Bidirectional Modulation of Alcohol-Associated Memory Reconsolidation through Manipulation of Adrenergic Signaling.

Alcohol addiction is a problem of great societal concern, for which there is scope to improve current treatments. One potential new treatment for alcohol addiction is based on disrupting the reconsolidation of the maladaptive Pavlovian memories that can precipitate relapse to drug-seeking behavior. In alcohol self-administering rats, we investigated the effects of bidirectionally modulating adrenergic signaling on the strength of a Pavlovian cue-alcohol memory, using a behavioral procedure that isolates the specific contribution of one maladaptive Pavlovian memory to relapse, the acquisition of a new alcohol-seeking response for an alcohol-associated conditioned reinforcer. The β-adrenergic receptor antagonist propranolol, administered in conjunction with memory reactivation, persistently disrupted the memory that underlies the capacity of a previously alcohol-associated cue to act as a conditioned reinforcer. By contrast, enhancement of adrenergic signaling by administration of the adrenergic prodrug dipivefrin at reactivation increased the strength of the cue-alcohol memory and potentiated alcohol seeking. These data demonstrate the importance of adrenergic signaling in alcohol-associated memory reconsolidation, and suggest a pharmacological target for treatments aiming to prevent relapse through the disruption of maladaptive memories.This work was supported by a UK Medical Research Council Programme Grant (G1002231) to BJE and ALM and was conducted in the Behavioural and Clinical Neuroscience Institute (BCNI), an initiative jointly funded by the MRC and the Wellcome Trust. MJWS was supported by an MRC Doctoral Training Grant and the James Baird Fund at the Medical School of the University of Cambridge. ALM was partly supported by a BCNI lectureship and the Ferreras-Willetts Fellowship from Downing College, Cambridge.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2015.24

Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect.

Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours

Strain-dependent effects of D2 dopaminergic and muscarinic-cholinergic agonists and antagonists on memory consolidation processes in mice.

The interaction between muscarinic-cholinergic and dopaminergic systems in the modulation of memory storage of Y-maze discrimination (YMD) task was examined in C57BL/6 and DBA/2 strains of mice. In C57BL/6 mice, post-training systemic (i.p.) administration of the D2-agonist quinpirole facilitated retention and the D2-antagonist (-)-sulpiride impaired retention. Opposite effects were observed in DBA/2 strain. The facilitating or impairing effects of quinpirole and (-)-sulpiride were blocked by simultaneous post-training administration of muscarinic-cholinergic agonists and antagonists. The memory enhancing effects of the cholinergic agonist oxotremorine were not blocked by simultaneous administration of sulpiride in C57BL/6 mice or quinpirole in DBA/2 mice. Furthermore, the memory impairing effects of the cholinergic antagonist atropine were not blocked by simultaneous administration of quinpirole in C57BL/6 mice or sulpiride in DBA/2 mice. These findings indicate that the effects of D2-receptor agonists and antagonists on retention of YMD task are strain-dependent and mediated through muscarinic-cholinergic mechanisms

Strain-dependent involvement of D1 and D2 dopamine receptors in muscarinic cholinergic influences on memory storage.

These experiments examined the interaction of muscarinic and dopaminergic systems in influencing memory for one-trial inhibitory avoidance training in mice of the C57BL/6 and DBA/2 strains. In both strains, immediate post-training systemic administration of the muscarinic cholinergic agonist oxotremorine enhanced retention and the cholinergic antagonist atropine impaired retention. No effects were seen with injections 2 h post-training. Furthermore, the drugs did not affect retention performance of animals that received no footshock on the training trial. These results confirm previous findings indicating that muscarinic cholinergic drugs affect memory by influencing memory consolidation. In C57 mice, pretreatment with selective D1 or D2 dopamine (DA) receptor agonists (SKF 38393 or LY 171555, respectively) in otherwise non-effective doses (5 and 0.25 mg/kg, respectively) potentiated the effects of oxotremorine (0.04 mg/kg). Furthermore, in C57 mice pretreatment with selective D1 or D2 receptor antagonists (SCH 23390 or (-)-sulpiride) in otherwise non-effective doses (0.025 and 6 mg/kg, respectively) blocked the memory enhancing effects of oxotremorine. The memory impairing effects of atropine (3 mg/kg) were blocked by the D1 and D2 selective agonists and potentiated by the selective D1 or D2 antagonists. In contrast, in DBA mice, the D1 and D2 selective agonists antagonised the memory enhancing effects of oxotremorine (0.02 mg/kg) and potentiated the effects of atropine (2 mg/kg). Furthermore, the D1 and D2 antagonists potentiated the effects of oxotremorine and antagonised those of atropine. These findings indicate that although muscarinic cholinergic influences on memory storage are comparable in mice of these two strains, the cholinergic-dopaminergic interactions are opposite in the two strains. These results have implications for hypotheses of cholinergic and dopaminergic regulation of memory storage

Neuropeptide S Enhances Memory During the Consolidation Phase and Interacts with Noradrenergic Systems in the Brain

Neuropeptide S (NPS) has been shown to promote arousal and anxiolytic-like effects, as well as facilitation of fear extinction. In rodents, NPS receptors (NPSR) are prominently expressed in brain structures involved in learning and memory. Here, we investigate whether exogenous or endogenous NPS signaling can modulate acquisition, consolidation, or recall of emotional, spatial, and contextual memory traces, using two common behavioral paradigms, inhibitory avoidance (IA) and novel object recognition. In the IA paradigm, immediate and delayed post-training central NPS administration dose dependently enhanced memory retention in mice, indicating that NPS may act during the consolidation phase to enhance long-term memory. In contrast, pre-training or pre-test NPS injections were ineffective, suggesting that NPS had no effect on IA memory acquisition or recall. Peripheral administration of a synthetic NPSR antagonist attenuated NPS-induced IA memory enhancement, showing pharmacological specificity. NPS also enhanced hippocampal-dependent non-aversive memory in the novel object recognition task. In contrast, NPSR knockout mice displayed deficits in IA memory, novel object recognition, and novel place or context recognition, suggesting that activity of the endogenous NPS system is required for memory formation. Blockade of adrenergic signaling by propranolol attenuated NPS-induced memory enhancement in the IA task, indicating involvement of central noradrenergic systems. These results provide evidence for a facilitatory role of NPS in long-term memory, independent of memory content, possibly by acting as a salience signal or as an arousal-promoting factor