Attenuation of basal and cocaine-enhanced locomotion and nucleus accumbens dopamine in cannabinoid CB1-receptor-knockout mice - PubMed (original) (raw)

Attenuation of basal and cocaine-enhanced locomotion and nucleus accumbens dopamine in cannabinoid CB1-receptor-knockout mice

Xia Li et al. Psychopharmacology (Berl). 2009 May.

Abstract

Rationale: Effect of cannabinoid CB1 receptor deletion on cocaine's actions is controversial. This is partly based on findings in CB1-receptor-knockout (CB1(-/-)) mice with CD1 genetic background.

Objectives: In the present study, we used CB1(-/-) mice with a C57BL/6J genetic background to further investigate the role of CB1 receptors in cocaine's action.

Materials and methods: Locomotor activity was assessed using AccuScan locomotor chambers. Brain extracellular dopamine (DA) levels were measured by in vivo microdialysis and by fast-scan cyclic voltammetry in the nucleus accumbens (NAc).

Results: CB1(-/-) mice displayed a significant reduction in basal levels of locomotion and extracellular DA, as well as in cocaine-enhanced locomotion and extracellular DA, as compared to their wild-type (CB1(+/+)) littermates. The reduction in basal and cocaine-enhanced DA appears to be related to a reduction in basal DA release, not to an increase in DA clearance, as indicated by fast-scan cyclic voltammetry in brain slices. Pharmacological blockade of CB1 receptors by SR141716 inhibited locomotion and NAc DA release in CB1(+/+) mice.

Conclusions: The present findings suggest an important role for CB1 receptors in mediating cocaine's behavioral and neurochemical effects.

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Figures

Fig. 1

Fig. 1

Basal and cocaine-enhanced locomotor activity in CB1+/+ and CB1−/− mice. a shows basal locomotion data (distance) and cocaine-or saline-induced locomotion in CB1+/+ and CB1−/− mice. b shows mean basal locomotion in CB1+/+ and CB1−/− mice, indicating a significant reduction in locomotion in CB1−/− mice relative to their wild-type CB1+/+ littermates. c shows percent change from baseline in cocaine-induced locomotion, indicating that the duration of cocaine-enhanced locomotion was shorter in CB1−/− mice than in CB1+/+ mice. *p<0.05, **p<0.01, ***p<0.001, compared to CB1+/+ mice. ##p<0.01, ###p<0.001, compared to baseline

Fig. 2

Fig. 2

Basal and cocaine-enhanced NAc DA in CB1+/+ and CB1−/− mice. a shows basal and cocaine- or saline-induced changes in NAc DA in CB1+/+ and CB1−/− mice. b shows mean basal extracellular DA, indicating a significant attenuation of basal DA in CB1−/− mice relative to wild-type CB1+/+ littermates. c shows percent change in DA from baseline, indicating a significant attenuation of cocaine-enhanced DA in CB1−/− mice relative to CB1+/+ mice. *p<0.05, **p< 0.01, ***p<0.001, compared to CB1+/+ mice. #p<0.05, ##p<0.01, ###p<0.001, compared to baseline

Fig. 3

Fig. 3

NAc DA release in CB1−/− mice. a shows representative voltammetric signals recorded in brain slices from a CB1+/+ mouse and a CB1−/− mouse. A single-pulse stimulus (1 ms, 100 µA; arrowhead) was used to elicit NAc DA release. Inset of each signal shows the background-subtracted voltammogram obtained at the peak of the recorded current. b shows the input–output relationship of DA release elicited by single-pulse stimulation in the NAc, indicating attenuated DA release across a range of stimulus intensities in CB1−/− mice (_n_=28 slices from eight subjects) relative to CB1+/+ mice (_n_=23 slices from six subjects). c shows the mean decay time constants (tau, τ) of the DA signals, indicating that DA clearance (or uptake) was not different between CB1+/+ (_n_=18 slices from six subjects) and CB1−/− mice (_n_=15 slices from four subjects). **p<0.01, ***p<0.001, compared to CB1+/+ mice, repeated-measures ANOVA

Fig. 4

Fig. 4

Effect of SR141716 on locomotor activity in CB1+/+ mice. a shows locomotion after SR141716 (3, 10 mg/kg, i.p.) or vehicle. b shows overall mean locomotion (AUC data) after SR141716 or vehicle administration. ***p<0.001, compared to vehicle group

Fig. 5

Fig. 5

Effect of SR141716 on extracellular NAc DA levels in CB1+/+ mice. a shows extracellular DA after SR141716 (3 mg/kg, i.p.) or vehicle. b shows overall mean NAc DA (AUC data) after SR141716 or vehicle administration. **p<0.01, compared to vehicle group

Fig. 6

Fig. 6

Microdialyses probe locations in the NAc of mice. a Shows a representative probe track. Lines in b indicate the placement of probes in both the core and the shell of the NAc

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