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- All Subjects: Dopamine
- Creators: Hammer, Ronald
Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
ABSTRACT
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
ContributorsParga Becerra, Alejandro (Author) / Neisewander, Janet (Thesis advisor) / Hammer, Ronald (Thesis advisor) / Gallitano-Mendel, Amelia (Committee member) / McLoone, Jim (Committee member) / Vu, Jie (Committee member) / Arizona State University (Publisher)
Created2014