Augmentation of the neurochemical effects of cocaine in the ventral striatum and medial prefrontal cortex following preexposure to amphetamine, but not nicotine: An in vivo microdialysis study (original) (raw)
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European Journal of Pharmacology, 1999
The present study sought to investigate the contributions of the ventral prelimbicrinfralimbic cortices and shell subterritory of the nucleus accumbens as well as the dorsal prelimbicranterior cingulate cortices and core subregion of the nucleus accumbens to the acute Ž. systemic effects of cocaine 20 mgrkg i.p. on both locomotor activity and simultaneous dialysate dopamine levels using a dual-probe microdialysis design. Basal dopamine levels were significantly higher in the ventral medial prefrontal cortex compared with the dorsal medial prefrontal cortex and higher concentrations of dopamine were also observed in the core of the nucleus accumbens compared with its shell counterpart. Cocaine produced a significant decrease in dopamine levels in both the ventral and dorsal medial prefrontal cortices. In contrast, cocaine significantly increased dialysate dopamine in the shell of the nucleus accumbens, whereas only a slight increase in dopamine was observed in the core subregion of the nucleus accumbens. A significant negative relationship between dopamine levels in the ventral and dorsal medial prefrontal cortices and dialysate dopamine concentrations in the shell and core of the nucleus accumbens was observed. Finally, in both the ventral and dorsal medial prefrontal cortices, the magnitude of the locomotor response to cocaine was inversely related to dialysate dopamine levels. In contrast, the magnitude of the locomotor response to cocaine became progressively larger as dopamine levels increased in the shell of the nucleus accumbens. These results show a dissociation in the pattern of dopamine release in subterritories of both the medial prefrontal cortex and nucleus accumbens in response to the acute systemic administration of cocaine.
Inhibition of dopamine uptake by cocaine and nicotine: tolerance to chronic treatments
Brain Research, 1992
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.
Synapse, 1989
The effects of cocaine on dopamine (DA) neurotransmission were evaluated by in vivo microdialysis in the striatum of halothane-anesthetized rats. Intravenous cocaine produced a dose-dependent, transient increase of the extracellular concentration of DA, with a peak response within 10 min and a return to control level by 30 min. The sharp DA response pattern was abolished in a calcium-free environment, indicating that DA release enhanced by cocaine originates from a vesicular storage pool. Continuous administration of cocaine (via the perfusion medium) directly into the nigrostriatal terminal region also produced a dose-dependent increase in DA release. Low concentrations M) of cocaine maintained DA at a constant stable level, consistent with the effects observed after potent DA uptake inhibitory agents (e.g., nomifensine and Lu19005). However, continuous exposure to high concentrations (2 lop4 M) induced a transient elevation of DA within 20 min, following which DA decreased to a stable but high level; this decrease might reflect tolerance to the effect of cocaine. Administration of cocaine (lop3 M) into the substantia nigra did not change striatal DA release. The local striatal action of cocaine was less potent than amphetamine in elevating DA overflow and in its effect on DA metabolism. These findings suggest that the fast transient enhancement of DA by intravenous cocaine is most likely a consequence of the transient presence of cocaine in the terminal region, correlating with the well-known rapid pharmacokinetic and behavioral aspects of the drug.
Rats were treated with daily injections of saline or cocaine (20 mg/kg i.p. x 15 days) and, beginning 24 h after the last injection, administered saline or methamphetamine (6.25-50 mg/kg s.c., BID x 4 days) and sacrificed two weeks later. Repeated daily administration of cocaine potentiated the long-lasting striatal dopamine depletions caused by methamphetamine. The results suggest that human use of cocaine may increase the likelihood of neurotoxicity resulting from ingestion of high doses of methamphetamine. We now report that repeated injection of cocaine for two weeks enhances the neurotoxic effects of (+)-methamphetamine (MA) on dopamine, but not serotonin neurons in the rat. The current use of crack cocaine and the more recently introduced crystal form of MA or 'ice' has made stimulant abuse an important public health issue 3. The potential for adverse effects of cocaine and MA abuse arises from the occurrence of a compulsive use pattern characteristic of stimulants 3. This type of abuse, in which the drug is taken repeatedly over the course of several days, can induce a state which is indistinguishable from an acute psychotic episode in a schizophrenic individual 4's. In addition, exposure to high doses of MA as well as a number of structurally related agents has been shown to cause neurotoxicity in laboratory animals 15'2°'z2"23. Neurotoxicity, which in the case of MA, has been characterized by depletions of brain dopamine (DA) and/or serotonin (5-hydroxytryptamine, 5-HT), decreased numbers of presynaptic high-affinity uptake sites, and neuronal degeneration, is consistent with the ablation of DA-and/or 5-HT-containing nerve terminals 23. While it has been established that MA is neurotoxic, several reports indicate that cocaine is not 1°' ~3.19. However, it was recently shown that MA-induced DA release is enhanced following two weeks of daily injection of cocaine (20 mg/kg/day) in rats 1. Thus, it is possible for the abuse of combinations of cocaine and MA to have deleterious consequences. Male Sprague-Dawley rats (Harlan, IN), weighing 200-250 g at the start of the study were used. Food (Teklad Rat and Mouse Diet, Teklad, Winfield, IA) and water were continuously available. Rats were housed individually in stainless steel cages in a room with lights on a 12 hour dark-light cycle (lights on from 07.00 h-19.00 h) and temperature maintained at approximately 24 °C. In the first experiment, 48 rats (n = 6/group) were treated with single daily injections of cocaine HCI (20 mg/kg/injection) or saline for 15 days and then subjected to a 4-day regimen of MA HCI consisting of twice daily injections at 12 h intervals (0, 6.25, 12.5, or 25.0 mg/kg). The second experiment, designed to indirectly replicate the findings of the first experiment, was identical in all respects with the exception that, following the repeated exposure to cocaine (20 mg/kg/injection) or saline, rats (n = 6/group) were treated with either saline or MA HCI (50 mg/kg; BID x 4 days). Rats were killed by guillotine two weeks after the last daily injection of MA or saline and their brains were dissected over ice into various regions according to a previously published procedure 6. The brain sections were wrapped individually in aluminum foil and stored in liquid nitrogen until assayed for monoamines and metabolites using HPLC-EC 14. Cocaine HC1 was a gift from the National Institute on Drug Abuse (Rockville, MD) and methamphetamine HCI was purchased from Sigma Chemical Co. (St. Louis, MO). Data from each study were analyzed separately for statistical significance using two-way ANOVA followed by post hoc and a posteriori comparisons made using Dunnett's test.
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.
Synapse, 1993
The purpose of the present study was to examine the effects of chronic cocaine on dopamine (DA) and serotonin (5-HT) synthesis in several rat brain regions implicated in drug reinforcement. Male rats were treated twice daily with cocaine (15 mg/kg, ip) or saline for 1 week. After 42 h r of abstinence, rats were challenged with either cocaine (15 mgkg, ip) or saline, followed by the aromatic L-amino acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD-1015; 100 mgkg, ip). Animals were decapitated 30 min after NSD-1015 and discrete brain regions were microdissected from 300 pm frozen sections. Postmortem tissue levels of 3,4-dihydroxyphenylalanine (DOPA) and 5-hyroxytryptophan (5-HTP) were quantified by HPLC with electrochemical detection and used to estimate biosynthesis of DA and 5-HT, respectively. In chronic saline-treated rats, cocaine dramatically suppressed DA and 5-HT synthesis in all forebrain regions examined, including: medial prefrontal cortex, nucleus accumbens, caudate nucleus, olfactory tubercle, and basolateral amygdala. The degree of inhibition ranged from 35-65% and was more pronounced in 5-HT neurons compared to DA neurons in the same tissue sample. In general, chronic cocaine did not significantly alter basal levels of DOPA or 5-HTP; a notable exception was lateral hypothalamus, where chronic cocaine reduced basal DA synthesis to 75% of control. After repeated cocaine injections, the synthesisinhibiting effect of a challenge injection of cocaine was attenuated in many brain areas. These data suggest that whereas acute cocaine decreases DA and 5-HT synthesis in forebrain, chronic cocaine is not neurotoxic to DA and 5-HT neurons. In addition, the mechanism(s) mediating cocaine-induced suppression of monoamine synthesis may become desensitized by chronic exposure to the drug. tophan, Synthesis, Chronic cocaine
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
Psychopharmacology, 1991
Rats were pretreated with nine daily injections of eitherd-amphetamine SO4(1.0 mg/kg, 1P), nicotine bitartrate (0.6 mg base/kg, SC) or saline. The motor activating effects of these drugs were measured for 60 min postinjection. On the tenth day, they were given a challenge injection of cocaine HCl (10 mg/kg) or saline and activity was again measured for 60 min postinjection. Both amphetamine and nicotine enhanced motor activity, although the stimulating effect of nicotine was not apparent until the third exposure to the drug. When the response to cocaine was assessed in these pre-exposed rats, only the amphetamine-treated animals were sensitized; they demonstrated a greater cocaine-induced motor activation than their saline-pretreated counterparts. The nicotine pre-exposed rats failed to demonstrate sensitization to the behavioral effect of cocaine; their response was not greater than the rats that had received pre-exposure to saline. These data demonstrate that the response to cocaine can be influenced by prior drug experience and that the influence may be dependent on the neurochemical specificity of the drug.
European Journal of Pharmacology, 1997
. In this study, we examined the ability of a single injection of cocaine 20 mgrkg, i.p. to augment extracellular dopamine levels in the Ž . nucleus accumbens two weeks after pretreating rats with either saline 1 mlrkg, i.p. or the serotonin neurotoxin 3,4-methylenedioxy-Ž . methamphetamine 20 mgrkg, s.c., twice daily for 4 days . The level of dopamine in the nucleus accumbens was measured using in vivo microdialysis. Cocaine produced a 400% increase in extracellular nucleus accumbens dopamine levels in control rats, whereas in 3,4-methylenedioxymethamphetamine treated rats the increase produced by cocaine was 800%, which was significantly different from controls. This suggests that 3,4-methylenedioxymethamphetamine, a relatively common drug of abuse, may alter subsequent vulnerability to cocaine dependence and abuse. q 1997 Elsevier Science B.V.