Limbic Responsiveness to Procaine in Cocaine-Addicted Subjects

Adinoff, Bryon; Devous, Michael D.; Best, Susan M.; George, Mark S.; Alexander, Deanna; Payne, Kelly

doi:10.1176/appi.ajp.158.3.390

Cited by 55 publications

(57 citation statements)

References 43 publications

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“…Recent work by Cooper et al (2006) suggests that the effect of cocaine on sodium channels in the subiculum may alter cocaine reinstatement. Both preclinical (DC Cooper et al, unpublished observation) and clinical (Adinoff et al, 2001) studies further suggest that neural activation by other sodium channel-mediated local anesthetics (ie procaine, lidocaine) is an attenuated effect following chronic cocaine administration. Thus, the effect of cocaine on cholinergic systems discussed below may be affected by non-dopaminergic processes, including a direct effect on ACh receptors.…”

Section: Non-dopaminergic Effects Of Cocaine On Achmentioning

confidence: 98%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

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164

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Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

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Section: Non-dopaminergic Effects Of Cocaine On Achmentioning

confidence: 98%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

Self Cite

164

138

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“…Therefore, in the current study we employ fMRI to characterize the functional significance of the abnormalities in the PFC of cocaine abusers that have been previously documented as decreases in metabolism, blood flow or volume (Adinoff B et al, 2001;Adinoff B et al, 2003;Goldstein R et al, 2004;Goldstein R and N Volkow, 2002;Kosten T et al, 2004;Volkow ND et al, 1992;Volkow ND et al, 1988). Since we have previously shown that the decreases in PFC metabolism (including ACG and orbitofrontal cortex) in cocaine abusers was associated with depressed DA D2 receptor availability, we propose that the putative PFC abnormalities reflect in part dopaminergic dysfunction (Volkow ND et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence

et al. 2007

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Cocaine abstinence is associated with impaired performance in cognitive functions including attention, vigilance and executive function. Here we test the hypothesis that cognitive dysfunction during cocaine abstinence reflects in part impairment of cortical and subcortical regions modulated by dopamine. We used functional magnetic resonance imaging (fMRI) to study brain activation to a verbal working memory task in cocaine abusers (n = 16) and healthy controls (n = 16). Compared to controls, cocaine abusers showed: (1) hypoactivation in the mesencephalon, where dopamine neurons are located, as well as the thalamus, a brain region involved in arousal; (2) larger deactivation in dopamine projection regions (putamen, anterior cingulate, parahippocampal gyrus, and amygdala); and (3) hyperactivation in cortical regions involved with attention (prefrontal and parietal cortices), which probably reflects increased attention and control processes as compensatory mechanisms. Furthermore, the working memory load activation was lower in the prefrontal and parietal cortices in cocaine abusers when compared with controls, which might reflect limited network capacity. These abnormalities were accentuated in the cocaine abusers with positive urines for cocaine at time of study (as compared to cocaine abusers with negative urines) suggesting that the deficits may reflect in part early cocaine abstinence. These findings provide evidence of impaired function of regions involved with executive control, attention and vigilance in cocaine abusers. This widespread neurofunctional disruption is likely to underlie the cognitive deficits during early cocaine abstinence, and to reflect involvement of dopamine as well as other neurotransmitters.

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“…In this regard, it has been used as an affective challenge in healthy volunteers (Ketter et al, 1996;ServanSchreiber et al, 1998), and patients with mood disorders (Ketter et al, 1993) and panic disorder , as well as in individuals abusing alcohol (George et al, 1990) and cocaine (Adinoff et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Benson

Carson

Kiesewetter

et al. 2004

Neuropsychopharmacol

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The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([ 18 F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M 2 ) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to B90% of [ 18 F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC 50 ) for [ 18 F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC 50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M 2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

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Limbic Responsiveness to Procaine in Cocaine-Addicted Subjects

Cited by 55 publications

References 43 publications

The Role of Acetylcholine in Cocaine Addiction

The Role of Acetylcholine in Cocaine Addiction

Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

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