Early Life Stress Causes Refractoriness to Haloperidol-Induced Catalepsy

Abstract

The use of classic antipsychotic drugs is limited by the occurrence of extrapyramidal motor symptoms, which are caused by dopamine (DA) receptor blockade in the neostriatum. We examined the impact of early-life stress on haloperidol-induced catalepsy using the rat model of prenatal restraint stress (PRS). Adult "PRS rats," i.e., the offspring of mothers exposed to restraint stress during pregnancy, were resistant to catalepsy induced by haloperidol (0.5-5 mg/kg i.p.) or raclopride (2 mg/kg s.c.). Resistance to catalepsy in PRS rats did not depend on reductions in blood or striatal levels, as compared with unstressed control rats. PRS rats also showed a greater behavioral response to the DA receptor agonist, apomorphine, suggesting that PRS causes enduring neuroplastic changes in the basal ganglia motor circuit. To examine the activity of this circuit, we performed a stereological counting of c-Fos 1 neurons in the external and internal globus pallidus, subthalamic nucleus, and ventral motor thalamic nuclei. Remarkably, the number of c-Fos 1 neurons in ventral motor thalamic nuclei was higher in PRS rats than in unstressed controls, both under basal conditions and in response to single or repeated injections with haloperidol. Ventral motor thalamic nuclei contain exclusively excitatory projection neurons that convey the basal ganglia motor programming to the cerebral cortex. Hence, an increased activity of ventral motor thalamic nuclei nicely explains the refractoriness of PRS rats to haloperidol-induced catalepsy. Our data raise the interesting possibility that early-life stress is protective against extrapyramidal motor effects of antipsychotic drugs in the adult life.

Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction

“…Besides the well‐known role of cortical noradrenergic and glutamatergic transmission in mood disorders (Pittaluga et al ., ; Marrocco et al ., ; Nasca et al ., ), recent evidence strongly supports the notion that depression and anxiety is an inflammatory condition and that elevated levels of endogenous cytokines (including TNF‐α, Hashmi et al ., ) might have a role in eliciting these behaviours. Whether pathologically‐relevant amounts of CCL5 could participate in determining anxiety and depression in MS patients remains to be established, although the positive effects acute DMI exerts on thigmotaxis (being inactive on motor behaviour and clinical scores) could support this hypothesis.…”

“…Further studies are required to investigate the effect of acute early DMI on disease progression. Recent evidence has highlighted the role of glutamate in anxiety and mood disorders and several compounds with antidepressant activity are known to restore glutamatergic transmission to physiological levels (Bonanno et al, 2005;Marrocco et al, 2013;Nasca et al, 2013). The DMI-induced restoration of glutamate exocytosis might therefore well account for the decreased anxiety-like behaviour observed in EAE mice at 13 d.p.i.…”

Unilateral and Bilateral Cortical Resection: Effects on Spike-Wave Discharges in a Genetic Absence Epilepsy Model

“…The injection and recording times of both the experimental and control groups are presented in Figs 2 and 3 . Subsequent injections of haloperidol (half-life 2 hours [ 27 ]) and buprenorphine (half-life 2–4 hours [ 28 ]) were given in order to maintain an appropriate depth of anaesthesia, which was regularly monitored via toe pinch reflexes. After the end of the day, the rats were still anesthetized, they were given an overdose of ketamine (100mg/ml)/xylazine (20 mg/ml), systemically administered, without any sign of adverse reaction.…”