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Global actions of nicotine on the striatal microcircuit.

Plata V, Duhne M, Pérez-Ortega J, Hernández-Martinez R, Rueda-Orozco P, Galarraga E, Drucker-Colín R, Bargas J - Front Syst Neurosci (2013)

Bottom Line: Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs.We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons.This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

View Article: PubMed Central - PubMed

Affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México Mexico City, Mexico.

ABSTRACT

The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

No MeSH data available.


Related in: MedlinePlus

Nicotine inhibits Parkinsonian activity in the dopamine depleted striatal microcircuit. (A) Raster plots showing five epochs of activity in a DA-depleted striatal circuit. There is spontaneous neuronal activity in the absence of NMDA (first three epochs shows activity in a 6-OHDA rodent model of hemi-Parkinsonism, see Materials and Methods). However, significant synchronization is composed of the same neuron pool. Last two epochs show that nicotine reduces this activity. (B) Note that activity during DA deprivation exhibits significant peaks of synchronization. However, all are depicted with the same color since similarity indexes indicate that these vectors are built with a similar set of neurons presenting correlated activity in a recurrent mode. Note that these peaks disappear during nicotine. (C) Cumulative activity is significantly higher during DA-depletion than during DA-depletion with nicotine. (D) Similarity matrix shows similar neuronal vectors dominating the activity through the time in the DA depleted microcircuit. (E) LLE shows that the same network state keeps repeating its firing over time in the DA depleted tissue (all dots are of the same group-color), as though the circuit could not leave this dominant network state (Jáidar et al., 2010). Nicotine was capable to suppress this recurrent network state significantly. (F) The histogram shows that peaks of spontaneous synchronization are virtually abolished by nicotine. ***P < 0.005.
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Figure 5: Nicotine inhibits Parkinsonian activity in the dopamine depleted striatal microcircuit. (A) Raster plots showing five epochs of activity in a DA-depleted striatal circuit. There is spontaneous neuronal activity in the absence of NMDA (first three epochs shows activity in a 6-OHDA rodent model of hemi-Parkinsonism, see Materials and Methods). However, significant synchronization is composed of the same neuron pool. Last two epochs show that nicotine reduces this activity. (B) Note that activity during DA deprivation exhibits significant peaks of synchronization. However, all are depicted with the same color since similarity indexes indicate that these vectors are built with a similar set of neurons presenting correlated activity in a recurrent mode. Note that these peaks disappear during nicotine. (C) Cumulative activity is significantly higher during DA-depletion than during DA-depletion with nicotine. (D) Similarity matrix shows similar neuronal vectors dominating the activity through the time in the DA depleted microcircuit. (E) LLE shows that the same network state keeps repeating its firing over time in the DA depleted tissue (all dots are of the same group-color), as though the circuit could not leave this dominant network state (Jáidar et al., 2010). Nicotine was capable to suppress this recurrent network state significantly. (F) The histogram shows that peaks of spontaneous synchronization are virtually abolished by nicotine. ***P < 0.005.

Mentions: As already reported (Jáidar et al., 2010), the DA depleted striatum exhibited spontaneous activity and peaks of statistically significant synchronization that appear spontaneously in the absence of NMDA or any other excitatory drive (Figures 5A,B; first three epochs). This pathological activity is different to the one recorded in the control striatum without NMDA (leftmost epoch in Figure 1A). It is also different than NMDA-induced activity in control tissue (Carrillo-Reid et al., 2008; Jáidar et al., 2010). First three epochs in the raster plot of Figure 5A show Parkinsonian activity followed by addition of nicotine in the last two epochs. In fact, nicotine was added after the beginning of the fourth epoch to appreciate the quick action of nicotine. Activity histogram (Figure 5B) shows that the DA-depleted microcircuit presents significant peaks of synchronization. Note however, that in this case the peaks are composed by the same pool of neurons (same color red), having recurrent activity once and again (Jáidar et al., 2010) as it is the case with bicuculline actions when it is given alone (Carrillo-Reid et al., 2008). In other words, DA-depletion produces an increased activity with no alternation. Interestingly, addition of 1 μM nicotine to the bath saline (last two frames) abolished Parkinsonian activity and the peaks of synchronization (last two epochs in Figures 5A,B). Cumulative activity clearly shows more activity over time for the Parkinsonian microcircuit (Figure 5C): average rate of activity over time in the DA deprived circuit was: 170 ± 1 (act/min) while it was 54 ± 0.4 (act/min) after nicotine (n = 6; P < 0.006), showing that nicotine significantly reduced pathological activity.


Global actions of nicotine on the striatal microcircuit.

Plata V, Duhne M, Pérez-Ortega J, Hernández-Martinez R, Rueda-Orozco P, Galarraga E, Drucker-Colín R, Bargas J - Front Syst Neurosci (2013)

Nicotine inhibits Parkinsonian activity in the dopamine depleted striatal microcircuit. (A) Raster plots showing five epochs of activity in a DA-depleted striatal circuit. There is spontaneous neuronal activity in the absence of NMDA (first three epochs shows activity in a 6-OHDA rodent model of hemi-Parkinsonism, see Materials and Methods). However, significant synchronization is composed of the same neuron pool. Last two epochs show that nicotine reduces this activity. (B) Note that activity during DA deprivation exhibits significant peaks of synchronization. However, all are depicted with the same color since similarity indexes indicate that these vectors are built with a similar set of neurons presenting correlated activity in a recurrent mode. Note that these peaks disappear during nicotine. (C) Cumulative activity is significantly higher during DA-depletion than during DA-depletion with nicotine. (D) Similarity matrix shows similar neuronal vectors dominating the activity through the time in the DA depleted microcircuit. (E) LLE shows that the same network state keeps repeating its firing over time in the DA depleted tissue (all dots are of the same group-color), as though the circuit could not leave this dominant network state (Jáidar et al., 2010). Nicotine was capable to suppress this recurrent network state significantly. (F) The histogram shows that peaks of spontaneous synchronization are virtually abolished by nicotine. ***P < 0.005.
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Related In: Results  -  Collection

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Show All Figures
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Figure 5: Nicotine inhibits Parkinsonian activity in the dopamine depleted striatal microcircuit. (A) Raster plots showing five epochs of activity in a DA-depleted striatal circuit. There is spontaneous neuronal activity in the absence of NMDA (first three epochs shows activity in a 6-OHDA rodent model of hemi-Parkinsonism, see Materials and Methods). However, significant synchronization is composed of the same neuron pool. Last two epochs show that nicotine reduces this activity. (B) Note that activity during DA deprivation exhibits significant peaks of synchronization. However, all are depicted with the same color since similarity indexes indicate that these vectors are built with a similar set of neurons presenting correlated activity in a recurrent mode. Note that these peaks disappear during nicotine. (C) Cumulative activity is significantly higher during DA-depletion than during DA-depletion with nicotine. (D) Similarity matrix shows similar neuronal vectors dominating the activity through the time in the DA depleted microcircuit. (E) LLE shows that the same network state keeps repeating its firing over time in the DA depleted tissue (all dots are of the same group-color), as though the circuit could not leave this dominant network state (Jáidar et al., 2010). Nicotine was capable to suppress this recurrent network state significantly. (F) The histogram shows that peaks of spontaneous synchronization are virtually abolished by nicotine. ***P < 0.005.
Mentions: As already reported (Jáidar et al., 2010), the DA depleted striatum exhibited spontaneous activity and peaks of statistically significant synchronization that appear spontaneously in the absence of NMDA or any other excitatory drive (Figures 5A,B; first three epochs). This pathological activity is different to the one recorded in the control striatum without NMDA (leftmost epoch in Figure 1A). It is also different than NMDA-induced activity in control tissue (Carrillo-Reid et al., 2008; Jáidar et al., 2010). First three epochs in the raster plot of Figure 5A show Parkinsonian activity followed by addition of nicotine in the last two epochs. In fact, nicotine was added after the beginning of the fourth epoch to appreciate the quick action of nicotine. Activity histogram (Figure 5B) shows that the DA-depleted microcircuit presents significant peaks of synchronization. Note however, that in this case the peaks are composed by the same pool of neurons (same color red), having recurrent activity once and again (Jáidar et al., 2010) as it is the case with bicuculline actions when it is given alone (Carrillo-Reid et al., 2008). In other words, DA-depletion produces an increased activity with no alternation. Interestingly, addition of 1 μM nicotine to the bath saline (last two frames) abolished Parkinsonian activity and the peaks of synchronization (last two epochs in Figures 5A,B). Cumulative activity clearly shows more activity over time for the Parkinsonian microcircuit (Figure 5C): average rate of activity over time in the DA deprived circuit was: 170 ± 1 (act/min) while it was 54 ± 0.4 (act/min) after nicotine (n = 6; P < 0.006), showing that nicotine significantly reduced pathological activity.

Bottom Line: Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs.We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons.This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

View Article: PubMed Central - PubMed

Affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México Mexico City, Mexico.

ABSTRACT

The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

No MeSH data available.


Related in: MedlinePlus