Pharmacological investigations of a yohimbine-impulsivity interaction in rats.

Both impulsivity and stress are risk factors for substance abuse, but it is not clear how these two processes interact to alter susceptibility for the disorder. The aim of this project was to examine the pharmacology of a stress-impulsivity interaction in rats. To do so, we tested the effects of yohimbine on impulsive action and then assessed whether behavioural changes could be reduced by antagonists at different receptor subtypes. Male Long-Evans rats were injected with various doses of yohimbine (0-5.0 mg/kg) before testing in the response-inhibition task. In subsequent experiments, yohimbine (2.5 mg/kg) was injected following pretreatment with the following receptor antagonists: corticotropin-releasing factor receptor 1, antalarmin (0-20 mg/kg); glucocorticoid, mifepristone (0-30 mg/kg); noradrenergic (NA) α1, prazosin (0-2 mg/kg); NA α2, guanfacine (0-0.5 mg/kg); NA ß2, propranolol (0.5-2.0 mg/kg); dopamine D1/5, SCH 39166 (0-0.0625 mg/kg); µ opioid, naloxone (0-2 mg/kg); or 5-HT2A, M100907 (0.005-0.05 mg/kg). In all experiments, impulsive action was measured as increased premature responding. Yohimbine dose dependently increased impulsive action, but the effect was not reversed by antagonist pretreatment. None of the drugs altered any other behavioural measure. We conclude that stress-impulsivity interactions are likely mediated by a synergy of multiple neurotransmitter systems.

Behavioral traits predicting alcohol drinking in outbred rats: an investigation of anxiety, novelty seeking, and cognitive flexibility.

BACKGROUND: Most adults in Western society consume alcohol regularly without negative consequences. For a small subpopulation, however, drinking can quickly progress to excessive and chronic intake. Given the dangers associated with alcohol abuse, it is critical to identify traits that may place an individual at risk for developing these behaviors. To that end, we used a rat model to determine whether anxiety-related behaviors, novelty seeking, or cognitive flexibility predict excessive alcohol drinking under both limited and continuous access conditions. METHODS: Adult male rats were assessed in a series of behavioral tasks (elevated plus maze [EPM], locomotor activity, and discrimination/reversal learning in a Y-maze) followed by 6 weeks of daily, 1-hour access to alcohol in a free-choice, 2-bottle paradigm (10% alcohol vs. tap water). Next, subjects were given the opportunity to consume alcohol for 72 hours in drinking chambers that permit separate measures of each drinking bout. Half of the animals experienced a 2-week deprivation period between the limited and continuous access sessions. RESULTS: Time spent on the open arms of the EPM, but not novelty seeking or discrimination/reversal learning, predicted alcohol consumption during limited, 1-h/d access sessions to alcohol. Anxiety-related behavior also predicted the escalation of intake when animals were given 72 hours of continuous access to alcohol. Bout size, but not frequency, was responsible for the increased consumption by high-anxiety subjects during this period. Finally, intake during limited access sessions predicted intake during continuous access, but only in subjects with low intake during limited access. CONCLUSIONS: These findings confirm that preexisting anxiety-related behavior predicts alcohol intake under several schedules of alcohol access. Moreover, when access is unlimited, the high-anxiety-related group exhibited an increase in bout size, but not frequency, of drinking. In addition, we show that modest intake when alcohol is restricted may or may not progress to excessive intake when the drug is freely available.

Neurobiology of an endophenotype: modeling the progression of alcohol addiction in rodents.

Most adults in Western society consume alcohol on a regular basis with few or no negative consequences. However, for certain individuals, alcohol use escalates, leading to uncontrolled drinking bouts, craving, and repeated episodes of relapse. The transition from regulated to uncontrolled and compulsive drinking is a defining feature (i.e. an endophenotype) of alcohol addiction. This behavioral progression can be modeled in rodent paradigms that parallel the diagnostic criteria for addiction in humans. Using these criteria as a framework, this review outlines the neurobiological factors associated with increased vulnerability to excessive, compulsive, and dysregulated alcohol intake in rodents. We conclude by noting gaps in the literature and outline important directions for future research.

Increased impulsive action in rats: effects of morphine in a short and long fixed-delay response inhibition task.

RATIONALE: Impulsive action is mediated through several neurochemical systems, although it is not clear which role each of these plays in the inability to withhold inappropriate responses. Manipulations of the opioid system alter impulsive action in rodents, although the effects are not consistent across tasks. Previously, we speculated that these discrepancies reflect differences in the cognitive mechanisms that control responding in each task. OBJECTIVES: We investigated whether the effect of morphine, a mu opioid receptor (MOR) agonist, on impulsive action depends on the ability of the subjects to time the interval during which they must inhibit a response. METHODS: Male Long-Evans rats were trained in a response inhibition (RI) task to withhold responding for sucrose during a 4- or 60-s delay; impulsive action was assessed as increased responding during the delay. The rats were tested following an injection of morphine (0, 1, 3, 6 mg/kg). In a subsequent experiment, the effects of morphine (6 mg/kg) plus the MOR antagonist naloxone (0, 0.3, 1, 3 mg/kg) were investigated. RESULTS: Morphine increased impulsive action, but had different effects in the two conditions: the drug increased the proportion of premature responses as the 4-s interval progressed and produced a general increase in responding across the 60-s interval. Naloxone blocked all morphine-induced effects. CONCLUSIONS: The finding that morphine increases impulsive action in a fixed-delay RI task contrasts with our previous evidence which shows no effect in the same task with a variable delay. Thus, MORs disrupt impulsive action only when rats can predict the delay to respond.

RSK2 signaling in medial habenula contributes to acute morphine analgesia.

It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.

Effects of delta opioid receptors activation on a response inhibition task in rats.

RATIONALE: Response inhibition, a primary symptom of many psychiatric disorders, is mediated through a complex neuropharmacological network that involves dopamine, serotonin, glutamate, noradrenaline, and cannabinoid mechanisms. Recently, we identified an opioidergic contribution to response inhibition by showing that deletion of mu or delta opioid receptors in mice alters motor impulsivity. OBJECTIVES: We investigated this phenomenon further by testing whether pharmacological activation of opioid receptors disrupts the ability to inhibit a motor response. METHODS: Long-Evans rats were trained to withhold a lever-pressing response for sucrose until a discriminative stimulus (lever light) was presented. The delay to the discriminative stimulus (1 to 60 s) was varied, so animals could not predict, on any given trial, the length of the pre-response phase. Motor impulsivity was assessed as the inability to inhibit lever pressing prior to the discriminative stimulus. Rats were tested following an injection of the mu opioid receptor agonist morphine (0, 0.5, 1, 2, 4, 6, 8, or 10 mg/kg) or the delta receptor agonist SNC80 (0, 2.5, 5, or 10 mg/kg). RESULTS: SNC80 (10 mg/kg) increased premature responses and locomotor activity, but had no effect on the speed of responding or non-reinforced presses. The SNC80-induced decrease in accuracy was blocked by the delta opioid receptor antagonist naltrindole. Morphine had no effect on accuracy but increased locomotor activity (2 mg/kg). CONCLUSIONS: These findings point to a role for delta, but not mu, opioid receptors in disinhibition as measured in the response inhibition task. The results appear to contradict those of previous opioid receptor deletion studies; possible sources of these discrepant results are discussed.