Phasic‐like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine‐induced partial dopamine denervation

• Published in: Journal of neurochemistry 2013-05, Vol.125 (4), p.555-565
• Main Authors: Howard, Christopher D., Pastuzyn, Elissa D., Barker‐Haliski, Melissa L., Garris, Paul A., Keefe, Kristen A.
• Format: Article
• Language: English
• Subjects: Amphetamine-Related Disorders - genetics; Amphetamine-Related Disorders - physiopathology; Animals; Arc; Brain; Central Nervous System Stimulants - toxicity; Corpus Striatum - drug effects; Corpus Striatum - physiology; Cytoskeletal Proteins - genetics; Denervation - methods; Dopamine; Dopamine - physiology; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Early Growth Response Protein 1 - genetics; Electric Stimulation - methods; Gene expression; Gene Expression - drug effects; Gene Expression - physiology; Genes, Immediate-Early - genetics; Male; Medial Forebrain Bundle - drug effects; Medial Forebrain Bundle - physiology; Methamphetamine; Methamphetamine - toxicity; Nerve Tissue Proteins - genetics; Neurons; Neurotoxicity; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - physiopathology; preprotachykinin; Protein Precursors - genetics; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Rodents; striatum; Tachykinins - genetics; zif268
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12234

Methamphetamine‐induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity‐regulated, cytoskeleton‐associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine‐induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic‐ or tonic‐like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic‐like, but not tonic‐like, stimulation induced immediate‐early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine‐pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic‐like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine‐induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long‐term consequences of methamphetamine‐induced dopamine loss on basal ganglia functions. Methamphetamine (METH) neurotoxicity decreases striatal dopamine content. Associated with this dopamine depletion are deficits in phasic DA signaling, which is important for reward‐based learning, and dysregulation of striatal gene expression. Here, using electrical stimulation of the medial forebrain bundle to activate dopamine neurons, we show that augmenting phasic DA signaling normalizes striatal gene expression, despite METH‐induced partial DA depletions.