Learning and Memory in Addiction

Carmack, Stephanie A; Koob, George F.; Anagnostaras, Stephan

doi:10.1016/b978-0-12-809324-5.21101-2

Cited by 9 publications

(7 citation statements)

References 220 publications

(416 reference statements)

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“…However, the loss of disPCp place fields selectively in the saline-paired context does increase the relative representation of the drug-paired context by the hippocampal place cell population. This finding is broadly consistent with previous observations of the overrepresentation of rewarded locations by place cells and in line with the notion that addictive drugs may usurp the normal neural machinery for learning about reward or goal locations to achieve a similar enduring association with specific spatial locations (67)(68)(69).…”

Section: Discussionsupporting

confidence: 92%

Neural circuit dynamics of drug-context associative learning in the hippocampus

Sun

Giocomo

2021

Preprint

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The environmental context associated with previous drug consumption serves as a potent trigger for relapse to drug use. The mechanism by which existing neural representations of context are modified to incorporate information associated with a given drug however, remains unknown. Using longitudinal calcium imaging in freely behaving mice, we reveal that drug-context associations for psychostimulants and opioids are encoded in a subset of hippocampal neurons. In these neurons, drug context pairing in a conditioned place preference task weakened their spatial coding for the nondrug-paired context, with drug-induced changes to spatial coding predictive of drug-seeking behavior. Furthermore, the dissociative drug ketamine blocked both the drug-induced changes to hippocampal coding and corresponding drug-seeking behavior. Together, this work reveals how drugs of abuse can alter the hippocampal circuit to encode drug-context associations and points to the hippocampus as a key node in the cognitive process of drug addiction and context-induced drug relapse.

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Section: Discussionsupporting

confidence: 92%

Neural circuit dynamics of drug-context associative learning in the hippocampus

Sun

Giocomo

2021

Preprint

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“…Other head-to-head comparisons of psychostimulants versus MDMA have similarly found that rodents treated with methamphetamine and methylphenidate (Mori et al 2021 ) as well as amphetamine (Meyer et al 2002 ) exhibit significant place preference but those treated with comparable doses of MDMA do not. Altogether, our findings suggest that repeated use of MDMA at high (but not low) doses may lead to compulsive drug taking and drug-cue elicited craving, although MDMA may be less rewarding and less likely to provoke drug seeking than psychostimulants and other drugs that induce strong conditioned place preference (for reviews, see Carmack et al 2017 and Tzschentke 2007 ). Indeed, the level of locomotor activity seen after MDMA administration seems to suggest that even at high doses, it is only a very modest psychomotor stimulant.…”

Section: Discussionmentioning

confidence: 65%

“…The addictive potential of high-dose psychostimulants is reflected in their propensity to elicit dramatic locomotor stimulation, behavioral sensitization, conditioned place preference, and conditioned responding (Anagnostaras and Robinson 1996 ; Anagnostaras et al 2002 ; Carmack et al 2014 , 2017 ; Robinson and Berridge 1993 , 2003 , 2008 ; Shuman et al 2012 ). We found that treatment with low, clinically relevant doses of 0.01 and 1 mg/kg MDMA did not lead to any addiction-related behaviors, even when tested with the 10 mg/kg MDMA high-dose challenge.…”

Section: Discussionmentioning

confidence: 99%

“…Behavioral sensitization, conditioned place preference, and conditioned responding are behaviors that reflect the addictive potential 1 of a drug (Anagnostaras and Robinson 1996 ; Anagnostaras et al 2002 ; Carmack et al 2017 ; Robinson and Berridge 1993 , 2003 , 2008 ). Behavioral sensitization is a progressive increase in response following repeated administration of a drug and reflects dopamine system hyperactivation.…”

Section: Introductionmentioning

confidence: 99%

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MDMA and memory, addiction, and depression: dose-effect analysis

et al. 2022

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Rationale ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioral toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted. Objectives The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression. Methods We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice. Results High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors. Conclusions The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA dose is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1–2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies.

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“…Substance use disorder (SUD) is a phenomenon with multiple functional axes, including increased incentive salience of drug-related cues, attenuation of normal rewards with concomitant vulnerability to stress as well as impaired impulse control, executive function and memory (Carmack et al, 2016;Koob and Volkow, 2016;Uhl et al, 2019). Dopamine (DA) neurotransmission is implicated to some degree in all of those aspects, and thus, DAergic signaling in the mesocorticolimbic system is at the center of addiction etiology (Volkow et al, 2009(Volkow et al, , 2011Koob and Volkow, 2016).…”

Section: Introductionmentioning

confidence: 99%

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

et al. 2022

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Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli – context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

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Learning and Memory in Addiction

Cited by 9 publications

References 220 publications

Neural circuit dynamics of drug-context associative learning in the hippocampus

Neural circuit dynamics of drug-context associative learning in the hippocampus

MDMA and memory, addiction, and depression: dose-effect analysis

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

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