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Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice - PubMed

  • ️Sat Jan 01 2011

Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice

Zheng-Xiong Xi et al. Nat Neurosci. 2011.

Abstract

The presence and function of cannabinoid CB(2) receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB(1) receptor knockout (CB(1)(-/-), also known as Cnr1(-/-)) mice, but not in CB(2)(-/-) (Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB(1)(-/-) mice, but not in CB(2)(-/-) mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB(2) receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.

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Figures

Figure 1
Figure 1

Effects of JWH133 on cocaine self-administration. (a) Systemic administration of JWH133 (10, 20 mg/kg, i.p., 30 min prior to testing) inhibits cocaine self-administration under FR1 reinforcement in WT (one-way ANOVA, F2,16 = 13.09, P < 0.001) and CB1−/−(F2,10 = 5.01, P < 0.05), but not CB2−/− (F2,14=0.56, P = 0.58), mice. (b) Time course of JWH133’s attenuation of cocaine self-administration in WT mice on the test day. (c) Time course of recovery of cocaine self-administration in WT mice after JWH133 administration. (d) In WT mice, JWH133-induced attenuation of cocaine self-administration is prevented by pretreatment with the CB2 receptor antagonist AM630 (10 mg/kg, i.p., 30 min prior to JWH133), but not by pretreatment with the CB1 receptor antagonist AM251 (3 mg/kg, i.p.) (F5,40 = 6.31, P < 0.001). Neither AM630 nor AM251 altered cocaine self-administration in WT mice. Data are means ± s.e.m. * P < 0.05, ** P < 0.01, compared to vehicle (Veh) control groups. ### P < 0.001, compared to pre-JWH133 (−24 h) condition.

Figure 2
Figure 2

Effects of GW405833 or JWH133 on cocaine self-administration. (a) GW405833 (3, 10 mg/kg, i.p.) dose-dependently inhibited cocaine self-administration under FR1 reinforcement in WT mice (one-way ANOVA, F2,6 = 20.03, P < 0.01). (b) JWH133 (10, 20 mg/kg) or AM251 (3 mg/kg, i.p.) significantly lowered the cocaine self-administration break-point under PR reinforcement in WT mice (F3,37 = 13.83, P < 0.001). (c) Intranasal microinjections of JWH133 (50, 100 µg/nostril) dose-dependently inhibited cocaine self-administration under FR1 reinforcement (F2,18 = 14.34, P < 0.001). (d) Intravenous injection of the same micro-quantity (100, 200 µg) of JWH133 as used intranasally had no effect on cocaine self-administration (F2,16 = 1.59, P = 0.23). (e) Intra-NAc microinjections of JWH133 (0.3, 1, 3 µg/side) dose-dependently inhibited cocaine self-administration under FR1 reinforcement in WT mice. This inhibition was blocked by intra-NAc co-administration of AM630 (3 µg/side) (F3,24 = 4.49, P < 0.05). (f) Intra-NAc administration of JWH133 (3 µg/side) had no effect on cocaine self-administration in CB2−/− mice (F1,10 = 2.37, P = 0.15). Data are means ± s.e.m. * P < 0.05, *** P < 0.001, compared to vehicle control group.

Figure 3
Figure 3

Systemic administration of JWH133 (10, 20 mg/kg, i.p., 30 min prior to cocaine) dose-dependently inhibited cocaine-enhanced locomotion in WT (a, two-way ANOVA for repeated measures over time, F2,16 = 14.45, P < 0.001) and CB1−/− (b, F2,18=12.57, p<0.001), but not in CB2−/− (c, F2,12 = 0.17, P = 0.85), mice. Data are means ± s.e.m. ** P < 0.01, *** P < 0.001, compared to vehicle treatment group.

Figure 4
Figure 4

Effects of systemic or local intra-NAc administration of JWH133 or AM630 on locomotor activity. (a) Systemic administration of JWH133 (10, 20 mg/kg, i.p.) dose-dependently inhibited locomotion in WT (one-way ANOVA, F2,24 = 8.03, P = 0.002) and CB1−/− (F2,25 = 13.44, P < 0.001) mice, but not in CB2−/− (F2,14 = 3.36, P > 0.05) mice. (b) Intra-NAc microinjections of JWH133 (1, 3 µg/side) significantly inhibited locomotion in WT (F2,14=4.17, p<0.05) and CB1−/− (F2,12 = 4.91, P < 0.05), but not in CB2−/− (F2,14 = 0.04, P > 0.05), mice (c) Systemic administration of AM630 failed to alter locomotion in any strain of mice. (d) Intra-NAc administration of AM630 (1, 3, 10 µg/side) significantly augmented locomotion in WT (F3,21 = 4.62, P < 0.05) and CB1−/− (F2,12 = 10.57, P < 0.01), but not in CB2−/−(F2,14 = 0.05, P > 0.05), mice. Data are means ± s.e.m. * P < 0.05, ** P < 0.01, compared to vehicle control group.

Figure 5
Figure 5

Systemic administration of JWH133 (3, 10, 20 mg/kg, i.p.) dose-dependently inhibited basal (a, b, c) or cocaine-enhanced (d, e, f) extracellular NAc DA in WT (a, two-way ANOVA for repeated measures over time, F3,29 = 25.97, P < 0.001; d, F2,19 = 4.47, P < 0.05) and CB1−/− (b, F3,28 = 10.07, P < 0.001; e, F2,16 = 4.78, P < 0.05) mice, but not in CB2−/− (c, F2,23 = 0.10, P > 0.05; f, F2,22 = 1.53, P > 0.05) mice. AM630 alone (10 mg/kg, i.p.) failed to alter NAc DA in CB1−/− mice, while AM630 pretreatment (10 mg/kg, i.p.) prevented JWH133-induced inhibition of NAc DA in CB1−/− mice (b). Data are means ± s.e.m. * P < 0.05, ** P < 0.01, *** P < 0.001, compared to pre-drug baseline.# P < 0.05,## P < 0.01, compared to vehicle treatment group.

Figure 6
Figure 6

Effects of intranasal or intra-NAc local perfusion of JWH133 or AM630 on extracellular NAc DA. (a) Intranasal administration of JWH133 (50 µg/nostril) significantly lowered extracellular DA in WT and CB1−/− mice, but not in CB2−/− mice (two-way ANOVA for repeated measures over time, F2,15 = 10.81, P = 0.001). (b) Intra-NAc local perfusion of JWH133 lowered extracellular DA in WT and CB1−/− mice in a dose-dependent manner, while elevating extracellular DA in CB2−/− mice (F2,18=47.00, P < 0.001). (c) Intra-NAc local perfusion of AM630 elevated extracellular DA in WT and CB1−/− mice, but not in CB2−/− mice (F2,18 = 12.13, P < 0.001). Further, AM630-enhanced extracellular DA appears more robust in CB1−/− mice than in WT mice (F1,12 = 7.50, P < 0.05). (d) Renormalized data over new baselines 1 h before JWH133 administration from the data in Panel c, illustrating that intra-NAc local perfusion of AM630 blocked JWH133’s action on extracellular DA in WT and CB1−/− mice. Data are means ± s.e.m. * P < 0.05, ** P < 0.01, *** P < 0.001, compared to pre-drug baseline.

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References

    1. Parolaro D, Rubino T. The role of the endogenous cannabinoid system in drug addiction. Drug News Perspect. 2008;21:149–157. - PubMed
    1. Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(Suppl 1):10–14. - PubMed
    1. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77:299–318. - PubMed
    1. Griffin G, Tao Q, Abood ME. Cloning and pharmacological characterization of the rat CB2 cannabinoid receptor. J Pharmacol Exp Ther. 2000;292:886–894. - PubMed
    1. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–65. - PubMed

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