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Methamphetamine Self‐Administration in Mice Results in Both Pre‐ and Postsynaptic Changes in Dendritic Dopamine Neurotransmission in Midbrain Dopaminergic Neurons
Author(s) -
Hager Audrey M.,
Branch Sarah Y.,
DominguezLopez Sergio,
Sharpe Amanda L.,
Beckstead Michael J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1183.5
Subject(s) - dopamine , methamphetamine , ventral tegmental area , dopaminergic , neuroscience , postsynaptic potential , mesolimbic pathway , neurotransmission , midbrain , neurotransmitter , amphetamine , pharmacology , chemistry , medicine , biology , central nervous system , receptor
Dopaminergic neurons of the ventral midbrain are key mediators of substance abuse and addiction‐related behaviors. In the midbrain, dopamine release activates inhibitory postsynaptic currents through D2 autoreceptors (D2‐IPSCs) and G protein‐coupled potassium (GIRK) channels. Methamphetamine is a highly addictive psychomotor stimulant that acutely enhances D2‐IPSCs by decreasing uptake of the neurotransmitter dopamine. Chronic methamphetamine exposure can induce neurophysiological adaptations in midbrain dopaminergic neurons, but data regarding specific synaptic adaptations following self‐administration of methamphetamine is limited. In this study we investigated the effects of methamphetamine self‐administration in mice on synaptic determinants of dopamine neuron excitability. Adult mice were trained to nose‐poke under a fixed ratio 3 (FR3) schedule for intravenous infusions of methamphetamine (0.05 mg/kg/infusion) in daily 2 h sessions for 8 to 12 days. Their average intake of methamphetamine was 1.3 mg/kg/day. Subsequently, patch clamp electrophysiology was performed in brain slices containing substantia nigra and ventral tegmental area dopamine neurons to examine both pre‐ and postsynaptic changes. Interestingly, self‐administration of methamphetamine produced an overall downward shift in the methamphetamine (100nM‐3μM) concentration‐response curve of D2‐IPSCs compared to drug‐naïve controls. In addition, self‐administration of methamphetamine produced an increase in the paired‐pulse ratio of D2‐IPSCs that persists with subsequent stimulus events, indicating presynaptic effects on dopamine release. These results indicate an overall decrease in the strength of inhibitory synaptic transmission between midbrain dopamine neurons following methamphetamine self‐administration. This would be expected to produce an increase in neuronal firing that could enhance the reinforcing properties of methamphetamine in experienced individuals. Support or Funding Information 5R01DA032701‐03