The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats.
BACKGROUND
We have previously reported that selective antagonism of brain D3 receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR).


OBJECTIVE
In the present study, we investigated whether the selective D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR.


METHODS
Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate-frequency curve shift paradigm was used to measure brain-reward threshold (theta 0).


RESULTS
METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered ( approximately 10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH.


CONCLUSIONS
Selective antagonism of D3 receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D3 and non-D3 receptors. These findings support a potential use of selective D3 receptor antagonists for the treatment of METH addiction.
Spiller
Krista
K
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Xi
Zheng-Xiong
ZX
Peng
Xiao-Qing
XQ
Newman
Amy H
AH
Ashby
Charles R
CR
Heidbreder
Christian
C
Gaál
József
J
Gardner
Eliot L
EL
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005449:Fluorenes / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012201:Reward; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D005449:Fluorenes; C116818:NGB 2904; D009570:Nitriles; D010879:Piperazines; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; C120565:BP 897; D008694:Methamphetamine