Differences in the Pharmacokinetics of Cocaine in Naive and Cocaine‐Experienced Rats

Pan, Hwai‐Tzong; Menacherry, Stanley; Justice, Joseph B.

doi:10.1111/j.1471-4159.1991.tb11425.x

Cited by 157 publications

(128 citation statements)

References 16 publications

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“…When examined on a slower timescale, the frequency of dopamine transients from recordings in five animals that were naïve to cocaine correlated closely (r ¼ 0.8) to the computed local concentration of cocaine (Pan et al, 1991;Figure 3a). While the frequency of dopamine transients was unchanged by saline infusions, in the first minute after cocaine infusion, the frequency increased and then declined as the local cocaine concentration declined.…”

Section: Pharmacological Effects Of Cocaine On Dopaminergic Terminalsmentioning

confidence: 84%

Rapid Dopamine Signaling in the Nucleus Accumbens during Contingent and Noncontingent Cocaine Administration

Stuber

Roitman

Phillips

et al. 2004

Neuropsychopharmacol

204

231

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Cocaine acts as a reinforcer through its pharmacological effects on brain monoaminergic systems, which, through repeated pairings with environmental stimuli, lead to the development of conditioned effects of the drug. Both the pharmacological and conditioned aspects of cocaine are implicated in several facets of acquisition and maintenance of addiction, including drug craving. Here, we compare the effects of contingent (response dependent) and noncontingent (response independent) cocaine on rapid dopaminergic signaling in the core of the nucleus accumbens. Dopamine was monitored using fast-scan cyclic voltammetry. Noncontingent cocaine administered to both naïve and animals with a history of self-administration resulted in a profound increase in the frequency of transient dopamine release events that are not time-locked to any specific environmental stimuli. Pharmacological effects were detectable approximately 40 s after cocaine administration. In contrast, when animals where allowed to self-administer cocaine on an FR-1 schedule, dopamine transients (69712 nM) were consistently observed time-locked to each reinforced response (peaking approximately 1.5 s after response completion). Importantly, no pharmacological effect of cocaine was observed within the 10 s following noncontingent cocaine administration, indicating that dopamine signals time-locked to the reinforced response are a result of the pairing of the operant behavior, the drug-associated cues, and cocaine. These data demonstrate that this pharmacological action of cocaine occurs for an extended period following either contingent or noncontingent administration, but is distinct from those dopamine transients that are time-locked to each lever-press in self-administering animals.

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Section: Pharmacological Effects Of Cocaine On Dopaminergic Terminalsmentioning

confidence: 84%

Rapid Dopamine Signaling in the Nucleus Accumbens during Contingent and Noncontingent Cocaine Administration

Stuber

Roitman

Phillips

et al. 2004

Neuropsychopharmacol

204

231

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“…The white cue light at the end of the runway was also illuminated during the noncontingent condition. Intertrial intervals of 40 min (RMF) or 60 min (COC) were chosen to guarantee de facto elimination of the drug from the brain (Pan et al, 1991;Haidar et al, 1997;Hemby et al, 1997;Cox et al, 1999) before the start of the next trial. The operant level was determined with intravenous saline in another six rats, using a run-time cutoff of 60 s. Runway dimensions and experimental details have been published previously (Wakonigg et al, 2003a(Wakonigg et al, ,b, 2004.…”

Section: Methodsmentioning

confidence: 99%

Activation of Muscarinic and Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Core Is Necessary for the Acquisition of Drug Reinforcement

Crespo¹,

Šturm²,

Saria³

et al. 2006

J. Neurosci.

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Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of ϳ10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Our findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

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“…Brain-cocaine concentrations were calculated as previously described (Zimmer et al, 2011) using equations employed by Pan et al (1991). Briefly, the equation c ¼ dk vða À bÞ ðe Àbt À e Àat Þ estimates the amount of cocaine in the brain compartment at time t. This equation accounts for the dose of cocaine (d), the transfer of cocaine between the blood and the brain (k ¼ 0.233 min À1 ), the apparent brain volume (v ¼ 0.15 l kg À1 ), and the removal of cocaine from the blood through redistribution (a ¼ 0.642 min À1 ) and elimination (b ¼ 0.097 min À1 ).…”

Section: Brain-cocaine Concentration Modelmentioning

confidence: 99%

“…The application of a well-established mathematical model for estimating cocaine levels in brain (Ahmed and Koob, 2005;Nicola and Deadwyler, 2000;Pan et al, 1991;Wise et al, 1995) helps illustrate the important differences between the groups during daily self-administration sessions. Brain concentrations of cocaine rose relatively rapidly in all groups at the beginning of the session.…”

Section: Figurementioning

confidence: 99%

“…The equation used by Pan et al (1991) is based on standard pharmacokinetic principles that have been validated for many different drugs and in many different systems (Karan et al, 2009). However, the specific variables used to represent rat blood volume, cocaine redistribution and degradation must be verified in order to have confidence in applying the equation to this study.…”

Section: Figurementioning

confidence: 99%

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The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

Zimmer

Oleson

Roberts

2012

Neuropsychopharmacol

138

205

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Recent attempts to model the addiction process in rodents have focused on cocaine self-administration procedures that provide extended daily access. Such procedures produce a characteristic loading phase during which blood levels rapidly rise and then are maintained within an elevated range for the duration of the session. The present experiments tested the hypothesis that multiple fastrising spikes in cocaine levels contribute to the addiction process more robustly than constant, maintained drug levels. Here, we compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic measure of the motivation to self-administer drug. Two groups received intermittent access (IntA) to cocaine during daily 6-h sessions. Access was limited to twelve 5-min trials that alternated with 25-min timeout periods, using either a hold-down procedure or a fixed ratio 1 (FR1). Cocaine levels could not be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long access and 2-h short access sessions and two other control groups. Here, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine.

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Differences in the Pharmacokinetics of Cocaine in Naive and Cocaine‐Experienced Rats

Cited by 157 publications

References 16 publications

Rapid Dopamine Signaling in the Nucleus Accumbens during Contingent and Noncontingent Cocaine Administration

Rapid Dopamine Signaling in the Nucleus Accumbens during Contingent and Noncontingent Cocaine Administration

Activation of Muscarinic and Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Core Is Necessary for the Acquisition of Drug Reinforcement

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

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