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

Schramm MJ, Everitt BJ, Milton AL - Neuropsychopharmacology (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Cambridge, Cambridge, UK.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

A centrally active, but not peripherally active, β-adrenergic receptor antagonist disrupted the reconsolidation of a CS-alcohol memory. (a) An overview of the experimental timeline. The injection symbol represents an i.p. injection of the centrally active β-adrenergic receptor antagonist propranolol (PRO), the peripherally active β-adrenergic receptor antagonist nadolol (NAD) or vehicle (VEH) 30 min before the memory reactivation session. The numbers underneath the boxes refer to the number of sessions. (b) Administration of PRO before memory reactivation prevented a previously alcohol-associated CS from subsequently acting as a conditioned reinforcer. By contrast, administration of NAD at reactivation did not affect the CS-alcohol memory, such that the CS could subsequently act as a conditioned reinforcer in the same manner that it did for animals treated with VEH at reactivation. Asterisks denote statistically higher responding on the active than inactive lever; the dagger denotes active lever pressing that is significantly lower than the VEH control group. (c) When PRO was administered without a memory reactivation session, it did not subsequently impair the capacity of the alcohol-associated CS to act as a conditioned reinforcer, indicating that the disruption of the CS-alcohol memory with propranolol was reactivation-dependent. Asterisks denote statistically higher responding on the active than inactive lever. Data in b and c are square-root transformed and presented as means±SEM. (d) The administration of β-adrenergic receptor antagonists had no acute effect on performance during the memory reactivation session, as PRO nor NAD had any effect on the number of nosepokes made during the memory reactivation, or the number of response-contingent CS presentations earned during this session. Group sizes: (b and d) reactivated VEH=22; reactivated PRO=11; reactivated NAD=9; (c) non-reactivated VEH=13; non-reactivated PRO=13 rats per group.
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fig1: A centrally active, but not peripherally active, β-adrenergic receptor antagonist disrupted the reconsolidation of a CS-alcohol memory. (a) An overview of the experimental timeline. The injection symbol represents an i.p. injection of the centrally active β-adrenergic receptor antagonist propranolol (PRO), the peripherally active β-adrenergic receptor antagonist nadolol (NAD) or vehicle (VEH) 30 min before the memory reactivation session. The numbers underneath the boxes refer to the number of sessions. (b) Administration of PRO before memory reactivation prevented a previously alcohol-associated CS from subsequently acting as a conditioned reinforcer. By contrast, administration of NAD at reactivation did not affect the CS-alcohol memory, such that the CS could subsequently act as a conditioned reinforcer in the same manner that it did for animals treated with VEH at reactivation. Asterisks denote statistically higher responding on the active than inactive lever; the dagger denotes active lever pressing that is significantly lower than the VEH control group. (c) When PRO was administered without a memory reactivation session, it did not subsequently impair the capacity of the alcohol-associated CS to act as a conditioned reinforcer, indicating that the disruption of the CS-alcohol memory with propranolol was reactivation-dependent. Asterisks denote statistically higher responding on the active than inactive lever. Data in b and c are square-root transformed and presented as means±SEM. (d) The administration of β-adrenergic receptor antagonists had no acute effect on performance during the memory reactivation session, as PRO nor NAD had any effect on the number of nosepokes made during the memory reactivation, or the number of response-contingent CS presentations earned during this session. Group sizes: (b and d) reactivated VEH=22; reactivated PRO=11; reactivated NAD=9; (c) non-reactivated VEH=13; non-reactivated PRO=13 rats per group.

Mentions: In order to assess the integrity of the CS-ethanol memory following our experimental manipulations at reactivation, we used the acquisition of a new instrumental response (ANR) procedure (as used to investigate the reconsolidation of cocaine- and sucrose-associated memories in Milton et al, 2008) to assess whether the previously ethanol-associated CS was able subsequently to act as a conditioned reinforcer (Figures 1a and 2a). Briefly, in the first phase of the experiment animals were trained to self-administer ethanol with an instrumental response (a nosepoke), which led to the simultaneous presentation of a light, the pavlovian CS. Following the experimental manipulations of memory at reactivation, animals were tested repeatedly in the second phase of the experiment for the acquisition of a novel instrumental response (lever pressing) for the presentation of the CS alone. Pavlovian CSs that are capable of acting as conditioned reinforcers, because of their previous association with the ethanol reinforcer, support the acquisition of a new instrumental response, while CSs that are not (or are no longer) associated with primary reinforcement cannot. Thus, the ANR procedure provides a stringent assay for a specific psychological process that can only be supported when the CS-ethanol memory is intact.


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

Schramm MJ, Everitt BJ, Milton AL - Neuropsychopharmacology (2015)

A centrally active, but not peripherally active, β-adrenergic receptor antagonist disrupted the reconsolidation of a CS-alcohol memory. (a) An overview of the experimental timeline. The injection symbol represents an i.p. injection of the centrally active β-adrenergic receptor antagonist propranolol (PRO), the peripherally active β-adrenergic receptor antagonist nadolol (NAD) or vehicle (VEH) 30 min before the memory reactivation session. The numbers underneath the boxes refer to the number of sessions. (b) Administration of PRO before memory reactivation prevented a previously alcohol-associated CS from subsequently acting as a conditioned reinforcer. By contrast, administration of NAD at reactivation did not affect the CS-alcohol memory, such that the CS could subsequently act as a conditioned reinforcer in the same manner that it did for animals treated with VEH at reactivation. Asterisks denote statistically higher responding on the active than inactive lever; the dagger denotes active lever pressing that is significantly lower than the VEH control group. (c) When PRO was administered without a memory reactivation session, it did not subsequently impair the capacity of the alcohol-associated CS to act as a conditioned reinforcer, indicating that the disruption of the CS-alcohol memory with propranolol was reactivation-dependent. Asterisks denote statistically higher responding on the active than inactive lever. Data in b and c are square-root transformed and presented as means±SEM. (d) The administration of β-adrenergic receptor antagonists had no acute effect on performance during the memory reactivation session, as PRO nor NAD had any effect on the number of nosepokes made during the memory reactivation, or the number of response-contingent CS presentations earned during this session. Group sizes: (b and d) reactivated VEH=22; reactivated PRO=11; reactivated NAD=9; (c) non-reactivated VEH=13; non-reactivated PRO=13 rats per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663661&req=5

fig1: A centrally active, but not peripherally active, β-adrenergic receptor antagonist disrupted the reconsolidation of a CS-alcohol memory. (a) An overview of the experimental timeline. The injection symbol represents an i.p. injection of the centrally active β-adrenergic receptor antagonist propranolol (PRO), the peripherally active β-adrenergic receptor antagonist nadolol (NAD) or vehicle (VEH) 30 min before the memory reactivation session. The numbers underneath the boxes refer to the number of sessions. (b) Administration of PRO before memory reactivation prevented a previously alcohol-associated CS from subsequently acting as a conditioned reinforcer. By contrast, administration of NAD at reactivation did not affect the CS-alcohol memory, such that the CS could subsequently act as a conditioned reinforcer in the same manner that it did for animals treated with VEH at reactivation. Asterisks denote statistically higher responding on the active than inactive lever; the dagger denotes active lever pressing that is significantly lower than the VEH control group. (c) When PRO was administered without a memory reactivation session, it did not subsequently impair the capacity of the alcohol-associated CS to act as a conditioned reinforcer, indicating that the disruption of the CS-alcohol memory with propranolol was reactivation-dependent. Asterisks denote statistically higher responding on the active than inactive lever. Data in b and c are square-root transformed and presented as means±SEM. (d) The administration of β-adrenergic receptor antagonists had no acute effect on performance during the memory reactivation session, as PRO nor NAD had any effect on the number of nosepokes made during the memory reactivation, or the number of response-contingent CS presentations earned during this session. Group sizes: (b and d) reactivated VEH=22; reactivated PRO=11; reactivated NAD=9; (c) non-reactivated VEH=13; non-reactivated PRO=13 rats per group.
Mentions: In order to assess the integrity of the CS-ethanol memory following our experimental manipulations at reactivation, we used the acquisition of a new instrumental response (ANR) procedure (as used to investigate the reconsolidation of cocaine- and sucrose-associated memories in Milton et al, 2008) to assess whether the previously ethanol-associated CS was able subsequently to act as a conditioned reinforcer (Figures 1a and 2a). Briefly, in the first phase of the experiment animals were trained to self-administer ethanol with an instrumental response (a nosepoke), which led to the simultaneous presentation of a light, the pavlovian CS. Following the experimental manipulations of memory at reactivation, animals were tested repeatedly in the second phase of the experiment for the acquisition of a novel instrumental response (lever pressing) for the presentation of the CS alone. Pavlovian CSs that are capable of acting as conditioned reinforcers, because of their previous association with the ethanol reinforcer, support the acquisition of a new instrumental response, while CSs that are not (or are no longer) associated with primary reinforcement cannot. Thus, the ANR procedure provides a stringent assay for a specific psychological process that can only be supported when the CS-ethanol memory is intact.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Cambridge, Cambridge, UK.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus