Pia Bäckström

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.

Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking.

Neuroanatomical and pharmacological evidence implicates glutamate transmission in drug-environment conditioning that partly controls drug seeking and relapse. Glutamate receptors could be targets for pharmacological attenuation of the motivational properties of drug-paired cues and for relapse prevention. The purpose of the present study was therefore to investigate the involvement of ionotropic and metabotropic glutamate receptor subtypes in cue-induced reinstatement of cocaine-seeking behavior. Rats were trained to self-administer cocaine using a second-order schedule of reinforcement (FR4(FR5:S)) under which a compound stimulus (light and tone) associated with cocaine infusions was presented contingently. Following extinction, the effects of the competitive NMDA receptor antagonist CGP 39551 (0, 2.5, 5, 10 mg/kg intraperitoneally (i.p.)), two competitive AMPA/kainate antagonists, CNQX (0, 0.75, 1.5, 3 mg/kg i.p.) and NBQX (0, 1.25, 2.5, 5 mg/kg i.p.), the NMDA/glycine site antagonist L-701,324 (0, 0.63, 1.25, 2.5 mg/kg i.p.), and the mGluR5 antagonist MPEP (0, 1.25, 2.5, 5 mg/kg i.p.) on cue-induced reinstatement of cocaine seeking were examined. The AMPA/kainate receptor antagonists CNQX and NBQX, the NMDA/glycine site antagonist L-701,324, and the mGluR5 antagonist MPEP attenuated significantly cue-induced reinstatement. The NMDA antagonist CGP 39551 failed to affect reinstatement. Additional control experiments indicated that attenuation of cue-induced reinstatement by CNQX, NBQX, L-701,324, and MPEP was not accompanied by significant suppression of spontaneous locomotor activity. These results suggest that conditioned influences on cocaine seeking depend on glutamate transmission. Accordingly, drugs with antagonist properties at various glutamate receptor subtypes could be useful in prevention of relapse induced by conditioned stimuli.

Ionotropic Glutamate Receptor Antagonists Modulate Cue‐Induced Reinstatement of Ethanol‐Seeking Behavior

BACKGROUND Glutamatergic neurotransmission has been implicated in drug-environment conditioning, but little is known about the role of glutamate in alcohol seeking maintained by alcohol-associated cues. Therefore, we examined the effects of ionotropic glutamate receptor antagonists on cue-induced ethanol-seeking behavior in the extinction/reinstatement model. METHODS Rats were trained to orally self-administer ethanol (10% w/v) and a nonrewarding (80 microM) quinine solution on randomly alternating days. Ethanol and quinine availability were signaled by olfactory discriminative stimuli (S+/S-). In addition, ethanol delivery was accompanied by a light stimulus (CS+) and quinine delivery by an auditory stimulus (CS-). Thereafter, rats were subjected to extinction training during which responding had no programmed consequences. Reinstatement of responding was tested under three conditions: in the presence of the S-/CS-, S+/CS+, and S+/CS+ together with a small (0.2 ml) response-contingent oral ethanol dose at the beginning of the reinstatement session (S+/CS+/priming). We examined the effects of the noncompetitive NMDA receptor antagonist MK-801 (0, 0.05, 0.15 mg/kg intraperitoneally), the competitive NMDA antagonist CGP39551 (0, 5, 10 mg/kg intraperitoneally), the NMDA/glycine receptor antagonist L-701,324 (0, 2, 4 mg/kg intraperitoneally), the AMPA/kainate receptor antagonist CNQX (0, 0.5, 1.5 mg/kg intraperitoneally), and the opioid receptor antagonist naltrexone (0, 0.3, 1 mg/kg subcutaneously) on ethanol seeking under the S+/CS+/priming condition. RESULTS Presentation of the S+/CS+ stimulus condition reinstated extinguished responding, whereas presentation of the S-/CS- condition did not. Response-contingent ethanol priming enhanced reinstatement further. Under these reinstatement conditions, L-701,324, CNQX, and naltrexone inhibited ethanol-seeking behavior significantly. In contrast, MK-801 and CGP39551 failed to affect reinstated responding. CONCLUSIONS These results show that glutamate antagonism suppresses ethanol-seeking behavior induced by ethanol-paired stimuli. Furthermore, the data suggest that ionotropic glutamate receptors may have differential roles in mediation of this behavior.

Site-specific NMDA receptor antagonists produce differential effects on cocaine self-administration in rats

The effects of site-specific NMDA receptor antagonists on intravenous cocaine self-administration were examined in rats trained to self-administer cocaine (0.25 mg/infusion) on a fixed ratio (FR) 5 schedule with a 20-s time-out (TO) after each reinforcer. The non-competitive NMDA receptor antagonists, dizocilpine (MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate) (0.05-0.2 mg/kg i.p.) and memantine (1,3-dimethyl-5-amino-adamantane hydrochloride) (2.5-20 mg/kg i.p.), dose-dependently decreased cocaine self-administration, while the competitive NMDA receptor antagonist, CGP 39551 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid carboxyethylester) (2.5-15 mg/kg i.p.), and the NMDA/glycine receptor antagonist, L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)-phenyl-2(H)quinolone) (1.25-10 mg/kg p.o.), were without effect. Under a progressive ratio (PR) schedule, dizocilpine (0.15 mg/kg i.p.) increased the number of cocaine infusions in a manner similar to increasing the unit dose of cocaine, suggestive of potentiation of cocaine reward. Conversely, memantine (10 mg/kg i.p.) produced rate-decreasing effects on the PR schedule. These results demonstrate that NMDA receptor antagonists acting at different modulatory sites of the NMDA receptor do not share dizocilpines cocaine reward enhancing effects although they are all known to be effective blockers of NMDA receptor activity.

Differential behavioural sensitization to intermittent morphine treatment in alcohol-preferring AA and alcohol-avoiding ANA rats: role of mesolimbic dopamine

Alcohol‐preferring AA (Alko Alcohol) and alcohol‐avoiding ANA (Alko Non‐Alcohol) rats have well‐documented differences in their voluntary ethanol consumption and brain opioidergic systems. The aim of the present study was to investigate whether these rat lines differ in their susceptibility to morphine‐induced behavioural and neurochemical sensitization. The rats were given 15 injections of morphine (10 mg/kg, s.c.) or saline every other day. Locomotor activity and release of dopamine in the nucleus accumbens were monitored after a challenge with additional morphine injections (10 mg/kg) 1 and 5 weeks after withdrawal from the repeated treatment. Morphine increased locomotion more in the previously morphine‐treated rats than in the saline‐treated controls. Furthermore, AA rats were more sensitive to this effect of morphine than ANA rats. Accumbal morphine‐induced dopamine release was significantly higher in the morphine‐treated AA than ANA rats after the first challenge injection 1 week from withdrawal, but no differences were observed after the second challenge. The brain and plasma concentrations of morphine were similar among the lines suggesting that the differences in the effects of morphine cannot be explained in terms of differential pharmacokinetics of morphine in these lines. These data show that AA rats are more susceptible to morphine‐induced behavioural sensitization than ANA rats. Furthermore, it suggests that mesolimbic dopamine has at best only a transient role in the expression of opioid‐induced behavioural sensitization. The relationship between the mechanisms underlying the differential sensitivity of these rat lines to the effects of repeated morphine and voluntary ethanol drinking remains to be determined.

Attenuation of reinforcing and psychomotor stimulant effects of amphetamine by aripiprazole

Partial dopamine agonists are potential medications for the treatment of amphetamine addiction. They have been hypothesized to stabilize the dopamine system by acting as antagonists during high dopaminergic tone resulting from amphetamine use and as agonists during withdrawal. Aripiprazole is an atypical antipsychotic that acts as a partial D2 dopamine and a serotonin 5‐HT1A agonist and a serotonin 5‐HT2A antagonist. The aim of the present study was to examine the effects of aripiprazole on behaviors induced and maintained by d‐amphetamine. To this end, intravenous d‐amphetamine self‐administration [fixed ratio 3 (FR3) schedule, 0.02 mg/infusion] and d‐amphetamine‐induced (0, 1.5 mg/kg intraperitoneally) locomotor activity, as well as spontaneous locomotor activity and sucrose pellet self‐administration (FR3 schedule) were studied in male Wistar rats after aripiprazole (0, 0.3, 1, 3 mg/kg i.p.) administration. Aripiprazole pre‐treatment resulted in bidirectional effects on amphetamine self‐administration. The 1 mg/kg dose increased, and the highest dose decreased the number of amphetamine infusions. In the locomotor activity experiments, aripiprazole attenuated amphetamine‐induced activity dose‐dependently and tended to suppress spontaneous activity. The highest aripiprazole doses decreased also sucrose pellet self‐administration. The increase in amphetamine self‐administration with the intermediate aripiprazole dose, as well as the decrease in amphetamine‐induced locomotor activity, suggests that aripiprazole acted as a dopamine antagonist. Suppression of amphetamine and sucrose self‐administration by the highest aripiprazole dose was probably caused by non‐specific effects. Together, these results indicate that under conditions of dopaminergic stimulation, aripiprazole attenuates the reinforcing and psychomotor stimulant effects of d‐amphetamine, but the dose range for this effect is rather limited.

Dopaminergic modulation of reward-guided decision making in alcohol-preferring AA rats

Highlightsd‐Amphetamine acts as a promoter of irrational and unprofitable decision making.Restricted feeding might mask the anorexic effects of dopaminergic drugs.AA rats provide a new approach for studies on reward‐guided decision making. Abstract R**esults from animal gambling models have highlighted the importance of dopaminergic neurotransmission in modulating decision making when large sucrose rewards are combined with uncertainty. The majority of these models use food restriction as a tool to motivate animals to accomplish operant behavioral tasks, in which sucrose is used as a reward. As enhanced motivation to obtain sucrose due to hunger may impact its reward‐seeking effect, we wanted to examine the decision‐making behavior of rats in a situation where rats were fed ad libitum. For this purpose, we chose alcohol‐preferring AA (alko alcohol) rats, as these rats have been shown to have high preference for sweet agents. In the present study, AA rats were trained to self‐administer sucrose pellet rewards in a two‐lever choice task (one pellet vs. three pellets). Once rational choice behavior had been established, the probability of gaining three pellets was decreased over time (50%, 33%, 25% then 20%). The effect of d‐amphetamine on decision making was studied at every probability level, as well as the effect of the dopamine D1 receptor agonist SKF‐81297 and D2 agonist quinpirole at probability levels of 100% and 25%. d‐Amphetamine increased unprofitable choices in a dose‐dependent manner at the two lowest probability levels. Quinpirole increased the frequency of unprofitable decisions at the 25% probability level, and SKF‐82197 did not affect choice behavior. These results mirror the findings of probabilistic discounting studies using food‐restricted rats. Based on this, the use of AA rats provides a new approach for studies on reward‐guided decision making.