The neurotoxic mechanisms of amphetamine: Step by step for striatal dopamine depletion.

Amphetamine (AMPH) is a commonly abused psychostimulant that induces neuronal cell death/degeneration in humans and experimental animals. Although multiple neurotoxic mechanisms of AMPH have been intensively investigated, the interplay between these mechanisms has remained elusive. In this study, we used a rat model of AMPH-induced long-lasting striatal dopamine (DA) depletion and identified mechanisms of neurotoxicity, energy failure, excitotoxicity, and oxidative stress. Pretreatment with nicotinamide (NAM, a co-factor for the electron transport chain) blocked AMPH-induced free radical formation, energy failure, and striatal DA decrease. Also, MK-801 (a NMDA receptor antagonist) blocked AMPH-induced free radical formation and striatal DA but not energy failure decrease, indicating excitotoxicity may occur before free radical formation and after energy failure. Thus, these results show that during AMPH intoxication, energy failure, excitotoxicity, and free radical formation are orchestrated consecutively to mediate the depletion of striatal DA.

Implication of cerebral dopamine-beta hydroxylase for cardiovascular and mood regulation in rats.

The essentiality of the role of norepinephrine (NE) in the central nervous system has recently been reconsidered. NE exerts many effects and mediates a number of functions in living organisms. Dopamine-beta-hydroxylase (DBH) is the crucial enzyme for NE and epinephrine biosynthesis. Removal of this enzyme causes deficient NE at sympathetic terminals characterized by orthostatic hypotension in humans. The hypothesis tested in this study was that NE deficiency in the central nervous system caused autonomic failure in cardiovascular regulation. The immunotoxin anti-DBH-saporin (DSAP) was used to examine the putative role of cerebral NE. Male Sprague-Dawley rats were injected, intracerebroventricularly (icv), with DSAP and cardiovascular reactivity, as well as behavioral variables in the open-field locomotion test (OLT), sucrose intake test (SIT) and forced swim test (FST), were monitored for changes. The results indicated that treatment with DSAP caused significant reductions in spontaneous blood pressure (BP) and heart rate (HR), and a decrease in the rearing position on the OLT, in the same group of rats. In addition, a significant increase in mobility with low concurrent immobility frequencies was observed on the FST. However, there was no variation on the SIT. In conclusion, a deficiency in the cerebral DBH might dysregulate the autonomic outflows and, thus, leads to lower BP and HR. However, there was no mood change such as despair or anhedonia observed in the experiments.

Behavioral and cross sensitization after repeated exposure to modafinil and apomorphine in rats.

Repeated exposure to psychostimulant drugs has been known to produce behavioral sensitization, a phenomenon explicitly indexed by locomotion (LM) and stereotyped movements (SM). So far, no evidence has demonstrated that this phenomenon can be displayed following the administration of modafinil (MOD) in animal study. We, therefore, assessed the possibility of behavioral sensitization of MOD and a direct dopamine agonist, apomorphine (APO), and cross-sensitization of these two drugs with one other. Pretreatment with MOD (64 mg/kg) or APO (0.5 mg/kg or 1.0 mg/kg) for 10 consecutive days was followed by a short-term (3 days) or long-term (21 days) withdrawal. Rats were then challenged with the drug and reciprocally re-challenged with the counterpart drug. The results showed that following short-term and long-term washout periods, both MOD and APO successfully induced sensitization in LM and SM. There was no cross-sensitization; an even lesser magnitude in LM when MOD-sensitized rats were challenged with APO was observed. However, after both the short-term and long-term withdrawal periods, APO (1.0 mg/kg)-sensitized rats showed cross-sensitization in LM and SM to MOD (64 mg/kg) challenge. The magnitude of APO-MOD cross-sensitization was lesser than the behavioral sensitization induced by APO alone. Our results indicated behavioral sensitization could be induced in rats exposed to MOD. In addition, changes in dopaminergic receptor activities could be involved in cross-sensitization of APO to MOD but not vice versa.

Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task.

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.