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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

Global actions of nicotine in the striatal circuit are inhibitory. (A) Raster plot illustrating three brief epochs (3 min each) taken from larger movies (as in Figure 1A). Left epoch: the simultaneous activity of 80 neurons in the continuous presence of NMDA (2 μM; denoted by an arrow, cf., Figure 1). The arrow denotes that NMDA is maintained all the time during this experiment. Colored dots show neuronal vectors indicating spontaneous synchronous activity of neuron pools. Middle epoch: nicotine (1 μM) is added to the bath saline in the presence of NMDA. Note that activity is decreased and the absence of colored dots indicates that spontaneous events of synchronization are now absent. Right epoch: a partial nicotine washing off, two significant peaks of synchronization appear indicating that nicotine actions were reversible. (B) Activity histogram displaying multicellular activity. Significant peaks of synchronization (colored) appear during NMDA but not after addition of nicotine even if NMDA is present. (C) Cumulative activity taken from histogram in (B) (addition of all bars in the histogram over time in a given epoch) shows that rate of accumulated activity was significantly higher in the absence of nicotine. Nicotine lowered the rate of cumulative activity significantly in all slices tested (n = 6 slices; n = 3 epochs per slice were taken). (D) Matrix of vectors similarity along time, without nicotine. (E) Histogram compares the appearance of peaks of synchronization per 3 min epoch in NMDA and in NMDA plus nicotine: it is clear that nicotine significantly abolished NMDA-induced synchronous activity. **P < 0.025.
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Figure 2: Global actions of nicotine in the striatal circuit are inhibitory. (A) Raster plot illustrating three brief epochs (3 min each) taken from larger movies (as in Figure 1A). Left epoch: the simultaneous activity of 80 neurons in the continuous presence of NMDA (2 μM; denoted by an arrow, cf., Figure 1). The arrow denotes that NMDA is maintained all the time during this experiment. Colored dots show neuronal vectors indicating spontaneous synchronous activity of neuron pools. Middle epoch: nicotine (1 μM) is added to the bath saline in the presence of NMDA. Note that activity is decreased and the absence of colored dots indicates that spontaneous events of synchronization are now absent. Right epoch: a partial nicotine washing off, two significant peaks of synchronization appear indicating that nicotine actions were reversible. (B) Activity histogram displaying multicellular activity. Significant peaks of synchronization (colored) appear during NMDA but not after addition of nicotine even if NMDA is present. (C) Cumulative activity taken from histogram in (B) (addition of all bars in the histogram over time in a given epoch) shows that rate of accumulated activity was significantly higher in the absence of nicotine. Nicotine lowered the rate of cumulative activity significantly in all slices tested (n = 6 slices; n = 3 epochs per slice were taken). (D) Matrix of vectors similarity along time, without nicotine. (E) Histogram compares the appearance of peaks of synchronization per 3 min epoch in NMDA and in NMDA plus nicotine: it is clear that nicotine significantly abolished NMDA-induced synchronous activity. **P < 0.025.

Mentions: Raster plot in Figure 2A illustrates three epochs (3 min each separated by dashed vertical lines): the left epoch shows an activity similar to that described in Figure 1A in the continuous presence of 2 μM NMDA (arrow; NMDA was present all the time during this experiment): this activity reveals significant peaks of synchronization in the activity histogram below, the manifestation of assembly dynamics (Figure 2B colored). In NMDA presence, addition of 1 μM nicotine to the bath saline (middle epoch) drastically reduced the level of neuronal activity (horizontal bar indicates time of nicotine exposure). Nicotine reduced most circuit activity: less dots, absence of significant peaks synchronization. Note that the actions of nicotine were reversible upon washing (right epoch). Histogram of multicellular activity (Figure 2B; note significance level indicated by a dashed horizontal line) shows spontaneous and significant peaks of synchronization only in the presence of NMDA alone. Addition of nicotine abolished the peaks of synchronized activity even in the presence of NMDA (Figure 2B). Nonetheless, after nicotine was washed off, the peaks of synchronization begin to return (right epoch). By summating all activity from histogram in Figure 2B over time (all bars in the histogram for each epoch), we obtained a graph of cumulative cell activity (Figure 2C). It shows that total circuit activity in the presence of NMDA is much higher (ad hoc fitting of straight lines where slopes become the rate of accumulation along time ± estimation error). An average of a sample of experiments yields 479 ± 2 (act/min), which decays to 190 ± 1.5 (act/min) during nicotine (n = 6 slices; P < 0.005). Figure 2D shows the similarity matrix when nicotine is not present reassuring that assembly dynamics was present during NMDA. In addition, we counted the number of significant peaks of synchronization per epoch in the presence of NMDA and during nicotine in the continuous presence of NMDA (Figure 2E): an average of 3.3 ± 1.2 peaks/epoch in the control (NMDA) vs. 0.16 ± 0.4 peaks/epoch in the presence of nicotine (n = 6 slices; n = 3 epochs per slice; **P < 0.025).


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)

Global actions of nicotine in the striatal circuit are inhibitory. (A) Raster plot illustrating three brief epochs (3 min each) taken from larger movies (as in Figure 1A). Left epoch: the simultaneous activity of 80 neurons in the continuous presence of NMDA (2 μM; denoted by an arrow, cf., Figure 1). The arrow denotes that NMDA is maintained all the time during this experiment. Colored dots show neuronal vectors indicating spontaneous synchronous activity of neuron pools. Middle epoch: nicotine (1 μM) is added to the bath saline in the presence of NMDA. Note that activity is decreased and the absence of colored dots indicates that spontaneous events of synchronization are now absent. Right epoch: a partial nicotine washing off, two significant peaks of synchronization appear indicating that nicotine actions were reversible. (B) Activity histogram displaying multicellular activity. Significant peaks of synchronization (colored) appear during NMDA but not after addition of nicotine even if NMDA is present. (C) Cumulative activity taken from histogram in (B) (addition of all bars in the histogram over time in a given epoch) shows that rate of accumulated activity was significantly higher in the absence of nicotine. Nicotine lowered the rate of cumulative activity significantly in all slices tested (n = 6 slices; n = 3 epochs per slice were taken). (D) Matrix of vectors similarity along time, without nicotine. (E) Histogram compares the appearance of peaks of synchronization per 3 min epoch in NMDA and in NMDA plus nicotine: it is clear that nicotine significantly abolished NMDA-induced synchronous activity. **P < 0.025.
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Related In: Results  -  Collection

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Figure 2: Global actions of nicotine in the striatal circuit are inhibitory. (A) Raster plot illustrating three brief epochs (3 min each) taken from larger movies (as in Figure 1A). Left epoch: the simultaneous activity of 80 neurons in the continuous presence of NMDA (2 μM; denoted by an arrow, cf., Figure 1). The arrow denotes that NMDA is maintained all the time during this experiment. Colored dots show neuronal vectors indicating spontaneous synchronous activity of neuron pools. Middle epoch: nicotine (1 μM) is added to the bath saline in the presence of NMDA. Note that activity is decreased and the absence of colored dots indicates that spontaneous events of synchronization are now absent. Right epoch: a partial nicotine washing off, two significant peaks of synchronization appear indicating that nicotine actions were reversible. (B) Activity histogram displaying multicellular activity. Significant peaks of synchronization (colored) appear during NMDA but not after addition of nicotine even if NMDA is present. (C) Cumulative activity taken from histogram in (B) (addition of all bars in the histogram over time in a given epoch) shows that rate of accumulated activity was significantly higher in the absence of nicotine. Nicotine lowered the rate of cumulative activity significantly in all slices tested (n = 6 slices; n = 3 epochs per slice were taken). (D) Matrix of vectors similarity along time, without nicotine. (E) Histogram compares the appearance of peaks of synchronization per 3 min epoch in NMDA and in NMDA plus nicotine: it is clear that nicotine significantly abolished NMDA-induced synchronous activity. **P < 0.025.
Mentions: Raster plot in Figure 2A illustrates three epochs (3 min each separated by dashed vertical lines): the left epoch shows an activity similar to that described in Figure 1A in the continuous presence of 2 μM NMDA (arrow; NMDA was present all the time during this experiment): this activity reveals significant peaks of synchronization in the activity histogram below, the manifestation of assembly dynamics (Figure 2B colored). In NMDA presence, addition of 1 μM nicotine to the bath saline (middle epoch) drastically reduced the level of neuronal activity (horizontal bar indicates time of nicotine exposure). Nicotine reduced most circuit activity: less dots, absence of significant peaks synchronization. Note that the actions of nicotine were reversible upon washing (right epoch). Histogram of multicellular activity (Figure 2B; note significance level indicated by a dashed horizontal line) shows spontaneous and significant peaks of synchronization only in the presence of NMDA alone. Addition of nicotine abolished the peaks of synchronized activity even in the presence of NMDA (Figure 2B). Nonetheless, after nicotine was washed off, the peaks of synchronization begin to return (right epoch). By summating all activity from histogram in Figure 2B over time (all bars in the histogram for each epoch), we obtained a graph of cumulative cell activity (Figure 2C). It shows that total circuit activity in the presence of NMDA is much higher (ad hoc fitting of straight lines where slopes become the rate of accumulation along time ± estimation error). An average of a sample of experiments yields 479 ± 2 (act/min), which decays to 190 ± 1.5 (act/min) during nicotine (n = 6 slices; P < 0.005). Figure 2D shows the similarity matrix when nicotine is not present reassuring that assembly dynamics was present during NMDA. In addition, we counted the number of significant peaks of synchronization per epoch in the presence of NMDA and during nicotine in the continuous presence of NMDA (Figure 2E): an average of 3.3 ± 1.2 peaks/epoch in the control (NMDA) vs. 0.16 ± 0.4 peaks/epoch in the presence of nicotine (n = 6 slices; n = 3 epochs per slice; **P < 0.025).

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