Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

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.

Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens

“…In primates, striatal interneurons have been reported to show spontaneous inhibitory responses in response to conditioned reinforcers (Joshua et al, 2008;Kimura et al, 1984), suggesting that spontaneous inhibition of NAc FSIs may be a functional correlate of behavioral reward processing. Interestingly, a study from Wiltschko et al (2010) reported that systemic administration of high doses of a D2 receptor antagonist, eticlopride, caused strong inhibition in the spontaneous activity rates of NAc FSI populations recorded in rats, consistent with the present results. Furthermore, we have reported previously that specific blockade of D2 receptors within the shell (but not core) division of the NAc is sufficient to switch nicotine aversion behaviors into rewarding effects (Laviolette et al, 2008).…”

Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations

“…To ensure only this cell type entered our data set, we recorded units with low baseline activity (Ͻ5 Hz), and the firing rates we observed (1.37 spikes/s Ϯ 1.25, means Ϯ SD) are consistent with previous studies (Barnes et al 2005;Berke et al 2004;Mowery et al 2011;Schmitzer-Torbert and Redish 2008;Sharott et al 2009). Furthermore, we noted that the spike waveforms of the recorded units showed peak to valley intervals (means Ϯ SE) of 735 Ϯ 57 s and peak widths of 372 Ϯ 15 s, which are in agreement with previously reported MSN extracellular waveform characteristics (Wiltschko et al 2010). We recorded from 35 neurons.…”

Methylphenidate effects on blood serotonin and melatonin levels may help to synchronise biological rhythms in children with ADHD

“…Frontal and striatal abnormalities have been associated with ADHD. The underlying pathophysiology of ADHD may involve dysregulation of the noradrenergic frontocortical inhibition of dopaminergic striatal structures (Kelly et al, 2007;Wiltschko et al, 2010). 5-HT and melatonin perform a broad range of physiological functions.…”