Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Dr. Steven R. Laviolette

Abstract

Cannabinoid CB1 receptor (CB1R) transmission within the mesocorticolimbic system plays an important role in forming associative memories, and processing both positive and negative experiences. Opiates generally produce potent rewarding effects and previous evidence suggests that CB1 transmission may modulate the neural reward circuitry involved in opiate reward processing. The ventral tegmental area (VTA), medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and Nucleus Accumbens (NA) are all implicated in opiate-reward processing, contain high levels of CB1 receptors, and are all modulated by dopamine (DA). Although, CB1 transmission within these areas has been heavily implicated in associative memory and learning, the potential effects of CB1R modulation on these neural regions in regards to opiate related motivational information are not currently understood. Using a combination of unbiased conditioned place preference (CPP) paradigm and pharmacological manipulation, we examined the role of CB1 transmission within these neural circuitries in relation to opiate reward processing.

We report that activation or inhibition of CB1 transmission within the mPFC and BLA bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission. Furthermore, CB1-mediated intra-mPFC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. In contrast, CB1-mediated intra-BLA opiate motivational signaling is mediated through the NMDA transmission in the shell region of NA (NASh). Finally, using multi-unit, in vivo electrophysiological recordings in the NASh, we report that the ability of intra-BLA CB1R modulation to control opiate reward salience and motivational valence is associated with distinct reward or aversion neuronal activity patterns and bi-directional regulation of intra-NASh fast-spiking interneurons vs. medium spiny neurons. Our results provide evidence for a novel CB1 mediated motivational valence switching mechanism within the mPFC, and BLA, controlling dissociable subcortical reward and aversion pathways. Lastly, we report that CB1 mediated reward is localized to the CB1R’s located in the posterior region of the VTA.


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