Remote memory of drug experiences coexists with cognitive decline and abnormal adult neurogenesis in an animal model of cocaine‐altered cognition

Abstract

Cocaine addiction is a chronic disorder in which the person loses control over drug use. The past memories of the stimuli associated with the drug are a relevant clinical problem, since they trigger compulsive drug‐seeking and drug‐taking habits. Furthermore, these persistent drug‐related memories seemingly coexist with cognitive decline that predicts worse therapeutic output. Here, we use a new animal model of cocaine‐altered cognition that allowed to observe these events in the same individual and study their relationship. Mice were chronically administered cocaine in a conditioned place preference (CPP) apparatus for 14 days, and control mice received saline. After 28 days of cocaine withdrawal, animals were tested for retrieval of remote drug–associated memory as well as for cognitive performance in a battery of tests, including novel object and place recognition and spatial memory. The cocaine‐withdrawn mice showed persistent CPP memory while impaired in the cognitive tasks, displaying deficits in reference memory acquisition and working memory. However, the CPP expression was not associated with the defective cognitive performance, indicating that they were concomitant but independent occurrences. After completion of the experiment, adult hippocampal neurogenesis (AHN) was studied as a relevant neurobiological correlate due to its potential role in both learning and drug addiction. Results suggested a preserved basal AHN in the cocaine‐withdrawn mice but an aberrant learning‐induced regulation of these neurons. This paradigm may be useful to investigate maladaptive cognition in drug addiction as well as related therapies.

Salivary Cortisol Levels Are Associated with Craving and Cognitive Performance in Cocaine-Abstinent Subjects: A Pilot Study

“…We observed these cortisol measurements were positively associated with craving levels and negatively with the age of onset of drug consumption. Some studies about this topic have revealed that a deviation of cortisol secretion away from the homeostatic diurnal pattern in cocaine-dependent subjects was associated with reduced success at achieving early abstinence [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. This finding suggests a feed-forward cascade of effects of drugs on stress biology [ 58 ].…”

“…Concerning this, some studies have demonstrated the influence of parental history of substance abuse on the risk of early drug abuse in their offspring [ 63 , 64 ], and for instance, higher morning cortisol levels have been found among crack cocaine users with positive family history and lower treatment retention [ 44 ]. Indeed, activation of the HPA response may be an early dysregulation associated with excessive and early drug taking that ultimately sensitizes the extrahypothalamic CRH systems [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , ...…”

“…Despite preclinical and clinical studies having reported difficulties in attentional processes, processing speed or executive functions after chronic cocaine consumption, to date there have been no studies that have explored the involvement of cortisol levels in these deficits during the early/intermediate abstinence (≤3 months) [ 36 , 37 , 38 , 39 ]. This is a remarkable point because the neuropsychological status constitutes one of the most consistent risk factors for treatment dropout observed in recent studies [ 40 , 41 , 42 ].…”

Long‐term consequences of alcohol use in early adolescent mice: Focus on neuroadaptations in GR, CRF and BDNF

“…The behavioural tests (Figure 1) were performed based on previously published protocols from days 56-62 for mice in late adolescence and from days 78-84 for animals in adulthood. 44,45 This behavioural battery of tests allowed the assessment of exploratory activity, anxietyrelated behaviours and cognitive domains in the animals. Briefly, for an evaluation of compulsive and anxiety-like behaviours, the mice performed one session in the elevated-zero maze (EZM) and the marble burying test (MBt) (day 56 for adolescent mice and day 78 for adult animals).…”

Long-term consequences of alcohol use in early adolescent mice: focus on neuroadaptations in GR, CRF and BDNF

“…The behavioural tests (Fig. 1) were performed based on previously published protocols from days 56-62 for mice in late adolescence and from days 78-84 for animals in adulthood [44,45]. This behavioural battery of tests allowed the assessment of exploratory activity, anxiety-related behaviours and cognitive domains in the animals.…”