Effects Of Chronic Cocaine Research Articles

Neuroscience. A kinase to dampen the effects of cocaine?

Chronic exposure to cocaine results in long-term changes in the central nervous system (CNS). In their Perspective, [Gupta and Tsai][1] discuss new results, reported elsewhere, that elucidate the signaling pathways that promote and dampen down the effects of chronic cocaine on the CNS. They explain the part played by a cyclin-dependent kinase (Cdk5), which is switched on by the DFosB transcription factor and regulates PKA-dependent signaling pathways, resulting in a dampening of the effects of chronic cocaine. [1]: http://www.sciencemag.org/cgi/content/full/292/5515/236

Molecular and regional targets of cocaine in primate brain: liberation from prosaic views

Abstract The neurochemical processes underlying initial exposure to and reinforcing effects of cocaine are not fully understood. An enduring hypothesis of cocaine addiction is based on an underlying premise that dopamine is the acute mediator of the rewarding effects of cocaine and this nefarious role extends through each phase of addiction. Cocaine is an effective inhibitor of the dopamine transporter, thereby increasing extracellular dopamine levels. Euphoria is attributed to the cocaine-induced inundation of extracellular dopamine and the withdrawal and craving for cocaine after cessation of drug use are attributed to neuroadaptive processes to dampen dopaminergic transmission. Nevertheless, our understanding of the role of dopamine transporter blockade in cocaine addiction is not fully understood. The objectives of this laboratory are to investigate the primary targets of cocaine in the brain, those associated with the initial phase of cocaine use and that can provide leads for investigating neuroadaptive processes that may trigger addiction. Two prosaic views of the neurobiology of cocaine addiction are examined in this review. The first is based on the assumption that the dopamine transporter contributes significantly to the stimulant and reinforcing effects of cocaine, and focuses on how stimulant drugs of abuse such as cocaine bind to the dopamine transporter. We present evidence that the widespread assumption that dopamine transporter blockers require an amine nitrogen in their structure is incorrect as non-amines are effective blockers of transporters. The second prosaic view, based on the assumption that the dopamine transporter fulfills a paramount role in cocaine addiction, is assessed in view of mounting evidence that the transporter may not account for the full spectrum of cocaine's effects. Other targets of cocaine, which may be relevant to the acute and chronic effects of cocaine, are presented.

Chronic inhaled cocaine abuse may predispose to the development of pancreatic adenocarcinoma

Background: The acute and chronic effects of cocaine over various organ systems have been well documented. A more recent approach to the effects of this drug has focused on the immunological consequences of its exposure, with results that indicate a possible carcinogenic effect. Methods: A chart review was made in order to search for young pancreatic adenocarcinoma patients (arbitrarily defined as younger than 40) who made use of inhaled cocaine. This age was chosen because of a higher probability of cocaine addiction than at older ages. Results: Of the 198 patients with pancreatic adenocarcinoma, 13 were younger than 40 years (range 19 to 37) and 5 of these had abused inhaled cocaine for about a decade. One patient had abused marijuana, and there was no information on drug usage in the other 7 patient charts. Conclusion: Although this is a very small series, we believe there might be a possibility that chronic cocaine exposure predisposes to the development of pancreatic adenocarcinoma. Further studies are necessary.

The Effect of Chronic Cocaine on Cerebral Hemodynamics

Department of Anesthesiology, Harborview Medical Center, University of Washington, Seattle, Washington

Localization of Genes Mediating Acute and Sensitized Locomotor Responses to Cocaine in BXD/Ty Recombinant Inbred Mice

Sensitization to the psychostimulant effects of cocaine has received widespread attention because concomitant changes occur in neurochemical pathways that are part of the brain reward pathway. The current study was undertaken with the purpose of mapping genes determining sensitivity to the acute stimulant and sensitizing effects of cocaine. Sensitivity and sensitization to cocaine (5, 10, and 40 mg/kg) were measured in 25 BXD/Ty recombinant inbred (BXD RI) strains and the progenitor C57BL/6J (B6) and DBA/2J (D2) strains. Quantitative trait locus (QTL) mapping provisionally localized cocaine sensitivity genes to regions on all chromosomes except 6, 11, 17, and X; sensitization QTLs were localized to chromosomes 1-10, 13, 15, 18, 19, and X. Provisional QTLs for locomotion after saline injection in a novel setting were mapped to chromosomes 1, 3-6, 9, 12, 13, 18, and 19 and in a familiar setting to chromosomes 4-7, 9, 13, and 19. There were both common and unique QTL regions across the phenotypes. Evidence for a genetic association between magnitude of acute cocaine response and sensitization was obtained for only the 10 mg/kg dose. Some common QTL regions for cocaine, ethanol, and methamphetamine responses suggest the possibility that these drugs induce stimulant effects or sensitization through some common mechanisms. However, independent mechanisms were also indicated. Many candidate genes reside near the provisional QTLs mapped for cocaine responses, including genes coding a variety of neurotransmitter and hormone receptors. These data, once confirmed, should prove useful for directing investigations of acute and chronic cocaine effects down already suspected and novel avenues.

Neuroanatomical localization of the effects of (+)-HA966 on locomotor activity after cocaine injections to the nucleus accumbens of rats

Current research has shown that manipulation at the glycine site of the NMDA receptor by various compounds can modulate NMDA receptor function and its behavioural consequences. The present study was conducted in order to neuroanatomically localize the effects of (+)-HA966 upon the acute and chronic effects of cocaine. Locomotor activity of Sprague-Dawley rats pretreated with (+)-HA966 (60 μg) into the nucleus accumbens five min prior to receiving cocaine (20 mg/kg i.p.) was significantly less than locomotor activity of the vehicle pretreated rats. Repeated treatment with cocaine resulted in sensitization to the locomotor stimulant effects of cocaine. Co-administration of (+)-HA966 with cocaine prevented the sensitization to a subsequent cocaine challenge, in which activity was comparable to levels of naive individuals given an acute injection of cocaine. These results suggest that the glycine site on NMDA receptors in the nucleus accumbens plays an important role in both the acute and sensitized responses to cocaine on locomotor activity.

Cocaine accumulates in dopamine‐rich regions of primate brain after I.V. Administration: Comparison with mazindol distribution

Pharmacological and neurochemical evidence suggest that brain dopamine systems, and the dopamine transporter in particular, contribute significantly to the behavioral effects and reinforcing properties of cocaine. The first objective of this study was to determine whether the brain distribution of cocaine supports these conclusions. A high resolution neuroanatomical map of cocaine disposition in brain after i.v. administration was developed. [3H]Cocaine ([3H](-)-cocaine) was administered to squirrel monkeys (Saimiri sciureus) at a trace dose (0.001 mg/kg) and at doses at or above the threshold for producing behavioral effects (0.1 mg/kg, 0.3 mg/kg). After 15 min, ex vivo autoradiography revealed the highest accumulation of [3H]cocaine in dopamine-rich brain regions, including the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle. The norepinephrine-rich locus coeruleus, the hippocampus, and amygdala also accumulated large quantities of [3H]cocaine. Moderately high levels were found in the stria terminalis, medial septum, substantia nigra, and other regions. Lowest levels were found in the cerebellum. A high and positive correlation was established for the brain distribution of [3H]cocaine administered at trace or at behaviorally relevant doses (r: 0.94; P < 0.001). To determine whether radioactivity represented [3H]cocaine or its metabolic products, tissue extracts from brain regions with high levels of cocaine were subjected to thin layer chromatography using two solvent systems. In caudate-putamen, nucleus accumbens, cortex, and hippocampus, radioactivity comigrated with standard [3H]cocaine. In substantia nigra, less than 70% of the radioactivity comigrated with [3H]cocaine, suggesting that cocaine metabolites are generated more rapidly in the substantia nigra than in other brain regions. The second objective was to determine the brain distribution of mazindol, a potent norepinephrine and dopamine transport inhibitor with low abuse liability in humans. The disposition of intravenously administered [3H]mazindol in brain (0.001 mg/kg, 0.007 mg/kg) was surveyed by ex vivo autoradiography. In sharp contrast to [3H]cocaine distribution, the highest accumulation of [3H]mazindol was localized in the norepinephrine-rich pineal gland, discrete regions of the hypothalamus (paraventricular nucleus, supraoptic nucleus), and the locus coeruleus. Moderately high levels were detected in the caudate-putamen, nucleus accumbens, and other regions. The following conclusions were drawn: (1) Although dopamine-rich brain regions are principal targets of cocaine after i.v. administration to the nonhuman primate, other prominent targets of cocaine (locus coeruleus, hippocampus, and amygdala) may contribute to the acute and chronic effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)

Cocaine use increases [ 3HWIN 35428 binding sites in human striatum

Animal studies suggest that chronic cocaine exposure may increase the function and/or synthesis of the dopamine transporter (DAT) under certain conditions, but the literature is complex. In order to test the hypothesis that cocaine exposure alters the DAT in humans, preliminary studies were done characterizing [ 3HWIN 35428 binding in human striatum from normal controls. Following these experiments, the effects of chronic cocaine were examined in post mortem striatal specimens from 7 cocaine users and 7 controls matched for age and post mortem interval, employing quantitative autoradiography. Initial saturation experiments indicated that a one-site model was preferred with a K d of11±4nM. [ 3HWIN 35420 binding was then examined in cocaine users and controls at 0.5, 5, 10, and 50 nM radioligand concentrations. At each concentration of [ 3HWIN 35420, optical densities for cocaine-exposed subjects were increased in caudate, putamen, and accumbens. The results suggest that total numbers of binding sites were increased in cocaine users. Based on the present and previous results, it appears that the regulation of the DAT is fairly plastic, and is highly sensitive to cocaine dosing regimes and withdrawal intervals. Chronic adaptations induced by cocaine in the DAT could contribute to the symptoms of binging, withdrawal depression, and/or craving.

Fixed-ratio size as a determinant of tolerance to cocaine

Six studies, examining five drugs in three species, have demonstrated that tolerance development is impaired under relatively long fixed-ratio (FR) schedules compared with relatively short FR schedules. One such study demonstrated that substantial tolerance to the rate-reducing effects of cocaine in pigeons developed under the FR 5 and 25 components of a multiple schedule of food delivery, but little or no tolerance developed under the FR 125 component. The present study examined the acute and chronic effects of cocaine in three groups of pigeons. One group was exposed to a simple FR 5 schedule of food delivery, a second to a simple FR 125 schedule of food delivery, and a third to a simple FR 125 schedule that alternated across sessions with a multiple FR 125 FR 250 schedule. When administered acutely, cocaine (1-10mg/kg) produced dose-dependent rate decreases under all schedules. With chronic exposure to 5.56mg/kg cocaine, tolerance clearly developed under the FR 5 schedule. Evidence of tolerance under the FR 125 schedule was equivocal, but strongest when that schedule alternated with an FR 250 component under a multiple schedule arrangement. There was no consistent evidence of tolerance under the FR 250 component. These results suggest that, although the development of tolerance under an FR schedule may be affected by exposure to a longer schedule, tolerance to cocaine does not develop readily under "long" FR schedules, regardless of the context in which they appear.

The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat

The effects of treatment with the selective kappa-opioid receptor agonist U-69593 upon cocaine-induced changes in locomotor activity and stereotypy were examined in rats. U-69593 (0.16 mg/kg s.c.) administered either acutely or chronically attenuated both the motor stimulant effect and stereotypy produced by an acute injection of cocaine (20 mg/kg i.p.). Daily cocaine treatment resulted in sensitization to both effects of cocaine. In contrast, no such sensitized responses were seen in animals which had received U-69593 either prior to or in conjunction with daily cocaine treatment. These data demonstrate that activation of kappa-opioid receptors attenuates the acute and chronic effects of cocaine on locomotor activity and stereotypy. Given the inhibitory effects ascribed to both exogenous and endogenous kappa-opioid agonists upon dopamine release in the mesolimbic dopaminergic system, it is suggested that this action may underlie the observed effects of U-69593 on cocaine-induced changes in locomotor activity and stereotypy.

Conditioning, habituation and behavioral reorganization factors in chronic cocaine effects

Rats were administered cocaine (50.0 mg/kg i.p.) daily for 7 days in a Pavlovian paradigm either immediately prior (paired group) or 30 min following (unpaired group) a 20-min placement in an open field test environment. After 7 days of drug withdrawal, the animals were retested 3 days apart, once with saline and once with cocaine (50 mg/kg). Measurement of locomotion as distance traversed (m) revealed a higher level of locomotion in the paired group on all test trials. Analysis of the paired vs. unpaired differences indicated an antihabituation effect of cocaine rather than a hyperlocomotion or a conditioned locomotor effect. Rotation pattern analysis for each animal showed a new frequency distribution of rotations across four categories of diameter size in the paired but not in the unpaired group by Day 5. This new pattern was characterized by a shift in skewness toward large greater than or equal to 55 cm diameter rotations. These qualitative changes in rotation pattern point to a context specific behavioral reorganization process in response to repeated cocaine drug treatment.

Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT 2 receptor function

The acute and chronic effects of cocaine were evaluated on the 5-hydroxytryptamine (5-HT)-receptor 5-HT 2 mediated behavioral function, the head-twitch response (HTR), in mice. In a recent study, we reported that the (±)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane HCl (DOI)-induced HTR was dose dependently reduced by cocaine via indirect stimulation of serotonergic 5-HT 1A and adrenergic α 2 receptors. In the present investigation, the HTR was evoked by the nonselective 5-HT agonist 5-methoxy- N, N-dimethyltryptamine hydrogen oxolate (5-MeO-DMT). Cocaine by itself failed to produce HTR but dose dependently inhibited the 5-MeO-DMT-induced behavior. Cocaine's effects were not due to 5-HT 3 antagonism since acute administration of the more potent 5-HT 3 antagonist (ICS-205,930) failed to produce or modify the 5-MeO-DMT-induced behavior. During withdrawal from chronic cocaine treatment (5–20 mg/kg). 5-MeO-DMT-induced HTR was enhanced. Depending upon the cocaine dose used, the induced supersensitivity persisted up to 172 h following cessation of cocaine treatment. The mechanisms of cocaine-induced supersensitivity were further investigated using the more selective 5-HT 2 agonist DOI. Withdrawal from a low-dose (0.03–1.25 mg/kg) chronic cocaine treatment caused the DOI-induced HTR to increase, whereas withdrawal from a 5- and 10-mg/kg cocaine regimen had no significant effect. The maximal effect persisted up to 36 h following termination of cocaine treatment. Relative to vehicle-exposed controls, withdrawal from cocaine treatment enhanced the inhibitory potency of the 5-HT 1A agonist (±)-8-hydroxy-2-(di- n-propylamino)tetralin HBr (8-OH-DPAT) on DOI-induced HTR. Moreover, the 5-HT 1B/1C agonist 1-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP) and the 5-HT 3 agonist m-chlorophenylbiguanide HCl (mCPBG) failed to modify DOI-induced HTR in chronically vehicle-exposed mice but both agents reduced the induced behavior in the cocaine-treated group. Unlike changes in the sensitivity of serotonergic receptor subtypes, cocaine exposure failed to modify α 2 adrenoceptor sensitivity because clonidine was equipotent in inhibiting DOI-induced behavior in both groups treated chronically with vehicle and cocaine. Thus, the present study demonstrates a serotonergic component of cocaine's action in that low-dose chronic exposure enhances the functional sensitivity of serotonergic 5-HT 1A, 5-HT 2, and 5-HT 3 receptors.

Effect of chronic cocaine on dopamine synthesis in the nucleus accumbens as determined by microdialysis perfusion with NSD-1015

Reduced steady state formation of dihydroxyphenylalanine (DOPA) (47%) was found in the nucleus accumbens (N. ACC) of rats treated with ten days of repeated cocaine (10 mg/kg, i.p.) as compared to saline controls after NSD 1015 perfusion (10 −4 M) by microdialysis. In addition, prior to NSD 1015 perfusion, basal extracellular levels of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) in the N. ACC were 33% lower in the chronic cocaine-treated animals. The results indicate the rate of dopamine synthesis in the N. ACC is significantly reduced by repeated cocaine administration.

Acute and chronic effects of cocaine on isolation-induced aggression in mice

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5-5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.

Chronic cocaine reduces α 2-adrenoceptor elicited mydriasis and inhibition of locus coeruleus neurons

The effects of chronic cocaine (50 mg/kg per day for two weeks) administration on two α 2-adrenoceptor-mediated responses were studied in rats. Chronic administration of cocaine significantly (compared to sham controls) attenuated the α 2-adrenoceptor-mediared inhibition of noradrenergic locus coeruleus (LC) neurons as well as α 2-adrenoceptor elicited mydriasis. Noradrenergic LC neurons from the cocaine treated and sham groups differed significantly in their responsiveness to the inhibitory effects of clonidine (ED 50 values μg/kg: sham 7.35 ± 1.13 and cocaine-treated 17.17 ± 4.40, P < 0.05). The ED 50 values for the mydriatic response were sham 5.71 ± 0.49 and cocaine-treated 16.42 ± 0.69 μg/kg, respectively, P < 0.001. No differences in cardiovascular responses to systematically injected clonidine between the chronic cocaine- and sham-treated groups were observed. Chronic cocaine treatment attenuates the two α 2-adrenoceptor-mediated responses most likely via an interaction with central catecholaminergic neurotransmission.

Chronic cocaine effects on peripheral biogenic amines: a long-term reduction in peripheral dopamine and phenylethylamine production

The short- (during 12 h after last treatment) and long- (6 weeks after last treatment) term effects of repeated administration of cocaine on the total output of norepinephrine (NE) and its metabolites (sum NE), dopamine (DA) and its metabolites (sum DA) as well as the excretion of 5-hydroxyindoleacetic acid (5-HIAA) and phenylethylamine were evaluated in rats. The concentration of NE, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the celiac ganglion after 1,2 and 3 weeks of repeated cocaine administration were also measured. Sum NE remained unchanged during the cocaine treatment but NE and normetanephrine excretions were significantly decreased and increased respectively. 5-HIAA excretion was significantly reduced only after 3 weeks cocaine treatment. In the celiac ganglion NE and DOPAC contents showed tendencies towards being increased and decreased respectively. DA content was not changed. The excretions of DA, DOPAC, homovanillic acid (HVA) and phenylethylamine were significantly reduced during chronic exposure to cocaine. The above short-term changes in DA and phenylethylamine persisted for periods as long as 6 weeks after 1 week repeated exposure to cocaine. It is concluded that chronic exposure to cocaine can produce preferential long term deficiencies in the production of DA and phenylethylamine in the periphery. Peripheral noradrenergic and serotonergic neuronal systems are apparently minimally affected. The close association between DA or sum DA and phenylethylamine excretion suggest these 2 amines may coexistin the same neuron.

Effects of acute and daily cocaine administration on performance under a delayed-matching-to-sample procedure

Food deprived pigeons were trained under a procedure in which trials began with the transillumination of one of three keys by red or green light. Pecking this key extinguished the light behind it and, after a variable delay (0.05, 0.5, 1.0, 2.0 or 4.0 sec), was followed by illumination of the two other keys, one by red light and one by green. Pecks on the key that was the same color as the previously illuminated key could produce access to food. High levels of accuracy were obtained at all delays. The acute and chronic effects of cocaine on performance generated by this procedure (delayed-matching-to-sample) were studied. Acutely, cocaine (0.56–10.0 mg/kg) produced dose-related decreases in accuracy and in rate of completing trials. Accuracy at the longest delay was more sensitive to cocaine's effects. Daily administration of a comparatively large dose (5.6 mg/kg) resulted in tolerance to the rate-reducing and accuracy-reducing effects of large doses.

EFFECTS OF COCAINE AND d‐AMPHETAMINE ON THE REPEATED ACQUISITION AND PERFORMANCE OF CONDITIONAL DISCRIMINATIONS1

The acute and chronic effects of cocaine and d-amphetamine on food-reinforced behavior were investigated in pigeons responding on a two-component multiple schedule. In one component, the behavioral task consisted of the same chain of conditional discriminations each session (performance). In the other component, the chain of conditional discriminations was changed from session to session (learning). In comparison to control sessions, both acute cocaine and d-amphetamine increased errors in each component of the multiple schedule. Responding in the learning component, however, was generally disrupted at lower doses than those that affected responding in the performance component. At high doses, both drugs produced pauses in responding in each component in three of the four subjects. Pausing engendered by d-amphetamine was approximately twice as long as that under cocaine. Upon chronic administration, both the pausing and error-increasing effects of each drug diminished. Drug-induced changes in timeout responding, however, did not decrease during chronic administration. Redeterminations of the d-amphetamine dose-effect curves following chronic cocaine administration suggested the existence of cross-tolerance between cocaine and d-amphetamine. Both the acute and chronic data are consistent with the view that conditions of stimulus control may modulate the behavioral effects of drugs.