Opposite effects of stimulant and antipsychotic drugs on striatal fast-spiking interneurons - PubMed (original) (raw)

Comparative Study

. 2010 May;35(6):1261-70.

doi: 10.1038/npp.2009.226. Epub 2010 Jan 20.

Affiliations

Comparative Study

Opposite effects of stimulant and antipsychotic drugs on striatal fast-spiking interneurons

Alexander B Wiltschko et al. Neuropsychopharmacology. 2010 May.

Abstract

Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by distinguishing between medium spiny projection neurons (MSNs) and presumed fast-spiking interneurons (FSIs), in freely moving rats. The response of MSNs to both the stimulant amphetamine (0.5 or 2.5 mg/kg) and the antipsychotic eticlopride (0.2 or 1.0 mg/kg) remained highly heterogeneous, with each drug causing both increases and decreases in the firing rate of many MSNs. By contrast, FSIs showed a far more uniform, dose-dependent response to both drugs. All FSIs had decreased firing rate after high eticlopride. After high amphetamine most FSIs increased firing rate, and none decreased. In addition, the activity of the FSI population was positively correlated with locomotor activity, whereas the MSN population showed no consistent response. Our results show a direct relationship between the psychomotor effects of dopaminergic drugs and the firing rate of a specific striatal cell population. Striatal FSIs may have an important role in the behavioral effects of these drugs, and thus may be a valuable target in the development of novel therapies.

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Figures

Figure 1

Figure 1

Identification of striatal cell subpopulations. (a) Waveform duration was measured using spike peak width at half-maximum (‘x') and the peak-to-valley interval (‘y'). A distinct cluster of striatal neurons with characteristic brief waveforms (x<200 μs, y<455 μs) and tonic activity (<2% of inter-spike intervals >1 s; baseline firing rates 2–100 Hz) are presumed FSIs (red; _n_=69). The main cluster of cells with longer-duration waveforms are presumed MSNs (blue; _n_=203). Cells not falling into these classes are indicated in gray (_n_=17), except for a small cluster of cells (green; _n_=4) with the distinctive waveform shape of the ‘O-cells' in our previous studies (Berke et al, 2008; Gage et al, 2008). (b) Two examples each of mean MSN and FSI waveforms (left, central columns), with numbers indicating corresponding points in (a). Right column shows superimposed mean waveforms for all presumed MSNs and FSIs. (c) Recording locations for all striatal neurons. Each cell is indicated as a circle on a nearby atlas section (AP ranges for the three atlas sections: +2.75 to +1.55, +1.44 to + 0.35, +0.12 to −0.24, all mm relative to bregma), using the same color code and numbering as (a, b). Circle areas are proportional to the number of neurons recorded from each site.

Figure 2

Figure 2

Examples of drug-induced firing rate change and relationships to locomotor activity. (a–d) Show data from four separate sessions (one for each drug treatment), in each case plotting locomotor activity above the corresponding firing rate of three simultaneously recorded cells (one FSI at top, and two MSNs; average normalized waveforms are shown at left). Asterisks indicate pairs of neurons that were recorded on the same tetrode. For each neuron, the indicated r value is the overall correlation coefficient between firing rate and locomotor activity (across both saline and drug epochs). Gray blocks over firing rate graphs indicate analyzed saline and drug epochs (drug epoch is truncated), and mean firing rate during these epochs is shown on the right (on a log scale). Black circles indicate cells with significantly higher firing rates under drug than control (p<0.01, two-sample _t_-test), gray circles indicate cells with lower firing rates, and white circles indicate cells with similar firing rates under the two conditions. Low (a) and high eticlopride (b) cause a dose-dependent suppression of locomotor behavior, whereas low (c) and high (d) amphetamine cause a dose-dependent increase. Note that the firing rate of these FSI examples broadly tracks locomotor activity, and that MSN pairs recorded simultaneously from the same tetrode can show opposite directions of firing rate change.

Figure 3

Figure 3

FSIs show consistent drug-induced firing rate changes, whereas MSNs do not. (a and b) Scatter plots comparing spike firing rates (log scale) for MSNs (a) and FSIs (b), after injection of drug vs saline control. ‘Low etic'=0.2 mg/kg eticlopride, ‘high etic'=1 mg/kg eticlopride, ‘low amph'=0.5 mg/kg amphetamine, ‘high amph'=2.5 mg/kg amphetamine. Circle color key is the same as Figure 2. (c and d) Proportions of MSNs, FSIs with each type of drug response. As in (a and b), black indicates increases, gray decreases, and white no change. Numbers on bars indicate absolute numbers of cells in each category. (e and f) Mean firing rates for the MSN, FSI populations during saline and drug time blocks. Asterisks indicate significant differences between saline and drug log firing rates (*p<0.05, **p<0.01 paired _t_-test).

Figure 4

Figure 4

FSI firing rates are positively correlated with locomotor activity, whereas MSNs show no consistent relationship. (a) Scatter plots showing correlation coefficients (r) between individual neuron firing rates and locomotor activity, during each saline or drug epochs for which video was available. (b) Firing rate to locomotor activity correlation coefficients for all FSIs and MSNs. Darker colors indicate cells with significant (p<0.05) correlation. The distribution of FSI was markedly skewed toward positive values, whereas the MSN distribution was not.

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