Effects of melatonin and agomelatine in anxiety-related procedures in rats: interaction with diazepam.

The anxiolytic potential of melatonin and agomelatine, a potent MT(1/2) receptor agonist, and their combined effects with diazepam, were investigated in rats using the punished drinking test, the safety signal withdrawal operant paradigm, the elevated-plus-maze and hypophagia-induced novelty. In the punished drinking test, evening injections of melatonin (80 mg/kg, IP, but not 20 and 40 mg/kg) and agomelatine (40 mg/kg, IP) increased the number of foot shocks received. However, neither melatonin (40-80 mg/kg) nor agomelatine (20-40 mg/kg) released response suppression during the period associated with the safety signal withdrawal and affected rats' behaviour in the elevated-plus-maze. Furthermore, agomelatine (40 mg/kg) did not enhance food consumption in unfamiliar environment. However, the co-administration of melatonin (80 mg/kg) or agomelatine (20-40 mg/kg) with diazepam, at a dose (0.25 mg/kg) inactive on its own, induced an anxiolytic-like effect in the punished drinking test and the elevated plus-maze. These results indicate that, although mostly devoid of anxiolytic-like action per se, melatonin and agomelatine can potentiate the anxiolytic effects of diazepam.

Antidepressant-like effects of agomelatine, melatonin and the NK1 receptor antagonist GR205171 in impulsive-related behaviour in rats.

RATIONALE: Substance P receptor [neurokinin1 (NK1-R)] antagonists and melatonin(1/2) receptor (MT(1/2)-R) agonists have been claimed to be potential antidepressants (ADs). In animals, these compounds are active in validated models responsive to ADs, such as forced swimming test and chronic mild stress paradigms. Classical AD drugs are also known to be effective in pathologies characterized by an impulse control deficiency. In line with this clinical observation, previous studies demonstrated that classical ADs increased the capacity to wait for food reward in rats subjected to a paradigm aimed at assessing impulsive-related behaviour. OBJECTIVES: This study was conducted to investigate the effects of two MT(1/2)-R agonists, melatonin and agomelatine, and a NK1-R antagonist, GR205171, on tolerance to delay of food reward in rats. METHODS: Fasting rats were trained in a T-maze and allowed to choose between two magnitudes of reward: immediate but small reward (two pellets) vs 25-s delayed but large reward (ten pellets). Under this alternative, vehicle-injected rats selected the large-but-delayed reinforcer in less than 40% of the trials. RESULTS: Like the established ADs clomipramine (8 mg kg(-1), i.p.) and fluvoxamine (4 mg kg(-1), i.p.), melatonin (3 and 10 mg kg(-1), i.p.), agomelatine (10 and 30 mg kg(-1), i.p.) and GR205171 (30 mg kg(-1) but not 10 mg kg(-1), s.c.) significantly increased the number of choices of the large-but-delayed reward. The effect of melatonin (3 mg kg(-1), i.p.) was not counteracted by the MT(1/2)-R antagonist S22153 (40 mg kg(-1), i.p.) that exerted no effect on its own. CONCLUSION: These results suggest that MT(1/2)-R agonists and NK1-R antagonists enhance rats' tolerance to delay of gratification, an effect which may reflect their ability to improve impulse control. Further investigations are necessary to clarify the neurobiological mechanisms responsible for this effect.

Respective roles of dopamine D2 and D3 receptors in food-seeking behaviour in rats.

RATIONALE: Dopaminergic mechanisms are thought to be critically involved in reward-related processes and seeking behaviour. OBJECTIVE: To examine the involvement of dopamine in seeking behaviour supported by a natural reinforcer, food, and assess the role of D(2) and D(3) receptor subtypes in food-seeking, using an operant reinstatement procedure. METHODS: Wistar rats were subjected to a within-session extinction procedure. Experimental sessions consisted of a 15-min rewarded period during which each right lever press delivered one food pellet and initiated a 10-s time out period (FR1:TO(10s)), followed by a 45-min extinction period during which responding was no longer rewarded. The reinstating effects of dopaminergic drugs, food priming, or the combination of both treatments, were investigated during spaced test sessions. In dose range studies, dopamine receptor ligands were administered 20 or 30 min into the test sessions. In interaction studies, antagonists were injected immediately before testing. Food priming consisted of two pellets non-contingently delivered 45 min into the test sessions. RESULTS: Well trained rats emitted many responses during the rewarded period but almost none during extinction. During the last 15 min of the test sessions, non-rewarded responding was reinstated by the D(2)/D(3) agonist, apomorphine (0.125-0.25 mg/kg, SC), and the D(3) preferring agonist, 7-OH-DPAT (2-4 mg/kg, SC), but not by quinelorane (0.004-2 mg/kg, SC), another D(3) preferring agonist. In interaction studies, the D(2) preferring antagonist, raclopride (0.06-0.125 mg/kg, IP), and the D(3) preferring antagonist, l-nafadotride (1 mg/kg, IP), counteracted the reinstating effect of apomorphine and 7-OH-DPAT. Pellets non-contingently delivered during extinction, reinstated modest, but significant, responding. Such food-primed food-seeking was altered by neither nafadotride (0.015-1 mg/kg, IP) nor the D(2)/D(3) antagonists, amisulpride (0.25-1 mg/kg, IP) or sulpiride (2-4 mg/kg, IP). Food- and apomorphine-induced response reinstatement were additive, and food-primed food-seeking behaviour was potentiated by 7-OH-DPAT (0.125-1 mg/kg, SC) and quinelorane (7.5-15 micro g/kg, SC). Such a potentiation was reversed by two D(2) antagonists, haloperidol (0.05 mg/kg, IP) and raclopride (0.125 mg/kg, IP), but not by nafadotride (1 mg/kg, IP) and another D(3) preferring antagonist, S 33084 (0.25-2 mg/kg, SC). CONCLUSION: These results indicate that reinstatement of non-reinforced responding by non-contingent food delivery and by dopamine agonists probably depend on different mechanisms. The properties of D(2)/D(3) receptor agonists, to reinstate food seeking at larger doses, and to potentiate food-primed response reinstatement at lower doses, are preferentially mediated by D(2) rather than by D(3) receptors.