Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell.
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The localization of 5-hydroxytryptamine(4) (5-HT(4)) receptors suggests their role in the regulation of dopamine (DA) neurotransmission, a speculation that has been supported by neurochemical studies. Mesolimbic DA systems play a prominent role in mediating the behavioral effects of the abused psychostimulant cocaine, and the intent of the present study was to assess the role of 5-HT(4) receptors in the control of spontaneous and cocaine-induced activity. Systemic administration of the 5-HT(4) receptor partial agonist 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]1-propa none hydrochloride (RS 67333; 0.0001-1 mg/kg) or the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid-(diethylamino)ethyl ester hydrochloride (SDZ 205,557; 0.0001-1 mg/kg) did not significantly alter spontaneous activity, whereas SDZ 205,557 significantly attenuated cocaine-induced horizontal activity and rearing. To test the hypothesis that cocaine-elicited behaviors were modulated by 5-HT(4) receptors in the nucleus accumbens (NAc) shell, two separate groups of male rats were implanted with bilateral cannulas aimed at the NAc shell. Intra-NAc shell microinjections of either RS 67333 (1 or 3 microgram/0.2 microliter/side) or SDZ 205,557 (1-5 microgram/0.2 microliter/side) did not alter spontaneous activity observed after a systemic saline injection but did significantly attenuate the hyperactivity induced by systemic cocaine injection (10 mg/kg). These results support an involvement of 5-HT(4) receptors, particularly those in the NAc shell, in the locomotor stimulatory effects of cocaine. Furthermore, these data suggest that 5-HT(4) receptors may regulate behavioral processes dependent on mesolimbic DA pathways and may provide a novel target for the development of medications useful in the treatment of both drug dependence and psychiatric disorders. (+info)
Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.
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The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine. (+info)
Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade.
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These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the effect of three daily intra-ventral tegmental area (VTA) microinjections of neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the behavioral-activating effects of a subsequent challenge injection of cocaine in rats. Results indicated that, although NT-3 did not influence behavior across the three microinjection days, animals displayed a sensitized behavioral response to the subsequent cocaine challenge injection. In contrast, BDNF microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A second series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization to cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was microinjected into the VTA before three daily cocaine injections. Although PD98059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injections on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocampus were assessed. Results indicated that an acute cocaine injection resulted in a transient increase in NT-3 mRNA levels in the VTA. Collectively, these results suggest that NT-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progressive augmentation in behavioral activation with repeated administration. (+info)
Food and cocaine self-administration by baboons: effects of alternatives.
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The effects of the availability of an alternative reinforcer on responding maintained by food pellets or drug solutions were examined in 8 adult male baboons (Papio hamadrayas anubis). During daily 23-hr experimental sessions, baboons had access to both food pellets and fluid under a two-choice procedure, in which the response requirement, under a fixed-ratio schedule, differed for the two commodities. There were no restrictions on access to water, which was continuously available from a spout at the rear of each cage. In Experiment 1, the fixed-ratio requirement, or cost, for fluid delivery remained constant while the fixed-ratio requirement for pellets was changed every 2 or 3 days when (a) no fluid, (b) a dilute dextrose vehicle, (c) 0.008 mg/kg per delivery cocaine, (d) 0.016 mg/kg per delivery cocaine, or (e) 0.032 mg/kg per delivery cocaine was available concurrently. In Experiment 1, progressively increasing the response requirement for pellets decreased pellet intake, but for 4 baboons pellet intake at maximum pellet cost was lower when cocaine, compared to the vehicle, was available. Increasing the response requirement for pellets had variable effects on vehicle intake. However, increasing the response requirement for pellets increased intake of at least one dose of cocaine to a greater extent than vehicle in all 8 baboons. Thus, cocaine could be considered a more effective economic substitute than vehicle for pellets. Experiment 2 systematically varied the order in which the response requirements for a pellet delivery were presented and added a control condition in which cocaine doses, yoked to the amount self-administered, were given three times during the session by the experimenter. Again, pellet intake at maximal pellet cost was lower when cocaine, compared to the vehicle, was available. In contrast, experimenter-given cocaine doses did not alter responding maintained by pellets. Thus, the effects of self-administered cocaine on responding maintained by food pellets differed from the effects of experimenter-given cocaine on responding maintained by food pellets. (+info)
Cocaine upregulates the dopamine transporter in fetal rhesus monkey brain.
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Cocaine is a highly addictive drug that binds to the dopamine transporter (DAT), inhibits the reuptake of dopamine, and initiates multiple actions within midbrain dopaminergic systems. Using the rhesus monkey, we have investigated the consequences of in utero cocaine exposure on the expression of DAT in the fetal brain. By using the selective DAT ligand [125I]RTI-121 and tyrosine hydroxylase (TH) immunocytochemistry, we found that DAT binding sites are highly developed by day 70 of gestation and show a distribution pattern similar to TH. The rank order of specific 3beta-(4-[125I]iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([125I]RTI-121) binding densities was substantia nigra-ventral tegmental area > putamen > caudate > lateral hypothalamus > accumbens > linear/interfascicular nuclei >/= globus pallidus > prefrontal cortex. Furthermore, we observed that DAT mRNA was differentially expressed within fetal midbrain dopamine neurons with the highest levels detected in the ventral tier of the substantia nigra pars compacta, and the lowest levels in the ventral tegmental area and the linear/interfascicular nuclei. In utero cocaine exposure between days 22 and 70 significantly increased DAT mRNA expression, and the density of [125I]RTI-121 binding sites within midbrain dopamine neurons in the 70-d-old fetus. This increased DAT expression is accompanied by other presynaptic and postsynaptic neuronal changes, which collectively suggest that midbrain dopamine neurons are hypoactive after prolonged cocaine exposure, a state that may be a contributing factor in the development of attention deficit disorders observed in subjects exposed prenatally to cocaine. (+info)
Gamma-hydroxybutyrate and cocaine administration increases mRNA expression of dopamine D1 and D2 receptors in rat brain.
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The effects of acute and repeated gamma-hydroxybutyrate (GHB) and cocaine administration on D1 and D2 dopamine receptor mRNA expression were examined using in situ hybridization histochemistry in different rat brain structures rich in GHB receptors. Six hours after a single GHB administration (500 mg/kg i.p.), an increase in D1 and D2 mRNA expression was observed in almost all regions examined; whereas, acute cocaine injection (20 mg/kg i.p.) had no effect. Repeated exposure to GHB (500 mg/kg i.p. twice daily) for 10 days, followed by a 14-h withdrawal period, induced increasing effects on D1 and D2 dopamine receptor mRNA expression, similar to those caused by chronic treatment with cocaine (20 mg/kg i.p. once a day). These effects of GHB and cocaine on dopamine receptor mRNA expression could be a consequence, for both compounds, of the modulation of dopaminergic activity; thus, supporting the benefit of GHB in cocaine substitution therapy. (+info)
Drug testing with alternative matrices II. Mechanisms of cocaine and codeine deposition in hair.
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A 10-week inpatient study was performed to evaluate cocaine, codeine, and metabolite disposition in biological matrices collected from volunteers. An initial report described drug disposition in plasma, sebum, and stratum corneum collected from five African-American males. This report focuses on drug disposition in hair and sweat collected from the same five subjects. Following a three-week washout period, three doses of cocaine HCl (75 mg/70 kg, subcutaneous) and three doses of codeine SO4 (60 mg/70 kg, oral) were administered on alternating days in week 4 (low-dose week). The same dosing sequence was repeated in week 8 with doubled doses (high-dose week). Hair was collected by shaving the entire scalp once each week. Hair from the anterior vertex was divided into two portions. One portion was washed with isopropanol and phosphate buffer; the other portion was not washed. Hair was enzymatically digested, samples were centrifuged, and the supernatant was collected. Sweat was collected periodically by placing PharmChek sweat patches on the torso. Drugs were extracted from sweat patches with methanol/0.2 M sodium acetate buffer (75:25, v/v). Supernatants from hair digests, hair washes, and sweat patch extracts were processed by solid-phase extraction followed by gas chromatography-mass spectrometry analysis for cocaine, codeine, 6-acetylmorphine, and metabolites. Cocaine and codeine were the primary analytes identified in sweat patches and hair. Drugs were detected in sweat within 8 h after dosing, and drug secretion primarily occurred within 24 h after dosing. No clear relationship was observed between dose and drug concentrations in sweat. Drug incorporation into hair appeared to be dose-dependent. Drugs were detected in hair within 1-3 days after the last drug administration; peak drug concentrations generally occurred in the following 1-2 weeks; thereafter, drug concentrations decreased. Solvent washes removed 50-55% of cocaine and codeine from hair collected 1-3 days after the last drug dose. These data may reflect removal of drug that was deposited by sweat shortly after dosing. Drug removed by washing hair collected 1-3 weeks after the last dose was minimal for cocaine but variable for codeine. Drug in these specimens was likely transferred from blood to germinative hair cells followed by emergence of drug in growing hair. These findings suggest that drug deposition in hair occurs by multiple mechanisms. (+info)
Immunoassay and GC-MS procedures for the analysis of drugs of abuse in meconium.
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The analysis of meconium specimens for metabolites of substances of abuse is a relatively accurate method for the detection of fetal exposure to drugs. Most of the methods reported in the literature before the early 1990s relied on radioimmunoassays. The purpose of this study was to develop and validate methods for meconium sample preparation for the screening and gas chromatography-mass spectrometry (GC-MS) confirmation of meconium extracts for cannabinoids, cocaine, opiates, amphetamines, and phencyclidine. EMIT and TDx immunoassays were evaluated as screening methods. The sample preparation method developed for screening included extraction and purification prior to analysis. Cutoff levels were administratively set at 20 ng/g for 11-nor-delta9-THC-9-COOH (THCCOOH) and phencyclidine and at 200 ng/g for benzoylecgonine, morphine, and amphetamines, although lower levels could be detected in meconium using the EMIT-ETS system. Ninety-five meconium specimens were subjected to the screening procedure with GC-MS confirmation of presumptive positives. In addition, 30 (40 for cocaine) meconium specimens were subjected to GC-MS analysis for all analytes regardless of the screening results to determine the false-negative rate, if any, of the immunoassay. Although there were no false negatives detected, the GC-MS confirmation rate for the immunoassay-positive specimens was generally low, ranging from 0% for amphetamines to 75% for opiates. The lowest rate of confirmed positives was found with the cannabinoids, suggesting that tetrahydrocannabinol (THC) metabolites other than free 11-nor-9-carboxy-delta9-THC may be major contributors to the immunoassay response in meconium. (+info)