The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early- and late-stage ...performance of cocaine-seeking behavior. Rats were trained to self-administer cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of α-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule FI15(FR10:S) so that cocaine-seeking performance became well established. At this stage, intra-aDLS, but not pDMS, α-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. α-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of cocaine-seeking behavior, supporting the theory of dynamic shifts in the striatal control over cocaine seeking between goal-directed and habitual performance.
It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D₁ receptors (D₁Rs) play a more ...significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D₁R and σ₁R were found to heteromerize in transfected cells, where cocaine robustly potentiated D₁R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D₁R stimulation in a dopamine transporter-independent and σ₁R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ₁R KO mice, providing evidence for the existence of σ₁R-D₁R heteromers in the brain. Therefore, these results provide a molecular explanation for which D₁R plays a more significant role in the behavioral effects of cocaine, through σ₁R-D₁R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.
Aims
To perform wastewater analyses to assess spatial differences and temporal changes of illicit drug use in a large European population.
Design
Analyses of raw wastewater over a 1‐week period in ...2012 and 2013.
Setting and Participants
Catchment areas of wastewater treatment plants (WWTPs) across Europe, as follows: 2012: 25 WWTPs in 11 countries (23 cities, total population 11.50 million); 2013: 47 WWTPs in 21 countries (42 cities, total population 24.74 million).
Measurements
Excretion products of five illicit drugs (cocaine, amphetamine, ecstasy, methamphetamine, cannabis) were quantified in wastewater samples using methods based on liquid chromatography coupled to mass spectrometry.
Findings
Spatial differences were assessed and confirmed to vary greatly across European metropolitan areas. In general, results were in agreement with traditional surveillance data, where available. While temporal changes were substantial in individual cities and years (P ranging from insignificant to <10−3), overall means were relatively stable. The overall mean of methamphetamine was an exception (apparent decline in 2012), as it was influenced mainly by four cities.
Conclusions
Wastewater analysis performed across Europe provides complementary evidence on illicit drug consumption and generally concurs with traditional surveillance data. Wastewater analysis can measure total illicit drug use more quickly and regularly than is the current norm for national surveys, and creates estimates where such data does not exist.
•Extended access cocaine self-administration impairs working memory in rats.•The degree of impairment is related to both cocaine intake and cocaine-seeking.•Higher PrL metabolic activity tracks ...working memory performance in cocaine rats.•Dysregulation of mGlu5 in the PrL is related to past working memory performance.•mGlu5-positive cells in the PrL are activated during relapse to cocaine-seeking.
Cocaine use disorder (CUD) is associated with prefrontal cortex dysfunction and cognitive deficits that may contribute to persistent relapse susceptibility. As the relationship between cognitive deficits, cortical abnormalities and drug seeking is poorly understood, development of relevant animal models is of high clinical importance. Here, we used an animal model to characterize working memory and reversal learning in rats with a history of extended access cocaine self-administration and prolonged abstinence. We also investigated immediate and long-term functional changes within the prelimbic cortex (PrL) in relation to cognitive performance and drug-seeking. Adult male rats underwent 6 days of short-access (1 h/day) followed by 12 days of long-access (6 h/day) cocaine self-administration, or received passive saline infusions. Next, rats were tested in delayed match-to-sample (DMS) and (non)match-to-sample (NMS) tasks, and finally in a single context + cue relapse test on day 90 of abstinence. We found that a history of chronic cocaine self-administration impaired working memory, though sparing reversal learning, and that the components of these cognitive measures correlated with later drug-seeking. Further, we found that dysregulated metabolic activity and mGlu5 receptor signaling in the PrL of cocaine rats correlated with past working memory performance and/or drug-seeking, as indicated by the analysis of cytochrome oxidase reactivity, mGlu5 and Homer 1b/c protein expression, as well as Arc mRNA expression in mGlu5-positive cells. These findings advocate for a persistent post-cocaine PrL dysfunction, rooted in ineffective compensatory changes and manifested as impaired working memory performance and hyperreactivity to cocaine cues. Considering the possible interplay between the neural correlates underlying post-cocaine cognitive deficits and drug-seeking, cognitive function should be evaluated and considered when developing neurobiologically-based treatments of cocaine relapse.
Structural information of butyrylcholinesterase (BChE) and its variants associated with several diseases are discussed here. Pure human BChE has been proved safe and effective in treating ...organophosphorus (OPs) poisoning and has completed Phase 1 and 2 pharmacokinetic (PK) and safety studies. The introduction of specific mutations into native BChE to endow it a self‐reactivating property has gained much progress in producing effective OPs hydrolases. The hydrolysis ability of native BChE on cocaine has been confirmed but was blocked to clinical application due to poor PK properties. Several BChE mutants with elevated cocaine hydrolysis activity were published, some of which have shown safety and efficiency in treating cocaine addiction of human. The increased level of BChE in progressed Alzheimer's disease patients made it a promising target to elevate acetylcholine level and attenuate cognitive status. A variety of selective BChE inhibitors with high inhibitory activity published in recent years are reviewed here. BChE could influence the weight and insulin secretion and resistance of BChE knockout (KO) mice through hydrolyzing ghrelin. The BChE‐ghrelin pathway could also regulate aggressive behaviors of BChE‐KO mice.
Highlights • Adolescent exposure to cocaine increases anxiety-like behavior in adult rats. • Adolescent exposure to cocaine impairs pyramidal neurons and increases activities of astrocytes in adult ...hippocampus. • Adolescent exposure to cocaine alters status of synaptic transmission, apoptosis, and inflammation in adult hippocampus. • Adolescent exposure to cocaine changes the levels of addiction-related proteins in adult hippocampus.
Rationale/objectives
This study examined the effects of propranolol vs. placebo, administered immediately after a “retrieval” session of cocaine cue exposure (CCE), on craving and physiological ...responses occurring 24 h later during a subsequent “test” session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up.
Methods
CD participants received either 40 mg propranolol or placebo immediately following a “retrieval” CCE session. The next day, participants received a “test” session of CCE that was identical to the “retrieval” session except no medication was administered. Participants underwent a “follow-up” CCE session 1 week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions.
Results
Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use.
Conclusions
This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered, and implications of the results for treatment were noted.
Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is available over prolonged periods of time. Here, ...we investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and gene expression in the dorsal medial prefrontal cortex (dmPFC) in adult male rats. Rats were allowed to self-administer intravenous cocaine (0.25 mg/infusion) under either limited cocaine—(1 h/day), prolonged cocaine—(6 h/day), or limited cocaine—(1 h/day) plus yoked cocaine-access (5 h/day); a control group received access to saline (1 h/day). One day after the final self-administration session, the rats were euthanized and the dmPFC was removed for quantification of mRNA expression of critical glutamatergic signaling genes,
Homer2
,
Grin1
,
and Dlg4
, as these genes and brain region have been previously implicated in addiction, learning, and memory. All groups with cocaine-access showed escalated cocaine intake during the first 10 min of each daily session, and within the first 1 h of cocaine administration. Additionally, the limited-access + yoked group exhibited more non-reinforced lever responses during self-administration sessions than the other groups tested. Lastly,
Homer2
,
Grin1
, and
Dlg4
mRNA were impacted by both duration and mode of cocaine exposure. Only prolonged-access rats exhibited increases in mRNA expression for
Homer2
,
Grin1
, and
Dlg4
mRNA. Taken together, these findings indicate that both contingent and non-contingent “excessive” cocaine exposure supports escalation behavior, but the behavioral contingency of cocaine-access has distinct effects on the patterning of operant responsiveness and changes in mRNA expression.
•Cocaine users had broad reductions in gray matter volume in the brain.•Reduced volume in prefrontal and posterior parietal cortices correlated with impulsivity.•Trait impulsivity correlated with ...left lateral prefrontal and posterior parietal regions.•Behavioral impulsivity mapped onto left medial prefrontal and posterior parietal regions.•The link between brain structure and impulsivity is similar in non-cocaine users.
Chronic cocaine use is associated with structural brain abnormalities within prefrontal regions implicated in impulsivity. Despite high levels of impulsivity among persons who use cocaine, it is not known how reductions in gray matter volume (GMV) may relate to trait and behavioral measures of impulsivity.
The sample included 39 active cocaine users (COC+) and 40 controls with no history of cocaine use (COC−). Participants had a brain scan on a 3 T MRI machine and completed out-of-scanner measures of trait impulsivity and delayed reward discounting. Whole-brain voxel-based morphometry was used to compare GMV between COC+ and COC−. Within regions that differed between groups, voxelwise correlations were conducted to examine the relationship between GMV and impulsivity.
In a whole-brain analysis, COC+ had broad reductions in GMV compared to COC− in bilateral frontal, parietal, occipital, and cerebellar regions. Lower GMV correlated with trait impulsivity in lateral prefrontal regions and with delayed reward discounting in medial prefrontal regions, while lower GMV correlated with both measures in the posterior parietal cortex. COC+ demonstrated significantly higher impulsivity than COC− on all measures, but the nature of the correlation with GMV was similar in both groups.
Reflecting the multi-faceted nature of impulsivity, these results show that trait and behavioral measures of impulsivity map differentially onto altered brain morphology. While the brain-behavior patterns were similar in COC+ and COC−, suggesting that impulsivity varies on a continuous spectrum, cocaine-related abnormalities in frontal-parietal brain systems may contribute to heightened impulsivity.
One of the key mechanisms for the stabilization of synaptic changes near the end of critical periods for experience-dependent plasticity is the formation of specific lattice extracellular matrix ...structures called perineuronal nets (PNNs). The formation of drug memories depends on local circuits in the cerebellum, but it is unclear to what extent it may also relate to changes in their PNN. Here, we investigated changes in the PNNs of the cerebellum following cocaine-induced preference conditioning. The formation of cocaine-related preference memories increased expression of PNN-related proteins surrounding Golgi inhibitory interneurons as well as that of cFos in granule cells at the apex of the cerebellar cortex. In contrast, the expression of PNNs surrounding projection neurons in the medial deep cerebellar nucleus (DCN) was reduced in all cocaine-treated groups, independently of whether animals expressed a preference for cocaine-related cues. Discriminant function analysis confirmed that stronger PNNs in Golgi neurons and higher cFos levels in granule cells of the apex might be considered as the cerebellar hallmarks of cocaine-induced preference conditioning. Blocking the output of cerebellar granule cells in α6Cre-Cacna1a mutant mice prevented re-acquisition, but not acquisition, of cocaine-induced preference conditioning. Interestingly, this impairment in consolidation was selectively accompanied by a reduction in the expression of PNN proteins around Golgi cells. Our data suggest that PNNs surrounding Golgi interneurons play a role in consolidating drug-related memories.
•Cocaine preference memory increases expression of PNN proteins surrounding Golgi cells in the cerebellar apex.•PNNs surrounding DCN projection neurons are unrelated to cocaine preference memory.•The persistence of Pavlovian drug-related memories is impaired in α6-cacna1a KO mice.•α6-Cacna1a mice show reduced expression of PNN around Golgi cells in the dorsal cerebellar cortex.
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