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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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Histograms illustrating the mean firing rate (a) and mean coefficient of variation (percent) (b) of STN neurons recorded in intact (white square) and 6-OHDA-lesioned (black square) rats; **p < 0.01; ***p < 0.001 vs. corresponding basal value (Student's t test). Distribution of firing patterns (c) of STN neurons in intact and lesioned rats; **p < 0.01 vs. intact group (Chi-squared (χ2) test). d Samples of spontaneous spiking activity recorded in the STN of an intact (top) and a lesioned rat (bottom). Vertical lines represent spike events. Note the increase in the basal firing rate as well as in the bursting discharge in lesioned rats
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Fig1: Histograms illustrating the mean firing rate (a) and mean coefficient of variation (percent) (b) of STN neurons recorded in intact (white square) and 6-OHDA-lesioned (black square) rats; **p < 0.01; ***p < 0.001 vs. corresponding basal value (Student's t test). Distribution of firing patterns (c) of STN neurons in intact and lesioned rats; **p < 0.01 vs. intact group (Chi-squared (χ2) test). d Samples of spontaneous spiking activity recorded in the STN of an intact (top) and a lesioned rat (bottom). Vertical lines represent spike events. Note the increase in the basal firing rate as well as in the bursting discharge in lesioned rats

Mentions: All recorded neurons exhibited the typical electrophysiological characteristics of STN neurons, including a biphasic waveform and a duration of 1.0–1.5 ms. The mean basal firing rate of STN neurons in 6-OHDA-lesioned rats was significantly higher than that found in intact rats (14.0 ± 1.2 vs. 7.1 ± 0.5 Hz, n = 21 and n = 60, respectively, p < 0.0001, Student's t-test; Fig. 1a, d). The coefficient of variation also increased following lesion (83.5 ± 10.6 vs. 60.6 ± 3.2, p < 0.01, Student's t test; Fig. 1b). Consistently, STN neurons in lesioned rats exhibited more bursting discharge than those in intact rats (χ2 = 11.58, df = 2, p < 0.01; Fig. 1c). Thus, in intact rats, 71% of STN neurons exhibited a tonic-firing pattern, 23% a bursting pattern, and 6% a random pattern. In contrast, in lesioned rats, 36% of STN neurons exhibited a tonic-firing pattern, while 64% presented a bursting firing pattern. These observed changes are consistent with the generally accepted idea that the STN is hyperactive in the Parkinsonian state (Bergman et al. 1994; Hassani et al. 1996; Vila et al. 2000; Ni et al. 2001; Magill et al. 2001).Fig. 1


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)

Histograms illustrating the mean firing rate (a) and mean coefficient of variation (percent) (b) of STN neurons recorded in intact (white square) and 6-OHDA-lesioned (black square) rats; **p < 0.01; ***p < 0.001 vs. corresponding basal value (Student's t test). Distribution of firing patterns (c) of STN neurons in intact and lesioned rats; **p < 0.01 vs. intact group (Chi-squared (χ2) test). d Samples of spontaneous spiking activity recorded in the STN of an intact (top) and a lesioned rat (bottom). Vertical lines represent spike events. Note the increase in the basal firing rate as well as in the bursting discharge in lesioned rats
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045509&req=5

Fig1: Histograms illustrating the mean firing rate (a) and mean coefficient of variation (percent) (b) of STN neurons recorded in intact (white square) and 6-OHDA-lesioned (black square) rats; **p < 0.01; ***p < 0.001 vs. corresponding basal value (Student's t test). Distribution of firing patterns (c) of STN neurons in intact and lesioned rats; **p < 0.01 vs. intact group (Chi-squared (χ2) test). d Samples of spontaneous spiking activity recorded in the STN of an intact (top) and a lesioned rat (bottom). Vertical lines represent spike events. Note the increase in the basal firing rate as well as in the bursting discharge in lesioned rats
Mentions: All recorded neurons exhibited the typical electrophysiological characteristics of STN neurons, including a biphasic waveform and a duration of 1.0–1.5 ms. The mean basal firing rate of STN neurons in 6-OHDA-lesioned rats was significantly higher than that found in intact rats (14.0 ± 1.2 vs. 7.1 ± 0.5 Hz, n = 21 and n = 60, respectively, p < 0.0001, Student's t-test; Fig. 1a, d). The coefficient of variation also increased following lesion (83.5 ± 10.6 vs. 60.6 ± 3.2, p < 0.01, Student's t test; Fig. 1b). Consistently, STN neurons in lesioned rats exhibited more bursting discharge than those in intact rats (χ2 = 11.58, df = 2, p < 0.01; Fig. 1c). Thus, in intact rats, 71% of STN neurons exhibited a tonic-firing pattern, 23% a bursting pattern, and 6% a random pattern. In contrast, in lesioned rats, 36% of STN neurons exhibited a tonic-firing pattern, while 64% presented a bursting firing pattern. These observed changes are consistent with the generally accepted idea that the STN is hyperactive in the Parkinsonian state (Bergman et al. 1994; Hassani et al. 1996; Vila et al. 2000; Ni et al. 2001; Magill et al. 2001).Fig. 1

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.

Show MeSH