Patricia Duffy

Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals

Repeated administration of cocaine to rodents produces a progressive augmentation in motor activity known as behavioral sensitization. By using microdialysis in the ventral striatum, some studies have found that the development of behavioral sensitization is associated with a similar augmentation in dopamine release, while others have not. It was postulated that differences in doses and withdrawal periods may account for the discrepancies between studies. Rats were behaviorally sensitized to daily peripheral injections using two cocaine treatment regimens (15 mg/kg, i.p. x 5 d or 30 mg/kg, i.p. x 5 d). Using in vivo microdialysis in the ventral striatum, the effect of acute cocaine (15 mg/kg, i.p.) on extracellular dopamine content and motor behavior was examined at various times after discontinuing daily treatments. Twenty- four hours after discontinuing the low dose of daily cocaine, the increase in motor activity and extracellular dopamine elicited by an acute cocaine challenge was significantly elevated. In contrast, following the higher daily treatment regimen there was a significant augmentation in motor activity, but the increase in extracellular dopamine produced by cocaine was significantly reduced. When rats were challenged 10-14 d after discontinuing either dosage regimen of daily cocaine, the increase in both motor activity and extracellular dopamine was augmented. In general, the increase in extracellular dopamine by an acute cocaine challenge increased over time when rats were challenged between 1 and 22 d after discontinuing daily cocaine. Basal concentrations of extracellular dopamine were determined by measuring the in vivo flux of dopamine across the dialysis membrane, and there was no significant difference at 24 hr or 2 weeks following the last daily injection of saline or cocaine. It is concluded that behavioral sensitization to cocaine is generally associated with an augmentation in extracellular dopamine in the ventral striatum, but that high doses of daily cocaine produce apparent tolerance to the augmentation in extracellular dopamine during the early withdrawal period.

Selective activation of dopamine transmission in the shell of the nucleus accumbens by stress

A microdialysis probe was placed in either the shell or core compartment of the nucleus accumbens and rats were exposed to mild footshock. Extracellular dopamine levels in the shell of the nucleus accumbens were elevated during the 20-min collection period immediately after discontinuing footshock. In contrast, the levels of dopamine remained unaltered in the core of the nucleus accumbens.

A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior.

This study investigated the effect of ionotropic glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration and the reinstatement of cocaine-seeking behavior. The stimulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or N-methyl-D-aspartate glutamate receptors in the nucleus accumbens with either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or 1-aminocyclobutane-cis-1,3-dicarboxylic acid, respectively, decreased the number of cocaine-reinforced responses, suggesting an enhancement in the rewarding properties of cocaine. In contrast, blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors with N-methyl-D-aspartate, or N-methyl-D-aspartate receptors with dizocilpine maleate or 2-amino-5-phosphonovaleric acid had no selective effect on the maintenance of cocaine self-administration. Following one week of extinction from the reinforcing cue of the drug-paired lever, both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid and 1-aminocyclobutane-cis-1,3-dicarboxylic acid treatment in the nucleus accumbens reinstated cocaine-seeking behavior. However, alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid treatment increased responding only on the drug-paired lever, while 1-aminocyclobutane-cis-1,3-dicarboxylic acid increased responding on both the drug-paired and non-drug-paired levers. These results suggest that stimulation of glutamate receptors in the nucleus accumbens augments the reinforcing effect of cocaine, yet glutamate transmission is not required to maintain cocaine self-administration. In addition, increased glutamate transmission in the nucleus accumbens may be involved in facilitating the relapse to cocaine-seeking behavior.

Similar effects of daily cocaine and stress on mesocorticolimbic dopamine neurotransmission in the rat

Daily exposure to cocaine or stress has been shown to enhance the motor stimulant effect of a subsequent injection of acute cocaine. Considering that both cocaine and stress enhance dopamine neurotransmission in the central nervous system, it was of interest to determine the effects of daily cocaine and stress on the capacity of acute stress to alter dopamine neurotransmission. Rats were injected with cocaine (15 mg/kg, ip) for 3 days or exposed to daily 20 min of footshock stress (0.3 mA/200 msec/sec) for 10 days. Ten to 14 days later, the rats were exposed to acute footshock or sham shock for 0, 5, 10, or 20 min, and the concentration of dopamine and its metabolites was measured in the A10 and A9 dopamine regions, nucleus accumbens, striatum, and prefrontal cortex. It was found that the daily treatments resulted in an enhancement of dopamine metabolism in the prefrontal cortex and nucleus accumbens in response to acute footshock. In contrast, dopamine metabolism was diminished in the A10 region, and no change was measured in the striatum or A9 region. It is proposed that pretreatment with cocaine or stress alters the response of the mesocorticolimbic dopamine neurons to subsequent stress, so that axonal dopamine neurotransmission is enhanced in the terminal fields and somatodendritic dopamine neurotransmission is diminished. Furthermore, the long-lasting influence of daily cocaine and stress on mesocorticolimbic dopamine responsiveness to subsequent stressful experiences may be relevant in the etiology of psychostimulant-induced psychosis.

Repeated Cocaine Administration Alters Extracellular Glutamate in the Ventral Tegmental Area

Abstract: The present study determined if repeated cocaine injections alter the effect of cocaine on extracellular glutamate in the ventral tegmental area (VTA). All rats were treated with daily cocaine (15 mg/kg i.p. × 2 days, 30 mg/kg i.p. × 5 days) or saline for 7 days. At 21 days after discontinuing the daily injections, a dialysis probe was placed into the VTA and the extracellular levels of glutamate were estimated. A systemic injection of cocaine (15 mg/kg i.p.) elevated extracellular glutamate in the VTA of rats pretreated with daily cocaine but not in the daily saline‐pretreated subjects. No significant change in glutamate was produced by a saline injection in either pretreatment group. In a group of rats pretreated with daily cocaine, the D1 antagonist SCH‐23390 (30 µM) was infused through the dialysis probe prior to the acute injections of saline and cocaine. SCH‐23390 prevented the increase in extracellular glutamate associated with the acute administration of cocaine. Behavioral data were collected simultaneously with the measures of extracellular glutamate. The behavioral stimulant effect of cocaine was greater in cocaine‐pretreated than saline‐pretreated subjects, and the behavioral augmentation in cocaine‐pretreated rats was partly blocked by SCH‐23390. These data support the hypotheses that repeated cocaine administration produces an increase in the capacity of D1 receptor stimulation to release glutamate in the VTA and that this mechanism partly mediates behavioral sensitization produced in rats treated with daily cocaine injections.

A Comparison of Axonal and Somatodendritic Dopamine Release Using In Vivo Dialysis

Abstract: The release of endogenous dopamine from the axon terminal field in the nucleus accumbens and from the A10 dopamine cell bodies of conscious rats was measured using intracranial dialysis. Release of dopamine from both areas was calcium‐dependent and markedly inhibited by the presence of the D2 agonist, quinpirole, in the dialysis buffer. However, the addition of tetrodotoxin to the buffer produced less of a decrease in dopamine in the A10 region than in the nucleus accumbens. When dopamine release was examined by substituting K+ for Na+ or by adding amphetamine to the buffer, the evoked release was significantly less in the A10 region than in the nucleus accumbens. Likewise, enhanced extracellular dopamine following blockade of reuptake by nomifensine addition to the dialysis buffer was not as great in the A10 region as in the nucleus accumbens. These data argue that, in general, axonal and somatodendritic dopamine release are regulated by similar factors, although somatodendritic release is less influenced by action potential generation and less responsive to some releasing agents.

Effects of Daily Cocaine and Morphine Treatment on Somatodendritic and Terminal Field Dopamine Release

Abstract: Daily injections of cocaine or morphine into rodents produces behavioral sensitization such that the last daily injection results in a greater motor stimulant effect than the first injection. To evaluate a role for brain dopamine in behavioral sensitization to cocaine and morphine, tissue slices from the ventromedial mesencephalon (containing dopamine cell bodies), the nucleus accumbens, and striatum (dopamine terminal fields) were obtained from rats pretreated with daily cocaine, morphine, or saline 2–3 weeks earlier. When the tissue slices were depolarized by increasing potassium concentration in the superfusate, the release of endogenous dopamine from the ventromedial mesencephalon of cocaine‐ and morphine‐pretreated rats was significantly decreased. In contrast, the release of dopamine from the nucleus accumbens and striatum was either unaltered or slightly enhanced in rats pretreated with cocaine and morphine. When dopamine was released by amphetamine, a significant decrease in dopamine release from the ventromedial mesencephalon of cocaine‐pretreated rats was measured. No other significant changes were measured after amphetamine‐induced release. It is postulated that the decrease in dopamine release from the ventromedial mesencephalon of cocaine‐ and morphinesensitized rats results in less somatodendritic autoreceptor stimulation, and thereby produces an increase in dopamine neuronal activity.

Glutamatergic and dopaminergic afferents to the prefrontal cortex regulate spatial working memory in rats

The integrity of the prefrontal cortex is critical for the expression of working memory. The prefrontal cortex is innervated by dopaminergic afferents from the ventral tegmental area and glutamatergic afferents from the mediodorsal thalamus. To determine the role of dopaminergic and glutamatergic afferents in the regulation of working memory, rats were trained to perform a spatial delayed alternation task in a T-maze. The microinjection of the ionotropic glutamate antagonists 6-cyano-7-nitroquinoxaline-2,3-dione or 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid into the prefrontal cortex impaired working memory. Consistent with a role for glutamate receptor activation, microinjecting the GABA(B) agonist baclofen into the mediodorsal thalamus produced a dose-dependent disruption of working memory. In contrast, inhibition of the mesocortical dopamine projection was without effect on working memory. The blockade of D1 and/or D2 dopamine receptors with SCH-23390 and sulpiride was without effect on working memory. Likewise, the microinjection of baclofen into the ventral tegmental area did not impair working memory. However, stimulating mu-opioid receptors in the ventral tegmental area with [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin produced a dose-dependent impairment of working memory that was reversed by blocking D1 dopamine receptors with SCH-23390 in the prefrontal cortex. These data demonstrate that increased dopamine tone or reduced glutamate tone in the prefrontal cortex disrupts working memory in a spatial delayed alternation task.

Behavioral and neurochemical sensitization following cocaine self-administration

To determine if behavioral and neurochemical sensitization results from cocaine self-administration, rats were trained to self-administer cocaine for 20 consecutive days (26.5 ± 2.6 mg/kg, IV/day). At 24 h or 21 days after discontinuing cocaine self-administration or yoked saline control, rats were administered an acute injection of saline IP, followed 60 min later by cocaine (15 mg/kg, IP). Cocaine-induced changes in motor activity were monitored with a photocell apparatus and alterations in extracellular dopamine in the ventral striatum were measured with microdialysis. There was no difference between treatment groups in the basal level of extracellular dopamine as determined by in vitro calibration. Neither the motor stimulant response nor the increase in extracellular dopamine following an acute cocaine challenge given after 24 h of withdrawal was different between rats which self-administered cocaine and yoked saline controls. However, when the cocaine challenge was given 21 days after discontinuing cocaine self-administration both the motor response and extracellular dopamine content in the ventral striatum were significantly augmented in rats that self-administered cocaine. While no correlation was observed between the average amount of cocaine self-administered each day and the cocaine-induced alterations in extracellular dopamaine at either 24 h or 21 days of withdrawal, a significant positive correlation was measured between the increase in photocell counts and the average daily cocaine administration at 21 days of withdrawal. These data show that cocaine self-administration produces an augmentation in the acute behavioral and neurochemical response to a cocaine challenge that resembles the sensitization previously demonstrated with repeated noncontingent administration.

Dopamine regulation of extracellular glutamate in the nucleus accumbens

The capacity of dopamine to alter extracellular glutamate in the nucleus accumbens was examined by passing 1, 10 and 100 microM of amphetamine, the D(2/3) agonist, quinpirole, or the D1 agonist, SKF-82958 through a microdialysis probe. It was found that amphetamine and quinpirole produced a dose-dependent reduction in the basal levels of extracellular glutamate, while SKF-82958 was without significant effect. The capacity of the D1 antagonist, SCH-23390 (1.0 mg/kg, i.p.) or the D2 antagonist, sulpiride (10 mg/kg, i.p.) to block the reduction in extracellular glutamate by amphetamine (100 microM) was examined. Both SCH-23390 and sulpiride prevented the reduction in extracellular glutamate by amphetamine. The data indicate that, similar to the striatum, glutamate release in the nucleus accumbens is modulated by presynaptic dopamine receptors.