Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain

Though the blockade of dopamine transporters (DAT) is associated with cocaine's and methylphenidate's reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1-2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29+/-3% and 32 + 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25+/-10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [1C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25-30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA.     

Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration

Astrocytes actively participate in synaptic plasticity and respond to insult or metabotropic glutamate receptor activation with increased expression of the intermediate filament glial fibrillary acidic protein (GFAP). Extended withdrawal from repeated cocaine administration induces many forms of neuroplasticity. The present study with rats utilized a 3-week withdrawal period from daily cocaine administration (i.p.; 7 days) to investigate whether astrocytes participate in cocaine-mediated plasticity observed in brain nuclei associated with addiction. Following the 3-week withdrawal period, immunoblotting revealed increased GFAP expression in the prefrontal cortex (PFC) and in the shell and core compartments of the nucleus accumbens (NAshell and NAcore). Upregulation of GFAP did not occur in the striatum or in any brain region tested following shorter withdrawal times from repeated cocaine (24 h or 1 week) or following 2-h withdrawal from an acute cocaine injection (30 mg/kg i.p.). However, GFAP expression increased following a 3-week withdrawal from a single cocaine injection selectively in the NAshell. Cell counts revealed that astrocyte cell number increased only in the NAcore while immunoblots of a marker for immature or reactive astrocytes, vimentin, showed an increase only in the PFC following the 3-week withdrawal. Taken together, these results suggest that altered intermediate filament expression within forebrain astrocytes may be a significant part of the plasticity occurring during withdrawal from repeated cocaine. Furthermore, the increase in GFAP may arise from regionally distinct mechanisms, with the NAcore relying more on cell proliferation while the PFC relies on a larger reactive astrocyte population.     

Pergolide mesylate treatment of cocaine withdrawal

Side effects occasionally limit the use of bromocriptine for cocaine withdrawal. The recently released medication pergolide shares some pharmacologic properties with bromocriptine but differs in potency and dopamine receptor subtype specificity. The authors tested pergolide in the treatment of 21 patients experiencing cocaine withdrawal. Sixteen patients reported rapid improvement in sleep and decreased cocaine craving. Side effects were limited primarily to gastrointestinal complaints.     

Brain lesions induced by chronic cocaine administration to rats

Cocaine is a common drug of abuse, and its use has emerged as a major public health problem with neurological complications. In this work, the authors studied microscopic lesions produced in brain by chronic cocaine administration to rats. Twenty-five Wistar rats were exposed to 30 mg/kg/day ip of cocaine and sacrificed at 15, 30, 45, 60, and 90 days after treatment and compared to 25 control rats injected daily with saline. The parietal cortex (Cx), hippocampus (Hp), substantia nigra (SN), and cerebellum (Ce) were morphologically analyzed. The authors found progressive light microscopic lesions in all regions studied, including nuclear pyknosis and atrophy, interstitial edema, broken fibers, and necrosis. Results show that chronic treatment with cocaine in rats leads to selective severe lesions in different brain regions.     

Hyperlocomotion induced by dopamine or cholecystokinin + dopamine in the nucleus accumbens is not modified by chronic lithium treatment

1. Peptides such as cholecystokinin have been reported to modulate the effects of dopaminergic agonists on locomotion in rats. 2. The present experiments tested the possibility that lithium interacts with dopaminergic function through the same mechanism by which cholecystokinin potentiates dopaminergic function. 3. The results suggest that dietary lithium has no effect on the ability of either dopamine alone, or the combination of dopamine plus cholecystokinin, microinjected directly into the nucleus accumbens, to stimulate hyperlocomotion.     

Effects of chronic cocaine abuse on postsynaptic dopamine receptors

To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.     

Increased CRH mRNA levels in the rat amygdala during short-term withdrawal from chronic 'binge' cocaine

There is evidence that suggests that increased corticotropin-releasing hormone (CRH) release in the central nucleus of the amygdala underlies the anxiogenic and stress-like consequences of withdrawal that are common in phenomenology to all drugs of abuse. The present studies were undertaken to determine levels of CRH mRNA in the amygdala, and also in the hypothalamus, frontal cortex and brainstem after short-term (2 days) and intermediate-term (10 days) cocaine withdrawal (with continued saline injections) from chronic (14 days) 'binge' pattern cocaine administration (3 x 15 mg/kg per day at hourly intervals). Confirming our recent finding of an activation of stress responsive hypothalamic-pituitary-adrenal activity during early cocaine withdrawal, there was a significant elevation of plasma corticosterone level after 2-day cocaine withdrawal. There was also a significant elevation of CRH mRNA levels in the amygdala, but not in the hypothalamus, frontal cortex or brainstem after 2-day cocaine withdrawal. A negative correlation between amygdalar CRH mRNA and plasma corticosterone levels was found in the 2-day cocaine withdrawn rats but not in control rats, suggesting that CRH neurons in the amygdala may be differentially responsive to glucocorticoids after chronic cocaine exposure and withdrawal. There were no changes in either plasma corticosterone or amygdalar CRH mRNA levels after 10-day cocaine withdrawal. Our findings of an increase in amygdalar CRH gene expression during early cocaine withdrawal support a potentially important role for amygdalar CRH activity in the anxiogenic and aversive consequences of withdrawal from cocaine during a time when humans are most subject to relapse.     

Striatal dopamine,dopamine transporter,and vesicular monoamine transporter in chronic cocaine users

Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however, 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, –33%; tail, –39%) with a trend for reduction in nucleus accumbens (–27%). Striatal DAT protein (–25 to –46%) and VMAT2 (–17 to –22%) were reduced, whereas DAT determined by [³H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug.     

Inhibition of dopamine uptake by cocaine and nicotine: tolerance to chronic treatments.

Chronic administration of cocaine (50 mg/kg/day for 7 days, s.c. via an osmotic minipump) produced tolerance to inhibition of [3H]dopamine uptake by cocaine in rat striatum but did not produce cross-tolerance to inhibition of [3H]dopamine uptake by nicotine. Chronic nicotinic treatment (6 mg/kg/day for 7 days, s.c. via an osmotic minipump), however, produced tolerance to the inhibition of [3H]dopamine uptake by nicotine and cross-tolerance to inhibition of uptake by cocaine in rat striatum. Nicotine did not inhibit uptake of [3H]dopamine in the nucleus accumbens of saline-treated animals. In this tissue, both cocaine and nicotine treatments produced tolerance to cocaine, as in striatum. Unlike the effects on [3H]dopamine uptake, chronic cocaine infusion did not have any effect on the ability of cocaine to inhibit [3H]serotonin uptake in either brain region.     

Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine

We have previously shown that tracer concentrations of [¹¹C]cocaine binding to the dopamine transporter (DAT) in human and baboon striatum can be visualized using positron emission tomography (PET). To determine whether the concentration of dopamine normally present in the synaptic cleft can compete with [¹¹C]cocaine for transporter binding sites, we conducted baboon PET studies with drugs (sodium 4-hydroxybutyrate, four studies, 200 mg/kg gamma-vinylGABA, three studies, 300 mg/kg and citalopram, three studies, 2 mgkg) expected to decrease synaptic dopamine. Each study involved two [¹¹C]cocaine injections and PET scans separated by 2-4 h, with drug administration after the first injection, and without movement of the subject between scans. Time-activity data from striatum and from cerebellum were used with the arterial plasma input function to determine graphically by Logan plotting [¹¹C]cocaine distribution volumes for the brain regions. Specific binding of [¹¹C]cocaine to DAT in striatum was calculated as the distribution volume ratio (DVR) for striatum and cerebellum. In nine of the ten studies drug treatment produced a small increase in DVR (range, 1-ll%), and in seven of these studies the increase was >7%. The mean increase was 6.2 ± 4.1%. The reproducibility of the DVR measure was assessed by comparing [¹¹C]cocaine studies conducted without pharmacological treatments using individual baboons on separate days, and thus involving possible repositioning errors, as well as long-term changes in the state of the striatal dopamine system. For four individual baboons with three or four studies per animal the mean (±s.d.) values of DVR were 1.73 ± 0.03, 1.39 ± 0.03, 1.53 ± 0.06, and 1.54 ± 0.12. The maximum differences between baseline DVRs, expressed as percentage of the lowest value, were 5%, 5%, 9%, and 20%. For two other baboons with two studies each, the between study differences were 1% and 9%. Thus within-subject variability was quite low, even with repositioning. The results suggest that [¹¹C]cocaine binding to the DAT is sensitive to pharmacological alterations in the concentration of synaptic dopamine. However, the sensitivity of [¹¹C]cocaine to dopamine-depletion is less than that of the D2 receptor radioligand [¹¹C]raclopride, in agreement with literature in vitro binding studies, and is unlikely to be a serious issue in PET evaluations of DAT density. © 1995 Wiley-Liss, Inc.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D2 receptor agonist, SKF 38393, a selective D1 receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed by L-sulpiride, a D2 antagonist, and by a combination of reserpine with alpha-methyltyrosine (alpha-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D1 antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D2 receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D1 receptor level.     

Modulatory role for prolactin in the elevation of striatal dopamine receptor density induced by chronic treatment with dopamine receptor antagonists

The chronic administration of haloperidol (HAL), domperidone (DOM), or sulpiride (SUL) increased the density of striatal dopamine (DA) receptors in intact but not in hypophysectomized (Hypox) male rats. This effect was independent of changes in body weight of the rats and of the drugs' abilities to produce cataleptic behavior. All treatments of intact rats increased serum rat prolactin (rPRL) concentrations, while Hypox rats had rPRL levels equivalent to zero. At the doses used in these studies, the striatal DA receptor densities were increased only if the rPRL levels were also increased. Chronic cysteamine (CYS) treatment decreased body weight gain, acutely decreased cataleptic behavior to HAL, decreased serum rPRL levels, and prevented the increase in serum rPRL levels due to HAL administration. While CYS itself did not alter striatal DA receptor density, it prevented the increase in density associated with the chronic administration of HAL (1 mg/kg). Since CYS decreased rPRL levels, these results lend further support to the hypothesis that rPRL (and prolactin in general) is a pituitary hormone with modulatory action on the increase in striatal DA receptor density.     

Immune cell activity during the initial stages of withdrawal from chronic exposure to cocaine or morphine

The immunosuppression accompanying illicit drug use has been shown to contribute to a decreased resistance to a variety of pathogens; however, there is relatively little information on how long these effects persist following withdrawal from chronic drug exposure. To begin to address this question, Sprague-Dawley male rats were administered either cocaine (10 mg/kg, i.p., b.i.d.) for 7 days or morphine (escalating doses up to 40 mg/kg, s.c., b.i.d.) for a 10-day period. Control groups of animals received similar saline injections for equivalent time periods. Drug administration was abruptly discontinued and animals were sacrificed at 2, 24, 72 or 96 h following the last dose. At these time points, proliferation responses of peripheral blood T-lymphocytes stimulated by concanavalin A (Con A) and plasma levels of corticosterone were measured. Plasma corticosterone levels of cocaine- or morphine-treated animals were found to be significantly elevated 24 h following drug cessation as compared to saline animals. At this time, proliferation responses were significantly decreased and were further suppressed during cocaine and morphine withdrawal at 96 and 72 h, respectively. These results suggest that abrupt cessation of cocaine or morphine administration leads to activation of stress-related pathways that may contribute to an increased susceptibility of infection during the initial withdrawal phase.     

Selective dopamine transporter inhibition by cocaine analogs.

Several isopropyl and phenyl esters of 3 beta-(4-substituted phenyl) tropan-2 beta-carboxylic acid analogs of cocaine are relatively more potent and selective than cocaine and some other compounds in inhibiting dopamine uptake. These analogs can be used as binding ligands and as tools for elucidating the mechanisms of action of cocaine.     

Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine.

Rats were treated for 10 days with cocaine (20 mg/kg, i.p.) followed by either 1 or 10 days of abstinence. On the test day a microdialysis method was performed in which dopamine (DA) was added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) to generate a series of points that can be interpolated to determine the concentration of no net flux, which represents the extracellular DA concentration. The slope of the line generated by this method is the in vivo recovery of the dialysis probe. After 1 day of abstinence, there was no significant difference in basal DA levels in the nucleus accumbens (N ACC) between cocaine treated (4.1 +/- 0.3 nM; mean +/- SEM) and saline-treated (3.9 +/- 0.2 nM) groups. However, there was a significant increase in the slope of the cocaine-treated group (0.91 +/- 0.04 vs. 0.67 +/- 0.08; P greater than 0.03). After 10 days of abstinence, there were reduced basal extracellular levels of DA in the N ACC of the cocaine-treated group as compared with saline-treated controls (P less than 0.002). The basal extracellular DA concentration in the N ACC was 2.1 +/- 0.3 nM for the cocaine group and 3.9 +/- 0.2 nM for the control group. The slopes of the curves were not significantly different for the cocaine (0.63 +/- 0.07) and saline (0.64 +/- 0.09) groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subchronic cocaine treatment enhances cocaine-induced dopamine efflux, studied by in vivo intracerebral dialysis

Repeated administration of cocaine in animals results in behavioral sensitization. In order to investigate the neurochemical mechanism underlying such behavioral sensitization, we designed the following two experiments. In both experiments, rats were pretreated with cocaine (20 mg/kg i.p.) or saline, once daily for 14 consecutive days. Exp. 1: 7 days after withdrawal from the drug, the stereotyped behavioral response to a challenge of cocaine (20 mg/kg i.p.) was measured. Exp. 2: 7 days after withdrawal from the drug, we measured extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after the challenge administration of cocaine using an in vivo intracerebral dialysis technique. The rats pretreated with cocaine (20 mg/kg i.p.) exhibited behavioral augmentation in response to a challenge of cocaine. The challenge administration of cocaine caused an increase in DA and a decrease in DOPAC. The DA level in the striatal perfusates of the cocaine-pretreated rats was significantly greater than that in the saline-pretreated rats. These results suggest that the increased extracellular DA concentration in the striatum plays an important role in the cocaine-induced behavioral sensitization.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D₂ receptor agonist, SKF 38393, a selective D₁ receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed byl-sulpiride, a D₂ antagonist, and by a combination of reserpine with α-methyltyrosine (α-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D₁ antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D₂ receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D₁ receptor level.