Nucleus accumbens hyperpolarization-activated cyclic nucleotide-gated channels modulate methamphetamine self-administration in rats

Rationale Methamphetamine addiction is believed to primarily result from increased dopamine release and the inhibition of dopamine uptake. Some evidence suggests that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in the functional modulation of dopaminergic...

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Bibliographic Details
Published in:Psychopharmacology 2016-08, Vol.233 (15-16), p.3017-3029
Main Authors: Cao, Dan-Ni, Song, Rui, Zhang, Shu-Zhuo, Wu, Ning, Li, Jin
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal - drug effects
Biomedical and Life Sciences
Biomedicine
Cardiovascular Agents - pharmacology
Central Nervous System Stimulants - administration & dosage
Dopamine
Dopamine - metabolism
Drug addiction
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - antagonists & inhibitors
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism
Male
Methamphetamine
Methamphetamine - administration & dosage
Microdialysis
Neurobiology
Neurosciences
Nucleus accumbens
Nucleus Accumbens - drug effects
Nucleus Accumbens - metabolism
Original Investigation
Pharmacological research
Pharmacology/Toxicology
Physiological aspects
Psychiatry
Psychopharmacology
Pyrimidines - pharmacology
Rats
Rats, Sprague-Dawley
Rodents
Self Administration
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Summary:Rationale Methamphetamine addiction is believed to primarily result from increased dopamine release and the inhibition of dopamine uptake. Some evidence suggests that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in the functional modulation of dopaminergic neurons and the pathophysiology of related diseases. However, little is known about the effects of HCN channels on methamphetamine addiction. Objectives The present study investigated the role of brain HCN channels in methamphetamine addiction. Results Acute intracerebroventricular (i.c.v.) injection or bilateral intra-accumbens microinjections of non-selective HCN channel blocker ZD7288 (0.3125 and 0.625 μg) significantly reduced both methamphetamine (0.0125 or 0.05 mg/kg/infusion)-induced self-administration under fixed ratio 2 reinforcement and the breakpoint of methamphetamine (0.05 mg/kg/infusion) under progressive ratio reinforcement in rats. Moreover, compared with i.c.v. injection, bilateral intra-accumbens microinjections of ZD7288 exerted stronger inhibitory effects, suggesting that blockade of HCN channels in the nucleus accumbens reduced the reinforcing effects of and motivation for methamphetamine. We also found that ZD7288 (0.625 and 1.25 μg, i.c.v.) significantly decreased methamphetamine (1 mg/kg, intraperitoneal (i.p.))-induced hyperactivity with no effect on the spontaneous activity in rats. Finally, in vivo microdialysis experiments showed that the HCN channel blockade using ZD7288 (0.625 and 1.25 μg, i.c.v.) decreased methamphetamine (1 mg/kg, i.p.)-induced elevation of extracellular dopamine levels in the nucleus accumbens. Conclusions These results indicate that HCN channels in the nucleus accumbens are involved in the reinforcing properties of methamphetamine and highlight the importance of HCN channels in the regulation of dopamine neurotransmission underlying methamphetamine addiction.
ISSN:0033-3158
1432-2072
DOI:10.1007/s00213-016-4349-z