Effects of CATECHIN on reserpine-induced vacuous chewing movements: behavioral and biochemical analysis.

This study evaluated the effect of (+)-catechin, a polyphenolic compound, on orofacial dyskinesia (OD) induced by reserpine in mice. The potential modulation of monoaminoxidase (MAO) activity, tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD67) immunoreactivity by catechin were used as biochemical endpoints. The interaction of catechin with MAO-A and MAO-B was determined in vitro and in silico. The effects of catechin on OD induced by reserpine (1 mg/kg for 4 days, subcutaneously) in male Swiss mice were examined. After, catechin (10, 50 or 100 mg/kg, intraperitoneally) or its vehicle were given for another 20 days. On the 6th, 8th, 15th and 26th day, vacuous chewing movements (VCMs) and locomotor activity were quantified. Biochemical markers (MAO activity, TH and GAD67 immunoreactivity) were evaluated in brain structures. In vitro, catechin inhibited both MAO isoforms at concentrations of 0.34 and 1.03 mM being completely reversible for MAO-A and partially reversible for MAO-B. Molecular docking indicated that the catechin bound in the active site of MAO-A, while in the MAO-B it interacted with the surface of the enzyme in an allosteric site. In vivo, reserpine increased the VCMs and decreased the locomotor activity. Catechin (10 mg/kg), decreased the number of VCMs in the 8th day in mice pre-treated with reserpine without altering other behavioral response. Ex vivo, the MAO activity and TH and GAD67 immunoreactivity were not altered by the treatments. Catechin demonstrated a modest and transitory protective effect in a model of OD in mice.

Gabapentin reduces haloperidol-induced vacuous chewing movements in mice.

Tardive dyskinesia (TD) is a common adverse effect observed in patients with long-term use of typical antipsychotic medications. A vacuous chewing movement (VCM) model induced by haloperidol has been used to study these abnormalities in experimental animals. The cause of TD and its treatment remain unknown, but several lines of evidence suggest that dopamine receptor supersensitivity and gamma-aminobutyric acid (GABA) insufficiency play important roles in the development of TD. This study investigated the effects of treatment with the GABA-mimetic drug gabapentin on the development of haloperidol-induced VCMs. Male mice received vehicle, haloperidol (1.5 mg/kg), or gabapentin (GBP, 100 mg/kg) intraperitoneally during 28 consecutive days. Quantification of VCMs was performed before treatment (baseline) and on day 28, and an open-field test was also conducted on the 28th day of treatment. The administration of gabapentin prevented the manifestation of haloperidol-induced VCMs. Treatment with haloperidol alone reduced the locomotor activity in the open-field test that was prevented by co-treatment with gabapentin. We did not find any differences among the groups nor in the tyrosine hydroxylase (TH) or glutamic acid decarboxylase (GAD) immunoreactivity or monoamine levels in the striatum of mice. These results suggest that treatment with gabapentin, an analog of GABA, can attenuate the VCMs induced by acute haloperidol treatment in mice without alterations in monoamine levels, TH, or GAD67 immunoreactivity in the striatum.

Behavioral and neurochemical effects induced by reserpine in mice.

RATIONALE: Reserpine, a monoamine-depleting agent, which irreversibly and non-selectively blocks the vesicular monoamine transporter, has been used as an animal model to study several neurological disorders, including tardive dyskinesia and Parkinson's disease. OBJECTIVE: The purpose of this study was to examine if motor deficits induced by reserpine in mice could be related to alterations in the expression of dopaminergic system proteins such as tyrosine hydroxylase (TH) and dopamine transporter (DAT) and in the activity of monoamine oxidase (MAO). METHODS: Mice received either vehicle or reserpine (0.1, 0.5, or 1 mg/kg, s.c.) for four consecutive days. Two, 20, or 60 days after reserpine withdrawal, behavioral, and neurochemical changes were evaluated. RESULTS: Reserpine at a dose of 0.5 and 1 mg/kg increased vacuous chewing movements (VCMs) and reduced locomotion. Behavioral changes were accompanied by reduction in TH immunoreactivity in the striatum evaluated on days 2 and 20 after the last injection of 1 mg/kg reserpine. Furthermore, negative correlations were found between VCM and MAO-A or MAO-B on day 2 and TH striatal immunoreactivity on day 20 after the last injection of 1 mg/kg reserpine. A positive correlation was observed between VCMs and DAT immunoreactivity in the substantia nigra on day 2 after the last injection of 0.5 mg/kg reserpine. CONCLUSIONS: These findings suggest that the pharmacological blockage of vesicular monoamine transporter (VMAT) by reserpine caused neurochemical and behavioral alterations in mice.

Opioid mechanisms are involved in the disruption of arcaine-induced amnesia by context pre-exposure.

Previous exposure to the training context disrupts glutamatergic N-methyl-d-aspartate receptor (NMDAr) antagonist-induced amnesia, indicating that novelty is necessary for such an amnestic effect. While there are reports that novelty-related release of opioids cause amnesia, no study has addressed whether the amnestic effect of NMDAr antagonists involve opioid mechanisms. In this study we investigated whether pharmacological manipulation of the opioid system immediately after context pre-exposure alters the amnestic effect of arcaine, a NMDAr antagonist. Adult male Wistar rats were habituated (pre-exposed) to a fear conditioning training apparatus or to a different context (open field). Immediately after pre-exposure, animals were injected with saline or naloxone (0.5 mg/kg, i.p.) or anti-beta-endorphin antibody (1:500, i.c.v.). Forty eight hours after pre-exposure session, all animals were subjected to fear conditioning acquisition protocol and saline or arcaine (30 mg/kg, i.p.) was administered immediately after training. Testing was carried out 24 h later, and freezing responses due to re-exposure to the training apparatus were recorded. Pre-exposure to the training apparatus prevented the impairment of memory induced by post-training arcaine. Administration of naloxone or anti-beta-endorphin antibody, immediately after pre-exposure to the training apparatus, reinstated the amnesic effect of post-training arcaine. The results suggest that endogenous opioid mechanisms are involved in the pre-exposure-induced loss of the amnestic effect of arcaine.

Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats.

RATIONALE: Arcaine is a competitive antagonist of the polyamine binding site at the N-methyl-D-aspartic acid receptor which induces state-dependent recall. However, no study has addressed the involvement of other neurotransmitter/neuromodulators in arcaine-induced state dependency. OBJECTIVES: The current study investigates whether the opioid system is involved in arcaine-induced state-dependent memory retrieval of the inhibitory avoidance task (IA) in rats. RESULTS: The systemic administration of arcaine (30 mg/kg, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) 0, 3, 6, or 9 h post-training, reduced step-down latencies at testing. Arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) injection 30 min before testing reversed the performance deficit induced by administration of arcaine or morphine 0, 3 or 6, but not 9 h post-training. The reversal of arcaine-induced impairment of IA performance was completely transferred to morphine and vice versa. The association of low and ineffective doses of morphine and arcaine (10 and 1.5 mg/kg, respectively) were additive and caused state dependency. Naloxone (2 mg/kg, 3 min post-training, or 1 mg/kg, 1 h pre-test, i.p.) reversed the amnesia and the state dependency induced by morphine and arcaine. CONCLUSION: These results suggest that state dependency induced by arcaine involves the opioid system.

Arcaine and MK-801 make recall state-dependent in rats.

RATIONALE: The polyamines putrescine, spermidine, and spermine are a group of aliphatic amines that may act as physiological modulators of the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor implicated in memory formation and consolidation. Arcaine is a competitive antagonist of the polyamine binding site at the NMDA receptor, the post-training administration of which impairs memory of various tasks. OBJECTIVES: In this study, we investigated whether the administration of arcaine and MK-801 alters the memory of the step-down inhibitory avoidance task, and whether the effects of these NMDA antagonists involve state-dependency mechanisms, in adult male Wistar rats. RESULTS: The administration of arcaine (30 mg/kg, i.p.) or MK-801 (0.03 mg/kg, i.p.) immediately after training impaired inhibitory avoidance performance at testing. Arcaine- and MK-801-induced performance impairment was reversed by the administration of arcaine (30 mg/kg, i.p.) and MK-801 (0.03 mg/kg, i.p.), respectively, 30 min before testing. Response transfer also occurred if arcaine substituted MK-801 at testing, and vice-versa. CONCLUSION: These results suggest that arcaine and MK-801 induce state-dependent recall and that, probably due to their ability to decrease NMDA receptor function, one drug can substitute for the other at testing, demonstrating a cross-state dependency between arcaine and MK-801.

Systemic administration of polyaminergic agents modulate fear conditioning in rats.

RATIONALE: The polyamines putrescine, spermine, and spermidine are a group of aliphatic amines that physiologically modulate the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor implicated in memory formation. OBJECTIVES: Given the potential application of these drugs in the treatment of memory disorders, we investigated whether agonists and/or antagonists of the NMDA receptor polyamine binding site alters the memory of fear conditioning and determined the time window in which fear conditioning is modulated by polyaminergic agents given by the systemic route. RESULTS: Post-training intraperitoneal administration of spermidine (10-100 mg/kg) immediately after training increased, whereas arcaine (10 mg/kg) and MK-801 (0.01-0.1 mg/kg) decreased contextual and auditory fear conditioning. Arcaine and MK-801, at doses that had no effect per se, reversed the facilitatory effect of spermidine. Memory of fear conditioning was impaired by polyaminergic blockade up to 180 min but not at 360 min after training. CONCLUSION: These results provide evidence that systemic administration of polyamine binding site ligands modulate early consolidation of fear conditioning.