Abstract
M5 muscarinic receptors are the only muscarinic receptor subtype expressed by mesencephalic dopamine neurons and provide an important excitatory input to mesolimbic and nigrostriatal dopamine systems. Here, we studied locomotion induced by systemic morphine (3, 10, and 30 mg/kg i.p.) in M5 knockout mice of the C57BL/6 (B6) and CD1 × 129SvJ background strains. M5 knockout mice of both strains showed reduced locomotion in response to 30 mg/kg morphine. B6 M5 knockout mice were less sensitive to naltrexone in either the antagonism of morphine-induced locomotion or in the reduction of locomotion by naltrexone alone. This suggests that M5 knockout mice are less sensitive to the effects of either exogenous or endogenous opiates on locomotion and that spontaneous locomotion in B6 mice is sustained by endogenous opiates. In B6 wild-type mice, ventral tegmental area (VTA) pretreatment with the muscarinic receptor antagonist atropine (3 μg bilateral), but not the nicotinic receptor antagonist mecamylamine (5 μg bilateral), reduced locomotion in response to 30 mg/kg morphine to a similar extent as systemic M5 knockout, suggesting that reduced morphine-induced locomotion in M5 knockout mice is due to the loss of M5 receptors on VTA dopamine neurons. In contrast, in M5 knockout mice, but not in wild-type mice, either intra-VTA atropine or mecamylamine alone increased locomotion by almost 3 times relative to saline and potentiated morphine-induced locomotion. Therefore, in M5 knockout mice, blockade of either VTA muscarinic or nicotinic receptors increased locomotion, suggesting that in the absence of VTA M5 receptors, VTA cholinergic inputs inhibit locomotion.
Footnotes
-
This study was supported by Canadian Institutes of Health Research [Grant MOP 14624].
-
This work was submitted in partial fulfillment of the requirements for doctoral dissertation: Steidl S (2008) Morphine-Induced Locomotion and Dopamine Efflux in Mice: Role of M5 Muscarinic Receptors and Cholinergic Inputs to the Ventral Tegmental Area. Ph.D. thesis. The University of Toronto, Toronto, ON, Canada.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.144824.
-
ABBREVIATIONS: VTA, ventral tegmental area; PPT, pedunculopontine tegmental nucleus; LDT, laterodorsal tegmental nucleus; 129, CD1 × 129 mice; B6, C57BL/6 mice; sal/sal, VTA saline then systemic saline; sal/mor, VTA saline then systemic morphine; ANOVA, analysis of variance; LSD, least significant difference.
- Received August 15, 2008.
- Accepted October 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|