Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys

Pw, Czoty; Justice, Jr Jb; Howell, LL

doi:10.1007/s002130050054

Cited by 48 publications

(56 citation statements)

References 43 publications

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“…In separate studies, a dose of 1.0 mg/kg cocaine increased extracellular dopamine in the caudate nucleus to about 300-350% of baseline within the first 10-20 min after i.m. administration (Czoty et al, 2002;Czoty et al, 2000). In these studies, the rate of onset of the dopamine increases corresponded well with the rate of onset of behavioral-stimulant effects following cocaine administration reported previously , despite the fact that drugs were administered intravenously in the behavioral studies and intramuscularly in the microdialysis studies.…”

Section: Discussionsupporting

confidence: 82%

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

Kimmel

O’Connor

Carroll

et al. 2007

Pharmacology Biochemistry and Behavior

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Although the behavioral-stimulant and reinforcing effects of cocaine and related psychomotor stimulants have been attributed to their actions at the dopamine transporter (DAT), the reinforcing effectiveness of these compounds varies. The properties that confer these differences are important considerations when developing agonist pharmacotherapies for the treatment of stimulant abuse. The present studies focused on the time course of action and pharmacological specificity of six 3-phenyltropane analogs of cocaine (RTI-112, RTI-126, RTI-150, RTI-171, RTI-177, and RTI-336) by observing their behavioral-stimulant, neurochemical, and reinforcing effects in squirrel monkeys. The faster-onset analogs (RTI-126, RTI-150, and RTI-336), and one of the slower-onset DAT selective analogs (RTI-177 and RTI-171) produced behavioral-stimulant effects, while the sloweronset nonselective analog RTI-112 did not. The time to the peak behavioral-stimulant effect and the peak caudate dopamine levels was strongly correlated, but the area under the curve of the time course of behavioral-stimulant effect and dopamine levels was not correlated. These results suggest that the rate of onset plays a more important role than duration of action in the stimulant effect of these analogs. In addition, the slower-onset nonselective analog (RTI-112) clearly did not exhibit any reinforcing effects while the faster-onset nonselective (RTI-126) and all the DAT-selective analogs showed robust reinforcing effects (RTI-150, and RTI-177) or showed trends towards reinforcing effects (RTI-336 and RTI-171). Hence, there was a general trend for compounds that had a faster onset and/or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects.

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Section: Discussionsupporting

confidence: 82%

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

Kimmel

O’Connor

Carroll

et al. 2007

Pharmacology Biochemistry and Behavior

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“…The present elevation of low average firing rates and reduction of high average firing rates at the high dose suggests that, under conditions of elevated striatal dopamine transmission by cocaine (Nicolaysen et al, 1988;Czoty et al, 2000;Stuber et al, 2005), there is a reduced range in overall sensorimotor output. We have previously reported that under opposite conditions the range of striatal sensorimotor firing increased.…”

Section: Discussionmentioning

confidence: 66%

Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

Tang

Mittler²,

Duke³

et al. 2007

J Pharmacol Exp Ther

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To examine the role of striatal mechanisms in cocaine-induced stereotyped licking, we investigated the acute effects of cocaine on striatal neurons in awake, freely moving rats before and after cocaine administration (0, 5, 10, or 20 mg/kg). Stereotyped licking was induced only by the high dose. Relative to control (saline), cocaine reduced lick duration and concurrently increased interlick interval, particularly at the high dose, but it did not affect licking rhythm. Firing rates of striatal neurons phasically related to licking movements were compared between matched licks before and after injection, minimizing any influence of sensorimotor variables on changes in firing. Both increases and decreases in average firing rate of striatal neurons were observed after cocaine injection, and these changes exhibited a dose-dependent pattern that strongly depended on predrug firing rate. At the middle and high doses relative to the saline group, the average firing rates of slow firing neurons were increased by cocaine, resulting from a general elevation of movement-related firing rates. In contrast, fast firing neurons showed decreased average firing rates only in the high-dose group, with reduced firing rates across the entire range for these neurons. Our findings suggest that at the high dose, increased phasic activity of slow firing striatal neurons and simultaneously reduced phasic activity of fast firing striatal neurons may contribute, respectively, to the continual initiation of stereotypic movements and the absence of longer movements.

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“…A stereotaxic apparatus was used to implant CMA/11 guide cannulae (CMA/Microdialysis, Acton, MA) bilaterally to target the caudate nuclei of three monkeys as described previously (Czoty et al, 2000). Anesthesia was initiated with Telazol (tiletamine hydrochloride and zolazepam hydrochloride, 5.0 mg) and atropine (0.1 mg).…”

Section: Methodsmentioning

confidence: 99%

“…Animals were closely monitored during recovery from anesthesia, and a minimum of 1 month was allowed before microdialysis experiments were performed. Following guide cannula implantation, accurate placement was verified in each monkey through use of magnetic resonance imaging as described previously (Czoty et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys

Czoty¹,

Ginsburg²,

Howell³

2002

J Pharmacol Exp Ther

108

100

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Preclinical studies have documented that serotonin (5-HT) can modulate the behavioral effects of cocaine. The present study examined the ability of 5-HT to attenuate the reinforcing and neurochemical effects of cocaine in nonhuman primates. In squirrel monkeys trained to self-administer cocaine (0.1 and 0.3 mg/injection) under a second-order schedule of i.v. drug delivery, the 5-HT uptake inhibitor alaproclate (3.0 and 10.0 mg/kg) and the 5-HT direct agonist quipazine (0.3-1.0 mg/kg) decreased response rates at doses that had no significant effect on behavior maintained by an identical schedule of stimulus termination. The neurochemical bases of the observed drug interactions on behavior were investigated further using in vivo microdialysis techniques in a separate group of awake monkeys to monitor drug-induced changes in extracellular dopamine (DA). Cocaine (1.0 mg/kg) elevated the concentration of DA in the caudate nucleus to approximately 300% of basal levels. Pretreatment with alaproclate or quipazine attenuated cocaine-induced increases in extracellular DA at the same pretreatment doses that decreased cocaine self-administration. The results obtained suggest that increasing brain 5-HT activity can attenuate the reinforcing effects of cocaine, ostensibly by decreasing the ability of cocaine to elevate extracellular DA in brain areas that mediate the behavioral effects. These findings extend those reported previously for the behavioral-stimulant effects of cocaine and identify a potential neurochemical mechanism underlying drug interactions on behavior.Abuse of stimulant drugs such as cocaine persists as a major health problem in the United States (Chilcoat and Johanson, 1998). Clearly, there is a great need for pharmacological treatments to combat abuse of these drugs; however, no pharmacotherapy has demonstrated sufficient efficacy for widespread clinical use (Carroll et al., 1999). A better understanding of the effects of cocaine on central nervous system neurochemistry will help identify effective approaches in developing medications for treating cocaine dependence.The behavioral-stimulant and reinforcing effects of cocaine have been linked to its ability to enhance dopaminergic neurotransmission by inhibiting DA uptake via transporter blockade (Ritz et al., 1987). The affinities of several cocainelike drugs for DA transporter correlate well with their potencies for supporting self-administration behavior (Ritz et al., 1987;Bergman et al., 1989). In humans, a significant correlation has been observed between DA transporter binding and the intensity of subjective effects produced by intravenous cocaine (Volkow et al., 1997). Cocaine affects neurotransmission in various brain DA systems, leading to a variety of behavioral effects. For example, the DA neurons of the substantia nigra pars compacta project to the caudate nucleus and putamen, the primate homologues of the rodent dorsal striatum (Parent et al., 1995), to modulate motor function. Facilitation of DA transmission in the nigrostriatal system...

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Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys

Abstract: The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors.

Cited by 48 publications

References 43 publications

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys

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