Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2013)

Addictions are multi-dimensional disorders, consisting of several behavioral, affective and cognitive dysfunctions that contribute to the compulsive and persistent drug-seeking and taking that is common to them. Cognitive control, which includes the ability to flexibly and adaptively inhibit undesirable actions (including drug-seeking), is a particularly relevant dimension of addiction, with deficits in cognitive control occurring in response to experience with drugs of abuse, as well as predicting the susceptibility for future drug-taking behaviors. The bi-directional relationship between cognitive control and substance dependence raises the possibility that these processes are governed by a common neural circuitry and emerging evidence indicates that the dopamine D2-like receptor system may be the point of convergence of these phenomena.

To determine the influence of the dopamine D2-like receptor system on cognitive control processes within the context of addictions, neuroimaging, behavioral and biochemical techniques were used to interrogate how naturally occurring and drug-induced variation in D2-like receptor system may alter cognitive-control processes. Individual differences in D2-like receptor availability, assessed with positron emission tomography, was positively related to adaptive responding following the reversal of stimulus-reward contingencies and to the sensitivity of individuals to positive feedback. Exposure to an escalating dose regimen of methamphetamine reduced D2-like receptor availability, and the degree of D2-like receptor dysfunction was correlated with the change in positive-feedback sensitivity. Cross-dimensional measurement of the D2-like receptor systems using in vivo and in vitro techniques provided evidence that deviations in D2-like receptor availability reflected actions on functionally and behaviorally relevant pools of D2-like receptors. Finally, evidence supporting the utility of spontaneous eye blink rate as a non-invasive measure of D2-like receptors was obtained from studies of rodents.

These studies provide converging support, at multiple levels of analyses, that the D2-like receptor is a common molecular determinant of addiction and cognitive control, providing a mechanistic explanation for the bi-directional relationship between these processes.

    Cover page: The Dopamine D2-like Receptor: At the Nexus Between Self-Control and Addiction
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2014)
    The procurement and consumption of palatable, calorie-dense foods is influenced by the nutritional and hedonic value of foods. Although many factors can influence the control over behavior by foods rich in sugar and fat, emerging evidence indicates that biological sex may play a particularly crucial role in the types of foods individuals seek out, as well as the level of motivation individuals will exert to obtain those foods. However, a systematic investigation of food-seeking and consumption that disentangles the effects of the major sex-biasing factors, including sex chromosome complement and organizational and activational effects of sex hormones, has yet to be conducted. Using the four core genotypes mouse model system, we separated and quantified the effects of sex chromosome complement and gonadal sex on consumption of and motivation to obtain a highly palatable solution [sweetened condensed milk (SCM)]. Gonadectomized mice with an XY sex chromosome complement, compared with those with two X chromosomes, independent of gonadal sex, appeared to be more sensitive to the reward value of the SCM solution and were more motivated to expend effort to obtain it, as evidenced by their dramatically greater expended effort in an instrumental task with progressively larger response-to-reward ratios. Gonadal sex independently affected free consumption of the solution but not motivation to obtain it. These data indicate that gonadal and chromosomal sex effects independently influence reward-related behaviors, contributing to sexually dimorphic patterns of behavior related to the pursuit and consumption of rewards.
      Cover page: Sex chromosome complement influences operant responding for a palatable food in mice
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2014)
      For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors.
        Cover page: In the blink of an eye: relating positive-feedback sensitivity to striatal dopamine D2-like receptors through blink rate.
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2022)

        Purpose

        Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue.

        Methods

        We used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [11C]UCB-J and [18F]Syn-VesT-1 to conduct the first assessment of synaptic density in the developing fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot.

        Results

        Image-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures.

        Conclusion

        While further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain.
          Cover page: Imaging the fetal nonhuman primate brain with SV2A positron emission tomography (PET)
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2014)
          For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors.
            Top