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Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Morera-Herreras T, Ruiz-Ortega JA, Linazasoro G, Ugedo L - Psychopharmacology (Berl.) (2010)

Bottom Line: Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed.Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway.These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Vizcaya, Spain.

ABSTRACT

Rationale: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.

Objective: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.

Results: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.

Conclusions: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

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Representative firing rate histograms illustrating the effect of intravenous (i.v.) administration of cumulative doses of WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on STN neuronal activity in intact (a) and 6-OHDA-lesioned rats (b). Both stimulatory and inhibitory effects were reversed by administration of the CB1 receptor antagonist rimonabant (250–2,000 μg/kg, i.v.). c The mean firing rate and (d) the mean value of the coefficient of variation of STN neurons following WIN 55,212-2 administration (31.25–250 μg/kg, i.v., doubling doses) in intact (white circle; n = 8) and lesioned rats (black circle; n = 8). Data are expressed as mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001 vs. corresponding basal value (one-way repeated measures ANOVA followed by the Student–Newman–Keuls test)
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Fig2: Representative firing rate histograms illustrating the effect of intravenous (i.v.) administration of cumulative doses of WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on STN neuronal activity in intact (a) and 6-OHDA-lesioned rats (b). Both stimulatory and inhibitory effects were reversed by administration of the CB1 receptor antagonist rimonabant (250–2,000 μg/kg, i.v.). c The mean firing rate and (d) the mean value of the coefficient of variation of STN neurons following WIN 55,212-2 administration (31.25–250 μg/kg, i.v., doubling doses) in intact (white circle; n = 8) and lesioned rats (black circle; n = 8). Data are expressed as mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001 vs. corresponding basal value (one-way repeated measures ANOVA followed by the Student–Newman–Keuls test)

Mentions: We next studied the effect of the synthetic cannabinoid agonist WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on the electrical activity of STN neurons in intact and lesioned rats (one cell per rat). In intact rats, WIN 55,212-2 increased the firing rate of STN neurons (maximal effect, 83 ± 27%; F4,39 = 27.86, p < 0.0001, one-way repeated measures ANOVA; n = 8; Fig. 2a, c). This agonist reduced the coefficient of variation (maximal effect, 26 ± 8%; F4,39 = 3,10, p < 0.05, one-way repeated measures ANOVA; Fig. 2d), and firing was essentially of the bursting discharge type (relative amount of neurons exhibiting bursting pattern significantly increased to 100%; χ2 = 4.29, df = 1, p < 0.05).Fig. 2


Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Morera-Herreras T, Ruiz-Ortega JA, Linazasoro G, Ugedo L - Psychopharmacology (Berl.) (2010)

Representative firing rate histograms illustrating the effect of intravenous (i.v.) administration of cumulative doses of WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on STN neuronal activity in intact (a) and 6-OHDA-lesioned rats (b). Both stimulatory and inhibitory effects were reversed by administration of the CB1 receptor antagonist rimonabant (250–2,000 μg/kg, i.v.). c The mean firing rate and (d) the mean value of the coefficient of variation of STN neurons following WIN 55,212-2 administration (31.25–250 μg/kg, i.v., doubling doses) in intact (white circle; n = 8) and lesioned rats (black circle; n = 8). Data are expressed as mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001 vs. corresponding basal value (one-way repeated measures ANOVA followed by the Student–Newman–Keuls test)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045509&req=5

Fig2: Representative firing rate histograms illustrating the effect of intravenous (i.v.) administration of cumulative doses of WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on STN neuronal activity in intact (a) and 6-OHDA-lesioned rats (b). Both stimulatory and inhibitory effects were reversed by administration of the CB1 receptor antagonist rimonabant (250–2,000 μg/kg, i.v.). c The mean firing rate and (d) the mean value of the coefficient of variation of STN neurons following WIN 55,212-2 administration (31.25–250 μg/kg, i.v., doubling doses) in intact (white circle; n = 8) and lesioned rats (black circle; n = 8). Data are expressed as mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001 vs. corresponding basal value (one-way repeated measures ANOVA followed by the Student–Newman–Keuls test)
Mentions: We next studied the effect of the synthetic cannabinoid agonist WIN 55,212-2 (31.25–250 μg/kg, i.v., doubling doses) on the electrical activity of STN neurons in intact and lesioned rats (one cell per rat). In intact rats, WIN 55,212-2 increased the firing rate of STN neurons (maximal effect, 83 ± 27%; F4,39 = 27.86, p < 0.0001, one-way repeated measures ANOVA; n = 8; Fig. 2a, c). This agonist reduced the coefficient of variation (maximal effect, 26 ± 8%; F4,39 = 3,10, p < 0.05, one-way repeated measures ANOVA; Fig. 2d), and firing was essentially of the bursting discharge type (relative amount of neurons exhibiting bursting pattern significantly increased to 100%; χ2 = 4.29, df = 1, p < 0.05).Fig. 2

Bottom Line: Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed.Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway.These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Vizcaya, Spain.

ABSTRACT

Rationale: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.

Objective: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.

Results: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.

Conclusions: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

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