Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats (original) (raw)
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Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys
Synapse, 2005
in vivo microdialysis; operant behavior; second-order schedule; nonhuman primates ABSTRACT Environmental cues are thought to play a role in drug craving, leading to the high relapse rate observed in cocaine abusers. Cocaine-paired cues can reinstate cocaine-maintained behavior in rodents and nonhuman primates and can induce changes in dopamine levels in the rodent striatum. In the present study, squirrel monkeys were trained to self-administer cocaine under a second-order schedule, and then were implanted with guide cannulae targeted at the caudate nucleus. Caudate dopamine levels were measured while the animals performed the behavioral task, selfadministering cocaine or saline under extinction conditions. In addition, animals received noncontingent (passive) cocaine infusions yoked to the drug self-administration sessions. Cocaine administration increased dopamine levels 2-fold, but a leftward shift was seen in the peak effect in animals self-administering cocaine as compared to animals passively receiving cocaine. Moreover, dopamine levels began to decline during the experimental session when animals were self-administering cocaine, even though they continued to receive cocaine injections. In contrast, dopamine levels declined below baseline during the session when animals were given access to saline. The results suggest that the environmental context associated with drug self-administration can modulate cocaine-induced elevations in extracellular dopamine. Synapse 56: 129-134, 2005. '
D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat
Pharmacology, biochemistry, and behavior, 1993
Previous work using systemic injections of dopamine receptor antagonists has established that dopamine D1 receptors may have a role in cocaine self-administration. The purpose of the present study was to test the hypothesis that these effects were mediated by dopamine D1 receptors in the region of the nucleus accumbens. Animals were trained to perform operant responses to self-administer cocaine via an IV catheter on a fixed-ratio 5 (FR 5) schedule of reinforcement. SCH23390, a selective D1 dopamine antagonist, significantly increased the self-administration of cocaine when injected into the nucleus accumbens. This increase in self-administration is thought to reflect decreases in the magnitude of the reinforcer, similar to the increase observed when the dose of cocaine is reduced. Similar doses of SCH23390 injected into the posterior caudate nucleus failed to alter cocaine self-administration. These data suggest that D1 receptors in the nucleus accumbens are important for the reinf...
Cocaine self-administration in dopamine-transporter knockout mice
Nature Neuroscience, 1998
The widespread abuse of cocaine, a highly addictive psychostimulant, places tremendous social, medical, and economic burdens on society. By improving our understanding of the underlying mechanisms of cocaine addiction, it may be possible to develop more effective therapeutic strategies and social policies aimed at reducing the abuse of cocaine. Cocaine inhibits the uptake of monoaminergic neurotransmitters from the extracellular space through its interaction with plasma membrane monoamine transporters 1 . This family of proteins, which includes the transporters for dopamine (dopamine transporter, DAT), norepinephrine (norepinephrine transporter, NET), and serotonin (serotonin transporter, SERT), acts to terminate monoaminergic transmission by rapid removal of the neurotransmitters from the synaptic cleft, back into the presynaptic terminals 2 .
Neuropsychopharmacology, 2002
The purpose of this study was to examine the time course of changes in dopamine D 1 -and D 2 -like receptor densities in monkeys self-administering cocaine. Experimentally naïve adult male rhesus monkeys (n ϭ 22) were divided into a food reinforcement group (n ϭ 6), in which responding was maintained by food presentation, or into four cocaine selfadministration groups (n ϭ 4/group), based on dose (0.03 or 0.3 mg/kg per injection) and duration of exposure (5 or ف 100 sessions). After the last session, monkeys were euthanized, brains were removed, frozen, and coronal sections through the striatum, rostral to the anterior commissure, were processed for D 1 ([ 3
Brain Research, 1995
This study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of the amygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effects of self-administered cocaine. Microinjection of SCH 23390 (0-4.0 p.g total dose) into any of the three brain regions dose-dependently increased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25 mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum, striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaine self-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent with the rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regional selectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in the nucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the 'extended amygdala' may be an important substrate for the reinforcing actions of cocaine.
In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0-4.0 mg/kg) four times daily for 14 consecutive days and sacrificed two weeks after the last injection. The densities of dopamine D 1 receptor binding sites, dopamine transporter binding sites and fl adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D 2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D 1, D2, dopamine transporter, fl), nucleus accumbens (D 1, D2, dopamine transporter) and substantia nigra (D2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre-and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.
Dopamine release during cocaine self-administration in rats: effect of SCH23390
Brain Research, 1995
This experiment tested the hypotheses that: (1) self-administration of cocaine would produce an increase in dopamine (DA) oxidation current in the nucleus accumbens (n. ace.); and (2) a faster rate of cocaine intake in the presence of a D t receptor antagonist would produce a greater increase in DA levels. Rats trained to self-administer cocaine under a fixed-ratio 2 schedule were implanted with stearate-modified graphite paste electrodes bilaterally in the n. ace. The effect of pretreatment with the D 1 receptor antagonist, SCH23390, on the DA oxidation current associated with self-administration of cocaine (1 mg/inj.) or saline was investigated using chronoamperometry. Pretreatment with SCH23390 produced a 2-fold increase in the amount of cocaine intake. This in turn resulted in a 2-fold increase in the DA oxidation current recorded in the n. ace. Pretreatment with SCH23390 did not, however, produce any significant change in either the number of saline injections received or the DA oxidation current recorded during saline self-administration. These findings show that cocaine increases DA oxidation currents in the n. ace., and that both the rate of cocaine self-administration and the magnitude of these currents increase even further following SCH23390. The results also imply that the baseline rate of cocaine self-administration does not result in the occupation of all possible DA transporter sites.
Neuropsychopharmacology, 2008
The selective breeding of Roman high-(RHA) and low-avoidance (RLA) rats for, respectively, rapid vs extremely poor acquisition of avoidant behavior in a shuttlebox has produced two phenotypes that differ in temperament traits, in mesocortical/mesolimbic dopamine system function, and in the behavioral and neurochemical responses to the acute and repeated administration of psychostimulants and opiates. The phenotypic traits of the RHA line predict higher susceptibility, compared with RLA rats, to the reinforcing properties of addictive substances like cocaine. The present study was designed to compare the acquisition, maintenance, reinstatement of drugseeking after long-term extinction, and reacquisition of intravenous cocaine self-administration (SA) behavior in the Roman lines. Compared with RLA rats, the rates of responding during cocaine SA acquisition were higher, extinction from cocaine SA was prolonged, and drug-induced reinstatement of cocaine-seeking behavior was more robust in RHA rats. Moreover, only RHA rats reacquired extinguished lever-pressing activity when a low reinforcing dose of cocaine was available. These findings are consistent with the view that subjects with genetically determined high responsiveness to the acute and chronic (ie, sensitizing) effects of psychostimulants, such as RHA rats, also display a higher propensity to self-administer cocaine. Further comparative studies in the Roman lines, using SA paradigms that distinguish mere drug-taking from the compulsive and uncontrolled drug use that characterizes addiction in humans, may eventually help to characterize the relationships among genotype, temperament traits, and neurobiological mechanisms involved in the individual vulnerability to cocaine addiction.
Neuroscience Letters, 2006
Dopamine (DA) responses in the nucleus accumbens (NAcc) and dorsal striatum (DS) are commonly associated with different aspects of cocaine effects. Enhanced NAcc DA has been most convincingly linked with the positive reinforcing effects of cocaine, while DS DA is thought to mediate cocaine-induced motoric effects. Though several studies have shown NAcc DA enhancement following cocaine self-administration, very little work has examined the effects of cocaine self-administration on DS DA. In this study, DA levels in the NAcc and DS, and locomotor responses to a single self-administered cocaine injection (1.5mg/kg) were assessed in operant-trained, drug-naïve Sprague-Dawley rats. Locomotor activity, NAcc and DS DA levels increased significantly over baseline activity immediately after cocaine injection. However, while basal and cocaine-stimulated NAcc DA concentrations (nM) were significantly greater than DS DA levels, the magnitude of response was statistically comparable between brain regions. These findings indicate that, though both the NAcc and DS are importantly involved in the dopaminergic response to self-administered cocaine in drug-naïve rats, basal DA differences in dialysis data are obscured by statistical conversions to baseline percentages.
Psychopharmacology
Rationale We have previously described a model in which adult outbred male Sprague–Dawley rats are classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced open-field activation. This model revealed important individual differences in cocaine's effects, including that LCRs exhibited greater responding than HCRs on a progressive ratio schedule of cocaine reinforcement. However, no LCR/HCR differences in acquisition of cocaine self-administration (0.25 mg/kg/12 s infusion) were observed under these conditions. Objectives To determine if LCRs and HCRs differ in the effectiveness of cocaine to function as a reinforcer under a broader range of conditions, the present study assessed the acquisition of cocaine self-administration (fixed ratio 1 schedule of reinforcement) as a function of i.v. cocaine dose (0.1875, 0.375, 0.5, 1, or 1.5 mg/kg/6 s infusion). Results LCRs and HCRs did not differ significantly on any measure of acquis...