New concepts in cocaine addiction: The dopamine depletion hypothesis

Dackis, Charles A.; Gold, Mark S.

doi:10.1016/0149-7634(85)90022-3

Cited by 573 publications

(236 citation statements)

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“…The present experiments showed that 10 days of binge-like cocaine SA produced a marked decrease in the ability of cocaine to inhibit DA uptake and also caused changes in DA terminal function suggestive of a hypodopaminergic state (see Dackis and Gold, 1985). The changes observed in this study were found at both time points examined (after 1 and 7 days).…”

Section: Discussionsupporting

confidence: 66%

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Mateo

Läck

Morgan

et al. 2005

Neuropsychopharmacol

124

139

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Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. Highintake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max. effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

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Section: Discussionsupporting

confidence: 66%

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Mateo

Läck

Morgan

et al. 2005

Neuropsychopharmacol

124

139

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Section: Pet Studies Of Presynaptic Da Synthesismentioning

confidence: 99%

“…Also, a decrease in presynaptic DA activity during cocaine abstinence or withdrawal is associated with relapse [36,37] .…”

Section: Pet Studies Of Presynaptic Da Synthesismentioning

confidence: 99%

“…Studies with PET and radionuclidelabeled L-dopa and their main fi ndings are summarized in [34,35] . Also, a decrease in presynaptic DA activity during cocaine abstinence or withdrawal is associated with relapse [36,37] .Methamphetamine (MA), another prevalent psychostimulant drug of abuse, induces more deleterious changes in the brain than cocaine when a toxic dose is used [35] . This is evident from the significant reductions in striatal [ 18 F] dopa uptake in MA-treated mice, suggesting the neurodegeneration of dopaminergic cells and DA synthesis in MA abuse [35] .…”

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confidence: 99%

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Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

et al. 2014

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Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the fi rst technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major fi ndings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms.Keywords: dopamine; dopaminergic system; drug addiction; positron emission tomography ·Review· Brain Dopaminergic System Dopamine (DA) is a catecholamine neurotransmitter in the nervous system. It has many functions in the brain, including punishment, reward, voluntary movement, mood, attention, motivation, sleep, working memory, and learning [1] .DA is synthesized by the hydroxylation and decarboxylation of L-tyrosine in DA neurons and, before being released into the synapse in response to an action potential, it is stored within presynaptic vesicles (Fig. 1). The action of DA occurs by binding to postsynaptic DA receptors, resulting in the formation of second messengers. There are fi ve subtypes of DA receptors, which can be grouped into two classes or families: D1-like and D-2 like [1,2] . The D1-like receptor family comprises the D1 and D5 receptors, encoded by genes with no introns, acting by way of Gs-proteins and activating adenylyl cyclase, thus increasing cAMP production [3,4] .The D2-like receptor family comprises the D2, D3, and D4 receptors, encoded by genes containing introns. D2-like receptors act via Gi-proteins, inhibit adenylyl cyclase activity, and thus decrease cAMP activity [3,5] .The action of DA in the synapse is terminated primarily by reuptake to the presynaptic membrane through the dopamine transporter (DAT) [6] . Otherwise, DA is partially removed by oxidation by monoamine oxidase orcatechol-O-methyltransferase in the synaptic cleft (Fig. 1).T h e d o p a m i n e r g i c n e u r o n s , w h o s e p r i m a r y neurotransmitter is DA, interconnect many areas of the brain to form a system which originates in the substantia nigra (SN) pars compacta, ventral tegmental area (VTA), and hypothalamus. The dopaminergic system is typically divided into four major pathways: mesocortical (from the VTA to the frontal cortex), mesolimbic (from the VTA to the nucleus accumbens), nigrostriatal (from the SN to the striatum), and tuberoinfundibular (from the hypothalamus to the pituitary gland). The mesostriatal and mesocortical pathways are currently recognized to contribute most to drug addiction [7] . Neurosci Bull October 1, 2014, 30(5): 765-776 766 Drug AddictionThe term addiction is derived from the Latin verb addicere, which referred to the Roman court action of binding a person to another. From the 17th century, addiction has been used to refer to psychoactive substances (...

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“…Striatal uptake of the [ 18 F] dopa or [ 11 C] L-dopa reflects the synthesis rate of DA in the terminals (Turjanski et al, 1999;Heinz et al, 2005). It has been showed that a decrease in dopaminergic presynaptic activity during abstinence or withdrawal is related to relapse in cocaine-dependent subjects (Dackis and Gold, 1985;Markou and Koob, 1991). PET imaging with [ 18 F] dopa has found in the detoxified cocaine abusers a delayed decrease in DA terminal activity in the striatum compared with controls (Bell et al, 1996;Wu et al, 1997).In the study of Heinz et al (2005), although no difference of striatal [ 18 F] dopa net influx, an index of DA synthesis capacity, was found between detoxified alcoholic patients and the control subjects, the results showed that a low DA synthesis capacity correlated with alcohol craving which was associated with a high relapse risk.…”

Section: Assessment Of Presynaptic Da Synthesis and Dat Of The Dopamimentioning

confidence: 99%

Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction

Hou¹,

Tian²,

Zhang³

2012

The Anatomical Record

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Dopamine (DA) is involved in drug reinforcement, but its role in drug addiction remains unclear. Positron emission tomography (PET) is the first technology used for the direct measurement of components of the dopaminergic system in the living human brain. In this article, we reviewed the major findings of PET imaging studies on the involvement of DA in drug addiction, especially in heroin addiction. Furthermore, we summarized PET radiotracers that have been used to study the role of DA in drug addiction. To investigate presynaptic function in drug addiction, PET tracers have been developed to measure DA synthesis and transport. For the investigation of postsynaptic function, several radioligands targeting dopamine one (D1) receptor and dopamine two (D2) receptor are extensively used in PET imaging studies. Moreover, we also summarized the PET imaging findings of heroin addiction studies, including heroin-induced DA increases and the reinforcement, role of DA in the long-term effects of heroin abuse, DA and vulnerability to heroin abuse and the treatment implications. PET imaging studies have corroborated the role of DA in drug addiction and increase our understanding the mechanism of drug addiction. Anat Rec, 295:722-733, 2012. V C 2012 Wiley Periodicals, Inc.Key words: positron emission tomography; dopamine; dopamine receptor; drug addiction; heroin BRAIN DOPAMINERGIC SYSTEM Dopamine (DA) is a catecholamine neurotransmitter in the nervous system that permits individual nerve fibers (neurons) to communicate with each other. DA has many functions in the brain, including important roles in behavior and cognition, voluntary movement, motivation, punishment and reward, sleep, mood, attention, working memory, and learning (Smythies, 2005).

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New concepts in cocaine addiction: The dopamine depletion hypothesis

Cited by 573 publications

References 53 publications

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction

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