Browsing by Subject "Dopaminergic mechanisms"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
Item Differential regulation of Ca²⁺ signals in dopamine neurons : a potential mechanism for neuroadaptive changes underlying drug addiction(2007-05) Cui, Guohong, 1974-; Morikawa, HitoshiA key adaptive change in the brain reward circuitry during the development of drug addiction is augmented dopamine (DA) release in response to addictive drugs. Potentiated glutamatergic synaptic transmission onto midbrain DA neurons has been suggested to be one of the cellular mechanisms mediating this change. Intracellular Ca2+ ([Ca2+ ]i) rise associated with postsynaptic bursts of action potentials (APs) and metabotropic glutamate receptor (mGluR) activation has been implicated in the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively, of glutamate transmission in DA neurons. In this dissertation, we found a unique mechanism that differentially regulates these two opposing Ca2+ signals. We performed patch-clamp recordings from DA neurons in acutely cut brain slices, and showed that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs, α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by weak, sustained (~1 sec) synaptic stimulation or bath application of selective agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals elicited by strong, transient activation of mGluRs. This differential regulation is mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it was blocked by IP3 receptor antagonist heparin and reproduced by photolytic application of IP3. We further showed that AP-induced Ca2+ transients were regulated by the firing context of dopamine neurons. Evoking APs repetitively at low frequency (2 Hz) mimicking the basal firing of DA neurons caused inactivation of IP3 receptors and inhibited AP-induced Ca2+ transients. IP3 facilitation of single AP-induced Ca2+ signals was completely abolished during the AP train, while facilitation of Ca2+ signals triggered by bursts of APs (5 spikes at 20 Hz) was attenuated by less than half, indicating that increased IP3 level selectively amplifies Ca2+ signals associated with bursts but not single APs in a tonicly firing neuron. Finally, we obtained evidence suggesting that psychostimulant amphetamine may augment burst-induced Ca2+ signals via both depression of basal firing and production of IP3. We propose that the differential Ca2+ regulation mechanisms described in this dissertation may induce a shift in the balance of plasticity toward burst-dependent LTP in DA neurons and may contribute to the development of drug addiction.Item Differential regulation of Ca²⁺ signals in dopamine neurons: a potential mechanism for neuroadaptive changes underlying drug addiction(2007) Cui, Guohong; Morikawa, HitoshiA key adaptive change in the brain reward circuitry during the development of drug addiction is augmented dopamine (DA) release in response to addictive drugs. Potentiated glutamatergic synaptic transmission onto midbrain DA neurons has been suggested to be one of the cellular mechanisms mediating this change. Intracellular Ca2+ ([Ca2+ ]i) rise associated with postsynaptic bursts of action potentials (APs) and metabotropic glutamate receptor (mGluR) activation has been implicated in the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively, of glutamate transmission in DA neurons. In this dissertation, we found a unique mechanism that differentially regulates these two opposing Ca2+ signals. We performed patch-clamp recordings from DA neurons in acutely cut brain slices, and showed that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs, α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by weak, sustained (~1 sec) synaptic stimulation or bath application of selective agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals elicited by strong, transient activation of mGluRs. This differential regulation is mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it was blocked by IP3 receptor antagonist heparin and reproduced by photolytic application of IP3. We further showed that AP-induced Ca2+ transients were regulated by the firing context of dopamine neurons. Evoking APs repetitively at low frequency (2 Hz) mimicking the basal firing of DA neurons caused inactivation of IP3 receptors and inhibited AP-induced Ca2+ transients. IP3 facilitation of single AP-induced Ca2+ signals was completely abolished during the AP train, while facilitation of Ca2+ signals triggered by bursts of APs (5 spikes at 20 Hz) was attenuated by less than half, indicating that increased IP3 level selectively amplifies Ca2+ signals associated with bursts but not single APs in a tonicly firing neuron. Finally, we obtained evidence suggesting that psychostimulant amphetamine may augment burst-induced Ca2+ signals via both depression of basal firing and production of IP3. We propose that the differential Ca2+ regulation mechanisms described in this dissertation may induce a shift in the balance of plasticity toward burst-dependent LTP in DA neurons and may contribute to the development of drug addiction.Item Genetic and experiential effects on dopaminergic systems(2002) Woolley, Sarah Cushing; Crews, David.; Bronson, F. H.Successful reproduction requires the coordination of relevant sensory inputs with motivational and motor systems primed by sex steroid hormones to produce an appropriate hierarchical sequence of movements. Both behavioral and neural phenotypes can be altered by social interactions that, in turn, can produce long term changes in cellular activity and signaling, neural circuitry, and sexual behavior. There is considerable variability in the type and direction of neural and behavioral change in response to social interactions, and the degree of plasticity may depend on intrinsic or genetic individual differences. Dopaminergic systems modulate the expression of social and sexual behaviors in a number of vertebrate species and intrinsic differences in dopaminergic systems may underlie intrinsic individual differences in the display of sexual behavior. Here, I present data on how social interactions, genotype, and steroid hormones can affect dopamine synthesis in limbic and midbrain nuclei. I investigated this in three model systems including knockout mice and two related species of whiptail lizard. The knockout mice have a targeted deletion of the progesterone receptor and display higher mount and intromission frequencies than wild-type males. Male whiptail lizards (Cnemidophorus inornatus) have natural variation in the display of courtship behaviors: some males are more sexually vigorous than others. Finally, individuals of the parthenogenetic species C. uniparens, which arose from two hybridization events involving the sexual species C. inornatus, display both maleand female-like sexual behaviors depending on reproductive state. In contrast, C. inornatus females only display receptive behavior, and this only during when preovulatory. In all three species, individuals that displayed greater levels of mounting behaviors had greater numbers of cells expressing tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra pars compacta. In addition, in male whiptail lizards and the related parthenogen, dopamine production in the dorsal hypothalamus was correlated with the propensity to display mounting behaviors. Dopamine can increase the display of mounting behavior in mice as well as in male and parthenogenetic whiptail lizards. My dissertation indicates that not only is dopamine sufficient to elicit mounting behavior, but differences in dopamine production may contribute to individual differences in behavioral phenotype.Item Involvement of mu-opiate receptors in ethanol-induced accumbal dopamine response(2003-08) Tang, Man Amanda, 1972-; Gonzales, Rueben AnthonyThe goal of this dissertation was to investigate the role of µ-opiate receptors in the regulation of ethanol-induced accumbal dopamine release using µ-opiate receptor knockout mice. Accumbal dopamine response to ethanol (2 g/kg, intraperitoneal injection, i.p.) was characterized in one of the parental strains that the knockout mice were developed on, C57BL/6; two strains of µ-receptor knockout mice (C57BL/6 x 129SvEv, C57BL/6 background); and the mixed genetic background mice pretreated with µ1-receptor antagonist, naloxonazine. Ethanol increases accumbal dopamine release in both male and female C57BL/6 mice. Thus, the C57BL/6 strain is a justifiable model system for studying the mechanisms involved in ethanol regulation of mesolimbic dopamine activity. Habituation to the i.p. procedure is required to detect a significant increase in accumbal dopamine response compared with saline controls in males. Therefore, it was routinely used for the remaining experiments. Accumbal dopamine response to ethanol was abolished in female, not in male knockout mice (C57BL/6 x 129SvEv). Similar results were obtained in the mixed genetic background mice that were pretreated with naloxonazine. The similarity of the results from the naloxonazine study to that of the knockout model suggests the absence of neurochemical compensations due to gene deletion. Finally, a decrease in accumbal dopamine release induced by ethanol was observed in both male and female knockout mice (C57BL/6). The gender difference seen in the mixed genetic background knockout mice may be due to the influence of one of the parental strains, 129SvEv, on the hybrid strain of the knockout mice. The results with both gene deletion and pharmacological blockade of the µ- opiate receptor support the hypothesis that µ-opiate receptors are a critical component of the mechanism by which ethanol stimulates accumbal dopamine release.