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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    546—Cocaine: Neural Mechanisms of Addiction IV

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    546.07: Distinct roles of PKC signaling at direct and indirect pathway medium spiny neurons during reinstatement of cocaine-seeking

    Location: Halls B-H

    Univ. of Pennsylvania, PHILADELPHIA, PA

    Abstract Body: Cocaine abuse in humans is frequently characterized by withdrawal from and relapse to chronic drug use. The relapse to cocaine seeking in rodents can be modeled as enhanced behavioral responding following exposure to a pharmacological trigger. In particular, reinstatement of cocaine seeking can be triggered by stimulation of dopamine receptors in the nucleus accumbens, a component of the mesolimbic dopamine reward pathway. Here, we show that microinjection of either D1-like or D2-like dopamine receptor agonists into the rat nucleus accumbens shell leads to reinstatement of cocaine-seeking behavior. Administration of the protein kinase C antagonist, chelerythrine, attenuates reinstatement induced by the D2-like, but not the D1-like dopamine receptor agonists. We explore the possible neuronal mechanisms for this phenomenon by evaluating the effects of chelerythrine at medium spiny neurons of the direct (D1-expressing) and indirect (D2-expressing) pathways. We find that exposure of brain slices to chelerythrine modulates excitatory and inhibitory synaptic signaling differently at D1- and D2-expressing neurons. Furthermore, sensitivity of evoked synaptic activity to chelerythrine is dependent upon the frequency of stimulation of synaptic afferents. These results suggest the possibility that distinct signaling patterns at neurons of the direct and indirect pathways in the nucleus accumbens shell underlie distinct roles of protein kinase C during reinstatement of cocaine seeking by agonists at D1-like and D2-like dopamine receptors.

    Lay Language Summary: We found that relapse to cocaine use in an animal model of addiction relies on activity of an intracellular signaling molecule known as protein kinase C (PKC). Blockade of PKC signaling attenuated cocaine relapse induced by activation of neurons that express the D2 type of dopamine receptor in the nucleus accumbens, an area of the brain responsible for encoding habitual drug use. Cocaine relapse could also be triggered by activation of the other dominant cell type in this brain region, the D1-expressing neurons, but relapse in this case was insensitive to disruption of PKC signaling.
    PKC is present in both D1- and D2-type cells and can be activated when either type is exposed to cocaine. Our findings suggest, however, that PKC plays very unique roles in these cell types, weakening the D2-mediated relapse, but having no effect on relapse induced by activation of D1 neurons.
    To investigate the possible mechanisms through which disruption of PKC activity affected the D1- or D2- type cells we examined how a PKC inhibitor, chelerythrine, influences signaling at these cells. The efficiency of neuronal signaling depends on a balance between excitatory and inhibitory signals at the synapse, a structure specialized for transmission of neuronal signals. Surprisingly, when we measured synaptic activity in the nucleus accumbens of animals exposed to cocaine, we found that chelerythrine similarly affects the balance of excitatory to inhibitory signaling in both D1- and D2-type cells. However, when we varied the timing of synaptic excitation, we found that chelerythrine promotes the transmission of low to medium frequency signals in D2-type cells, but has no effect in D1-type cells. In the same frequency range, the transmission of inhibitory synaptic signals is not affected by chelerythrine in either cell type.
    Together, these results suggest that PKC blockade should promote excitability of D2-type neurons, with little effect on D1-type cells. Moreover, these effects of PKC inhibition critically depend on the frequency of synaptic inputs. One interpretation of our results, therefore, is that attenuation of cocaine relapse by PKC inhibition occurs by interfering selectively with excitatory signaling at D2-type neurons. Further research is needed to investigate the mechanisms of frequency-dependence and to examine whether recruiting these mechanisms is sufficient to disrupt the relapse to cocaine-seeking.
    Cocaine use in humans is often described as a cycle in which an addict goes through a cocaine “binge” and then abstains from the drug, but only to relapse back to “bingeing” behavior after a period of time. Our results suggest that the relapse behavior can be disrupted by selectively targeting a specific signaling molecule in a unique population of neuronal cells.