Cocaine and the porcine coronary microcirculation: Effects of chronic cocaine exposure and hypercholesterolemia

AbstractPreclinical studies have implicated noradrenergic (NA) dysfunction in cocaine addiction. In particular, the NA system plays a central role in motivated behavior and may partake in the regulation of craving and drug use. Yet, human studies of the NA system are scarce, likely hampered by the difficulty in precisely localizing the locus coeruleus (LC). Here, we used neuromelanin imaging to localize the LC and quantified LC neuromelanin signal (NMS) intensity in 44 current cocaine users (CU; 37 men) and 59 nondrug users (NU; 44 men). We also employed fMRI to investigate cue-induced regional responses and LC functional connectivities, as quantified by generalized psychophysiological interaction (gPPI), in CU. Imaging data were processed by published routines and the findings were evaluated with a corrected threshold. We examined how these neural measures were associated with chronic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ). Compared to NU, CU demonstrated higher LC NMS for all probabilistic thresholds defined of 50–90% of the peak. In contrast, NMS of the ventral tegmental area/substantia nigra (VTA/SN) did not show significant group differences. Drug as compared to neutral cues elicited higher activations of many cortical and subcortical regions, none of which were significantly correlated with CCQ score. Drug vs. neutral cues also elicited “deactivation” of bilateral parahippocampal gyri (PHG) and PHG gPPI with a wide array of cortical and subcortical regions, including the ventral striatum and, with small volume correction, the LC. Less deactivation of the PHG (r = 0.40, p = 0.008) and higher PHG-LC gPPI (r = 0.44, p = 0.003) were positively correlated with the CCQ score. In contrast, PHG-VTA/SN connectivity did not correlate with the CCQ score. Together, chronic cocaine exposure may induce higher NMS intensity, suggesting neurotoxic effects on the LC. The correlation of cue-elicited PHG LC connectivity with CCQ score suggests a noradrenergic correlate of chronic cocaine craving. Potentially compensating for memory functions as in neurodegenerative conditions, cue-elicited PHG LC circuit connectivity plays an ill-adaptive role in supporting cocaine craving.

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Chronic cocaine exposure in the fetal rhesus monkey: consequences for early development of dopamine neurons

Journal of Neuroscience ◽

10.1523/jneurosci.15-11-07330.1995 ◽

1995 ◽

Vol 15 (11) ◽

pp. 7330-7343 ◽

Cited By ~ 36

Author(s):

OK Ronnekleiv ◽

BR Naylor

Keyword(s):

Rhesus Monkey ◽

Early Development ◽

Dopamine Neurons ◽

Cocaine Exposure ◽

Chronic Cocaine

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Cocaine-induced Impulsive Choices Are Accompanied by Impaired Delay-dependent Anticipatory Activity in Basolateral Amygdala

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_00131 ◽

2012 ◽

Vol 24 (1) ◽

pp. 196-211 ◽

Cited By ~ 10

Author(s):

Yanfang Zuo ◽

Xinsheng Wang ◽

Cailian Cui ◽

Fei Luo ◽

Peng Yu ◽

...

Keyword(s):

Decision Making ◽

Basolateral Amygdala ◽

Delayed Reinforcement ◽

Cocaine Exposure ◽

Reward Delivery ◽

Chronic Cocaine ◽

Delay Dependence ◽

Show Evidence ◽

Anticipatory Activity ◽

Delay Dependent

Addicts and drug-experienced animals have decision-making deficits in delayed reinforcement choice task, in which they prefer small immediate rewards over large delayed rewards. Here, we show evidence that this deficit is accompanied by changed coding of delay length in the basolateral amygdala (BLA). A subset of neurons in BLA demonstrated delay-dependent anticipatory activity (either increase or decrease as a function of delay to reward) in naive rats. After 30 days of withdrawal from chronic cocaine treatment (30 mg/kg/day for 10 days ip), the proportion of delay-dependent anticipatory neurons reduced, whereas delay-dependent activity in response to elapsed delay after reward delivery increased, both in the proportion of delay-dependent neurons and in the extent of delay dependence. Cocaine exposure increased, instead of decreased, BLA neuronal expectation for different reward magnitudes. These results indicate that BLA is critical for representing and maintaining the information of delayed reward before its delivery, and cocaine exposure may affect decision-making by impairing perception of delay instead of the ability to assess the differences in reward size.

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WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621185114 ◽

2017 ◽

Vol 114 (6) ◽

pp. 1395-1400 ◽

Cited By ~ 5

Author(s):

Ilaria Ceglia ◽

Ko-Woon Lee ◽

Michael E. Cahill ◽

Steven M. Graves ◽

David Dietz ◽

...

Keyword(s):

Dopamine Receptor ◽

Dendritic Spine ◽

Actin Polymerization ◽

Feedback Regulation ◽

Projection Neurons ◽

Spine Density ◽

Cocaine Exposure ◽

Chronic Cocaine ◽

D1 Dopamine Receptor ◽

Nmda Glutamate Receptor Antagonist

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.

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