presynaptic regulation of glutamate synaptic transmission by mu-opioid receptors in CeA neurons.

4-Aminopyridine↗
PubMed2004

Corticostriatal plasticity: life after the depression.

Experience-dependent changes in corticostriatal transmission efficacy are likely to support the role of the striatum in reinforcement-based motor learning. Whereas long-term depression at glutamatergic corticostriatal synapses has long been regarded as the normal form of striatal plasticity, recent work provides evidence that use-dependent potentiation can naturally occur at these connections through an increase in both synaptic efficacy and postsynaptic intrinsic excitability. By decreasing the weight of cortical inputs required to fire striatal output neurons, short-term and long-term potentiation at corticostriatal connections can jointly participate in the formation of sensorimotor links by which specific context-dependent patterns of cortical activity can engage selected motor programs.

Animals↗
PubMed2000

Contingent tolerance to amphetamine hypophagia: new insights into the role of environmental context in the expression of stereotypy.

A growing literature attests to the fact that the environment in which a drug is given can have a profound effect on the development and expression of tolerance and sensitization. The dominant paradigm for studying such context-dependency is based on Pavlovian conditioning, in which a distinctive environment serves as a conditioned stimulus. Context dependency is demonstrated when tolerance or sensitization is expressed only in the environment in which the drug was given chronically. An alternative paradigm for studying context-dependency is to manipulate the contingencies of reinforcement operating in the environment in which the drug is administered. For example, tolerance to amphetamine-induced hypophagia is contingent on having access to food while intoxicated [Carlton PL, Wolgin DL. Contingent tolerance to the anorexigenic effects of amphetamine. Physiol Behav 1971;7:221-223]. Such context-dependency can be explained in terms of an instrumental (or operant) conditioning model, in which food serves as a reinforcer for the learned suppression of stereotyped movements that interfere with ingestion. Research based on this model suggests that the expression of sensitized stereotyped responses is subject to an operant level of control.

Amphetamines↗
PubMed1998

Oxytocin receptor mRNA expression in rat brain: implications for behavioral integration and reproductive success.

The nonapeptide, oxytocin (OT), has been implicated in a wide range of physiological, behavioral and pharmacological effects related to learning and memory, parturition and lactation, maternal and sexual behavior, and the formation of social attachments. Specific G-protein linked membrane bound OT receptors mediate OTs effects. The unavailability of highly selective pharmacological ligands that discriminate the OT receptor from the highly homologous vasopressin receptors (V1a, V1b and V2 subtypes) has made it difficult to confirm specific effects of oxytocin, particularly in brain regions where OT and multiple AVP receptor subtypes may be coexpressed. Here, data on the oxytocin receptor (OTR) messenger ribonucleic acid (mRNA) localization in brain are presented in the context of a model that proposes a reproductive state-dependent role for steroid-hormone restructuring of neural circuits, and a role for oxytocin in the integration of neural transmission in pathways subserving: (1) steroid-sensitive reproductive behaviors; (2) learning; and (3) reinforcement. It is hypothesized that social attachments emerge as a consequence of a conditioned association between OT-related activity in these pathways and the eliciting stimulus.

Animals↗
PubMed2001

Anesthesiologists' interest in neonatal resuscitation certification.

STUDY OBJECTIVE: To survey graduates from our residency program to determine their involvement and their interest in becoming certified in neonatal resuscitation. DESIGN: Survey questionnaire. SETTING: Graduates from the University of Pennsylvania Anesthesia Program between 1989 and 1999. SUBJECTS: 212 individuals completed the residency; addresses were available for 189 and the response rate for these individuals was 156. RESULTS: Of the respondents with obstetric anesthesia responsibilities, 65% have been involved in resuscitation of the newborn. Sixteen percent were certified, but 81% were interested in certification. If the hospital had less than 1000 deliveries per year, the probability of the anesthesiologist having to perform neonatal resuscitation was 11.0 times greater than if the hospital had more than 1000 deliveries per year (confidence interval, 1.4--86). CONCLUSIONS: Despite guidelines recommending the contrary, anesthesiologists are involved in the resuscitation of the newborn. The majority of these individuals are not certified but are interested in becoming certified. The ASA should establish programs to offer the opportunity to learn and to reinforce these skills.

Analgesia, Obstetrical↗
PubMed1998

Humanized antibodies as potential therapeutic drugs.

BACKGROUND: Antibodies have been used therapeutically to treat a variety of clinical conditions. The introduction of monoclonal antibodies and more recently, engineered humanized antibodies has greatly refined and expanded the therapeutic potential of this modality of treatment. LEARNING OBJECTIVES: To reinforce the reader's knowledge of the therapeutic application of antibody in the treatment for different diseases. More specifically, to enhance reader's understanding of basic methods employed in the production and clinical use of humanized antibodies. DATA SOURCE: The MEDLINE database was used to review the humanized antibody related literature. CONCLUSION: Humanized antibodies provide a novel approach for the treatment of a broad range of diseases. Expanded use will depend on improvement in their efficacy (avidity and specificity), demonstration of their safety, and reduction of their immunogenicity.

Animals↗