Striatal Nitric Oxide Activity Better Predicts Motor Disability Than Proto‐Oncogenes

TL;DR

This study shows that nitric oxide activity in the striatum is a better predictor of motor disability than proto-oncogenes in mice treated with certain drugs.

Contribution

The study is the first to compare NOS activity with c-Fos immunoreactivity after multiple doses of D2 antagonists and NOS inhibitors.

Findings

All drugs induced catalepsy, but L-NOARG preserved motor balance.

EPS side effects correlated with NADPH-diaphorase activity in the dorsal striatum.

Higher doses of L-NOARG reduced c-Fos-IR in the dorsolateral striatum and nucleus accumbens.

Abstract

Extrapyramidal symptoms (EPS) are side effects observed after acute administration of D2 antagonists and nitric oxide synthase (NOS) inhibitors in rodents. To date, no study has examined NOS activity in parallel with c‐Fos immunoreactivity (c‐Fos‐IR) following multiple doses of these compounds. The aim of the present study was to evaluate whether catalepsy and motor balance deficits resulting from specific acute doses of haloperidol (Hal), metoclopramide (MCP), and L‐NOARG could correlate with changes in the number of c‐Fos‐IR and nNOS‐positive cells, as well as NADPH‐diaphorase activity in the striatum. Male Swiss mice received Hal (0.1–1 mg/kg, ip), MCP (1–45 mg/kg, ip), L‐NOARG (15–45 mg/kg, ip), or saline. An increased cataleptic effect was observed in all experimental groups. All doses of Hal and the higher doses of MCP resulted in deficits in the Rota‐rod test, whereas L‐NOARG did not affect Rota‐rod performance. Histochemical analysis revealed increased c‐Fos‐IR in the dorsal striatum following Hal, as well as in the dorsolateral striatum after low and intermediate clinically relevant doses of MCP. Both types of D2R antagonists led to an increase in NADPH‐diaphorase activity in the dorsal striatum. Similarly, the higher catalepsy‐inducing doses of L‐NOARG resulted in increased NADPH‐diaphorase activity in the dorsal striatum; however, these same doses also reduced c‐Fos‐IR in the dorsolateral striatum and nucleus accumbens (NAc). In conclusion, all drugs acutely induced catalepsy, with motor balance preserved after L‐NOARG treatment. Our findings suggest that EPS side effects may be attributed to NADPH‐diaphorase activity in the dorsal striatum.

The figure summarizes the experimental design in which mice received a single intraperitoneal injection of saline, haloperidol, metoclopramide, or L‐NOARG at different doses. Extrapyramidal (EPS) side effects were assessed using the catalepsy test and the Rota‐rod test. All drugs induced catalepsy and reduced motor performance, except for L‐NOARG. Acute EPS side effects were significantly correlated with NADPH‐d activity in the dorsal striatum for catalepsy and with nNOS/NADPH‐d activity in the dorsomedial striatum for Rota‐rod performance.

Figures