Pharmacokinetic Determinants of Drug Abuse and Dependence

Busto, Usoa E.; Sellers, Edward M.

doi:10.2165/00003088-198611020-00004

Cited by 80 publications

(27 citation statements)

References 42 publications

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“…It is well-documented that cocaine's rapid onset of action contributes to its highly-rewarding efficacy and addictive potential (Busto and Sellers, 1986;Kimmel et al, 2008;Kimmel et al, 2007), although not all studies support this view (Li et al, 2011). In rodents, different rates of cocaine delivery affect its addictive liability-drugs reaching the brain rapidly are more addictive than those that reach the brain slowly (Oldendorf, 1992;Samaha and Robinson, 2005;Wakabayashi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Song²,

et al. 2016

Neuropsychopharmacol

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Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaineassociated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction.

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Section: Discussionmentioning

confidence: 99%

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Song²,

et al. 2016

Neuropsychopharmacol

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“…We define the NAc DA response to cocaine as cocaine-induced changes in DA over baseline (i.e., percent of baseline). This is important because the rate of change in extracellular DA is positively correlated with a drug's rewarding efficacy and addictive potential; the faster the increase in extracellular DA, the higher the drug-induced reward and the psychomotor stimulation (32)(33)(34). In light of this, reduced DA elevation to cocaine suggests reduced cocaine reward in D 3 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Song

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Neuroimaging studies using positron emission tomography suggest that reduced dopamine D 2 receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D 3 receptors (D 3 Rs) in the neurobiology of addiction remains unclear, however. Here we report that D 3 R KO (D 3 −/− ) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D 3 −/− mice. In addition, D 3 −/− mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D 3 R deletion increases vulnerability to cocaine, and that reduced D 3 R availability in the brain may constitute a risk factor for the development of cocaine addiction.O ne of the most challenging issues in drug abuse research is understanding the etiology of addiction (1-3). Identification of neurobiological factors conferring vulnerability to drug use and abuse may provide important therapeutic targets for the development of medications to treat addiction. Cumulative evidence suggests that certain vulnerability traits, such as high impulsivity, stress reactivity, novelty-seeking, negative emotionality, and abnormal structure of the frontostriatal brain system, may predispose humans to drug abuse and addiction (4-8). However, the neurobiological mechanisms by which such traits affect drug-taking and drug-seeking behavior are poorly understood. PET studies suggest that reduced dopamine (DA) D 2 receptor (D 2 R) availability in the neostriatum is associated with reduced orbitofrontal cortex functional activity, which is linked to risk for impulsivity and compulsive cocaine administration in both humans (9-12) and nonhuman primates (2, 13). Whether reduced D 2 R availability is a determinant or consequence of cocaine abuse remains unclear, however (2,(12)(13)(14).It should be noted that the reduced D 2 R availability observed in PET or micro-PET studies is based on the use of D 2 R-preferring ligands, such as [ 11 C]raclopride (∼10-to 20-fold selectivity for D 2 over D 3 ). This raises the question of whether striatal D 3 Rs are also involved in increased susceptibility to drug-taking behavior. Compared with D 2 Rs, which are expressed uniformly throughout the striatum (15), D 3 Rs are expressed preferentially in the nucleus accumbens (NAc) shell, islands of Calleja, and olfactory tubercle (16,17). A recent neuroimaging study with the D 3 R-preferring ligand [ 11 C]-PHNO (with 10-fold selectivity for D 3 over D 2 ) revealed significant reduction in D 3 R binding in the dorsal striatum of heavy methamphetamine polydrug users (18). In rodents, a significant reduction in ...

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“…We do not try to account for high-dose recreational use of benzodiazepines under this heading. This is a different clinical phenomenon and the crucial factors may be related to pharmacokinetic considerations such as speed of onset of action and acute psychotropic, particularly euphoriant, effects (Busto & Sellers, 1986).…”

Section: Resultsmentioning

confidence: 99%

The biological basis of benzodiazepine dependence

Lader¹,

File²

1987

Psychol. Med.

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EDITORIALThe biological basis of benzodiazepine dependence 1Benzodiazepines are the most widely prescribed psychotropic drugs and while the specific neural pathways mediating their several therapeutic effects remain largely unknown, at least their initial site of action has been identified. For the last decade we have known that the central nervous system contains high affinity, stereospecific binding-sites for the benzodiazepines. These sites are found on a supramolecular complex with y-aminobutyric acid (GABA) receptors and with a chloride ionophore (channel across the cell membrane), which also has binding-sites for drugs such as the barbiturates (Olsen, 1982).Recently there has been a growing appreciation that benzodiazepines induce dependence and that tolerance can occur to their behavioural effects. Although initially these phenomena were linked with long-term use, more recent evidence suggests that similar changes can be observed after short-term or even a single administration.This review covers both the clinical evidence and relevant experimental studies and attempts to explore the possible underlying mechanism(s). Although the precise mechanism is still unknown, we conclude that both rebound and withdrawal symptoms are reflections of a common dependence mechanism and also that tolerance is simply another manifestation of this same mechanism. We further conclude that the same underlying mechanism mediates the rebound phenomena and tolerance seen after short-term or acute benzodiazepine administration. DEPENDENCEDependence is a hypothetical construct for the state induced by the compensatory change that occurs, for example, in the central nervous system as a result of drug administration. The nature of the compensatory change induced by the benzodiazepines remains unknown, but evidence for physical dependence comes from rebound and withdrawal symptoms. To date rebound and withdrawal have been separated in the literature because the former follows acute or short-term, and the latter chronic, drug treatment. We shall follow the literature and describe each separately, but we shall then argue that the two phenomena cannot be distinguished and therefore that each reflects the same common mechanism of dependence, albeit to a different degree. REBOUND SYNDROMERebound can be defined as the increase in severity of the original symptoms, beyond pre-treatment levels, after short or long-term drug administration. Rebound effects have been described after sleep-laboratory studies involving 1-2 weeks of benzodiazepine administration (Kales et al. 1983 a), as well as after longer-term administration (Adam et al. 1976;Oswald et al. 1982). Rebound insomnia after the use of benzodiazepines as hypnotics is now well-documented (for review, see Lader & Lawson, 1987). It is more severe than the original insomnia, and is characterized by a delayed onset of sleep and by frequent awakenings. The elimination half-life of the benzodiazepine is important in determining the timing and the severity of rebound. Short-acting drugs (e....

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Pharmacokinetic Determinants of Drug Abuse and Dependence

Cited by 80 publications

References 42 publications

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

The biological basis of benzodiazepine dependence

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Pharmacokinetic Determinants of Drug Abuse and Dependence

Cited by 80 publications

References 42 publications

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Increased vulnerability to cocaine in mice lacking dopamine D3receptors

The biological basis of benzodiazepine dependence

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Increased vulnerability to cocaine in mice lacking dopamine D₃receptors