Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice.

Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5mg/kg) or morphine (10mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.

Involvement of alpha1-adrenoceptors in conditioned place preference supported by nicotine in rats.

RATIONALE: The noradrenergic system might be a critical mediator of psychostimulants and opiates hedonic value. OBJECTIVES: The objective of this study is to evaluate the involvement of alpha1-adrenoceptors (alpha1-ARs) in nicotine incentive learning. MATERIALS AND METHODS: Rats, subjected to an unbiased conditioned place preference (CPP) procedure, received eight 30-min alternating nicotine (0.06 mg/kg) and saline pairings with distinct floor textures. The alpha1-AR antagonist, prazosin (0.125, 0.25, 0.5, or 1 mg/kg), was administered 30 min before nicotine pairings (acquisition) or one of the two 20-min test sessions conducted 24 h and 3 weeks after conditioning (expression). RESULTS: Pre-pairing injections of prazosin (0.5-1 mg/kg) prevented the acquisition of nicotine-CPP. On pre-test administration, prazosin (0.5 mg/kg) abolished the short-term expression of nicotine-CPP; whereas, none of the tested doses impaired its long-term expression. During a drug-free 3-week test session, nicotine-CPP was also weakened in rats given prazosin (0.5 mg/kg) before the 24-h test, while nicotine-CPP was reduced neither in animals given prazosin immediately after the first test session nor in those not subjected to the 24-h test. CONCLUSIONS: The activation of alpha1-ARs is one of the mechanisms that code for the incentive motivational value of nicotine. It participates also in the short-term, but not the long-term, control of behavior by nicotine-paired stimuli. The latter effect does not result from disruption by prazosin of either memory for the nicotine-cue association or reconsolidation processes at recall. Thus, differences exist in the neurobiological mechanisms that contribute to the incentive motivational value of nicotine and the short- and long-term "memory" of the incentive salience acquired by nicotine-paired cues.

Differential involvement of the endocannabinoid system in short- and long-term expression of incentive learning supported by nicotine in rats.

RATIONALE: We previously reported that the CB1 cannabinoid receptor antagonist, rimonabant, impaired the acquisition and the short-term (24 h), but not long-term (3 weeks), expression of conditioned place preference (CPP) induced by nicotine in rats. OBJECTIVE: To assess the time interval of efficacy of a single pretest injection of rimonabant to abolish nicotine-CPP, and the effects of chronic CB1 receptor blockade on long-term expression of nicotine-CPP. MATERIALS AND METHODS: Wistar rats were conditioned to nicotine (0.06 mg/kg, subcutaneous) using an unbiased one-compartment procedure. Two test sessions were conducted 24 h (without injection) and 1, 2, or 3 weeks later. Rimonabant (3 mg/kg, intraperitoneal) or vehicle was administered daily between the two test sessions. In addition, the CB1-stimulated [(35)S]GTP-gamma-S binding was assessed in rats from the 3-week experiment. RESULTS: The capacity of a single injection of rimonabant (3 mg/kg, 30 min pretest) to block the expression of nicotine-CPP disappeared within 1 week after conditioning. Daily administrations of rimonabant for 6, 13, or 20 days post-acquisition did not impair nicotine-CPP but allowed an additional pretest injection of rimonabant to retain its capacity to abolish long-term expression of nicotine-CPP. The CB1 receptor-mediated G-protein signaling was not altered in various brain areas of rats given rimonabant for 3 weeks. CONCLUSIONS: The endocannabinoid system is essential to the expression of nicotine-CPP during less than 1 week after conditioning but not later. However, endocannabinoid-dependent mechanisms are critically involved in the development of the neuroadaptive changes responsible for the shift from CB1-dependent to CB1-independent expression of nicotine incentive learning.

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.

Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats.

RATIONALE: The endocannabinoid system plays a role in mediating the appetitive value of a variety of reinforcing compounds, either natural rewards or drugs of abuse, but little is known about its involvement in the incentive properties of nicotine. OBJECTIVES: The objective of the study is to evaluate whether activation of CB1 cannabinoid receptors is necessary for the establishment and the short- and long-term expression of nicotine-induced conditioned place preference (CPP). This was studied in rats subjected to an unbiased, one-compartment place conditioning procedure, using the selective CB1 receptor antagonist, rimonabant, as a pharmacological tool. METHODS: Wistar rats, given previous experience with nicotine in their home cage, were subjected to eight alternating nicotine (0.006-0.6 mg/kg s.c.) and saline pairings with distinct floor textures in an open field and given a test session, with no nicotine injection, in the open field whose floor was covered by two quadrants of the saline-paired texture and two quadrants of the nicotine-paired texture. Rimonabant (0.3-3 mg/kg i.p.) was administered 30 min before each nicotine (0.06 mg/kg) pairing to assess its effect on the establishment of nicotine-CPP. To study the effects of CB1 receptor blockade on short- and long-term expression of nicotine-CPP, rimonabant was administered as a single injection 30 min before the test session, conducted either 24 h, 3 weeks or 12 weeks after the last conditioning session. RESULTS: Rats developed reliable and robust CPP to the 0.06- and 0.125-mg/kg doses of nicotine. Once established, CPP persisted for at least 12 weeks without additional exposure to nicotine and the test apparatus. Pre-pairing injections of rimonabant (3 mg/kg, but not lower doses) prevented the acquisition of nicotine-CPP, and a single pretest administration of rimonabant (3 mg/kg) abolished the expression of nicotine-CPP when the test session took place 24 h after the last conditioning session. However, rimonabant (3 mg/kg) did not antagonize the expression of nicotine-CPP when the test session was conducted 3 or 12 weeks after the acquisition phase. CONCLUSIONS: The endocannabinoids are a necessary component in both the perception by rats of the motivational value of nicotine and the short-term capacity of nicotine-paired conditioned stimuli to elicit approach behaviour. In contrast, the acute blockade of CB1 receptors no longer impairs the long-term control of behaviour by nicotine-associated environmental cues. These data provide support to the notion that the blockade of CB1 receptors can oppose tobacco dependence, withdrawal and even relapse, though the time window of efficacy and/or the schedule of administration remain to be established.

Blockade by the cannabinoid CB1 receptor antagonist, rimonabant (SR141716), of the potentiation by quinelorane of food-primed reinstatement of food-seeking behavior.

It has been shown previously that the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716), reduced the intake of palatable food as well as the self-administration of several drugs of abuse, suggesting that endocannabinoid systems play a role in brain reward function. The present study investigated whether a cannabinoid step was involved in food-seeking behavior induced by explicit stimuli, using an operant reinstatement procedure in rats. Experimental sessions consisted of a 15-min food rewarded period, followed by a 45-min extinction period. Rimonabant did not affect the response reinstatement induced by noncontingent delivery of food pellets, but prevented (0.03-0.3 mg/kg) the potentiation by quinelorane, a dopamine D3 receptor-preferring agonist, of food-seeking behavior. A possible link between cannabinoid processes and D3- and/or D2-mediated dopaminergic transmission was further investigated by studying Fos protein expression in cortico-limbic structures in D3 (D3-/-) and D2 (D2-/-) knockout mice. Rimonabant (10 mg/kg) increased Fos immunoreactivity in the prefrontal cortex (pFCortex) and in the shell but not the core of the nucleus accumbens (NAcc). Fos induction by this dose of rimonabant was not seen in mice lacking CB1 receptors, providing clear evidence for the involvement of CB1 receptors. In the NAcc shell, the effect of rimonabant was suppressed in D3-/-, but remained unchanged in D2-/- mice. In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion. In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes. Overall, these results are consistent with the notion that endocannabinoid functions control brain reward processes and in particular the capacity of explicit stimuli to precipitate food-seeking behavior.

Effects of a dopamine D3 receptor ligand, BP 897, on acquisition and expression of food-, morphine-, and cocaine-induced conditioned place preference, and food-seeking behavior in rats.

The present study addressed the role of dopaminergic D(3) receptors (D(3)R) in motivational processes in rats. The effects of the selective D(3)R partial agonist, BP 897 (0.25-1 mg/kg, i.p.), on the establishment and the expression of conditioned place preference (CPP) supported by food, morphine (4 mg/kg, s.c.), or cocaine (2 mg/kg, s.c.) were investigated using an unbiased, one-compartment, place-conditioning procedure. When administered alone, BP 897 (0.05-2 mg/kg, i.p.) did not support CPP; on the contrary, conditioned place avoidance (CPA) was observed at 1 mg/kg, suggesting that this dose of BP 897 could be perceived as aversive. When given before each cocaine injection during the conditioning phase, BP 897 (1 mg/kg) prevented the establishment of CPP, and a single administration of BP 897 (0.5 and 1 mg/kg) before the test session impaired the expression of cocaine CPP. In contrast, neither the establishment nor the expression of food- and morphine-CPP were significantly altered by BP 897 (up to 1 mg/kg), whereas the full but less selective D(3)/D(2)R agonists, 7-OH-DPAT (0.5-2 mug/kg, s.c.) and quinelorane (1 mug/kg, s.c.), prevented the acquisition of food CPP. In a within-session extinction schedule of lever pressing for food, BP 897 (0.06-2 mg/kg) was ineffective in potentiating response reinstatement induced by the noncontingent delivery of two food pellets, in contrast with quinelorane and 7-OH-DPAT where previous studies showed to be efficient in this respect (Duarte et al, 2003). These results indicate that BP 897 has no positive appetitive value on its own, and that a moderate degree of stimulation of D(3)R is not sufficient to modulate food-primed food-seeking behavior or alter incentive motivation for food, morphine, and/or their associated cues. However, D(3)R are likely involved in the perception of the rewarding value of cocaine and cocaine-paired cues. This suggests that the appetitive effects of cocaine are subserved by mechanisms different, at least in part, from those of morphine and food, and that D(3)R play a role only in the former.

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.