Effect of chronic "binge cocaine" on basal levels and cocaine-induced increases of dopamine in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice

In vivo microdialysis was used to measure the effect of chronic "binge" pattern cocaine administration on basal and cocaine-induced dopamine levels in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice. Mice were implanted with a guide cannula in the caudate putamen or nucleus accumbens and after 4 days recovery, one group received "binge" pattern cocaine administration for 13 days (15 mg/kg x 3, i.p. at hourly intervals) while another group received saline in the same pattern. On the day before microdialysis, dialysis probes were lowered into the caudate putamen and nucleus accumbens. The next morning, after baseline dopamine collection, all animals received "binge" cocaine administration. Dialysates were collected every 20 min and dopamine content was determined by HPLC with electrochemical detection. In the basal condition, the mean level of dopamine in the dialysate from both brain regions of mice pretreated with "binge" pattern cocaine administration was significantly lower than that of the mice pretreated with saline administration. The absolute levels of dopamine achieved following "binge" pattern cocaine challenge were lower in the mice that had received chronic cocaine administration. However, when expressed as percent increase over baseline, the dopamine response to cocaine in the nucleus accumbens was significantly higher in mice that received chronic than in mice that received acute cocaine administration. Chronic cocaine administration led to a lowering of both basal dopamine and the absolute levels of cocaine-induced increases of dopamine in the two brain regions, but enhanced the percent increases over the baseline in response to cocaine in the nucleus accumbens of both mouse strains.     

Acute 'binge' cocaine administration elevates dynorphin mRNA in the caudate putamen of C57BL/6J but not 129/J mice

Preprodynorphin mRNA was measured in the nucleus accumbens (NAc) and caudate putamen (CPu) after 3-day 'binge' pattern cocaine administration in C57BL/6J and 129/J mice, strains which differ in behavior and in dopamine increases in the CPu after 'binge' cocaine. In the CPu, there was increased preprodynorphin mRNA in C57BL/6J (P<0.05), but not in 129/J mice, with no differences in the NAc. Thus, 129/J mice are hyporesponsive to the preprodynorphin activating effects of acute 'binge' cocaine in the CPu.     

Dopamine and serotonin release in dorsal striatum and nucleus accumbens is differentially modulated by morphine in DBA/2J and C57BL/6J mice

Numerous studies have demonstrated that genetic factors significantly influence opioid ability to induce behavioral modification in mice. This differential sensitivity has been extensively studied, particularly in the DBA/2J and C57BL/6J strains. In the present study, using the "in vivo" microdialysis technique in these strains, we investigated the effect of morphine administration on the extracellular levels of dopamine (DA), serotonin (5-HT), and their metabolites in the nucleus accumbens and dorsal striatum--areas thought to be involved in morphine-induced locomotor hyperactivity. In the nucleus accumbens, morphine (20 mg/kg) significantly increased extracellular levels of DA in both strains. However, in dorsal striatum the morphine-induced increase of extracellular DA was lower in DBA/2J mice than in C57BL/6J. Moreover, morphine significantly stimulated 5-HT and 5-hydroxyindolacetic acid (5-HIAA) release both in nucleus accumbens and dorsal striatum of C57BL/6J mice, whereas it decreased 5-HT release without modifying 5-HIAA levels in DBA/2J mice. These results suggest that the different behavioral and biochemical responses to acute morphine described in these two strains could be mediated by different sensitivity of both the dopaminergic and the serotonergic systems.     

Mouse strain differences in locomotor,sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [³⁵S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D₁ and D₂ binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.     

Presynaptic dopaminergic function is largely unaltered in mesolimbic and mesostriatal terminals of adult rats that were prenatally exposed to cocaine

Fast-scan cyclic voltammetry in brain slices and postmortem tissue content assessment were used to evaluate presynaptic dopaminergic function in the caudate putamen and nucleus accumbens of adult male rats (180+ days old) that were prenatally treated with either cocaine or saline. Experiments were carried out to test whether there were differences in dopamine release, reuptake, autoreceptor function or the tissue levels of dopamine and its metabolites between cocaine- and saline-exposed rats. We report that presynaptic dopaminergic function remains largely intact in adult rats that were prenatally exposed to cocaine. The ability of terminals in the caudate putamen and nucleus accumbens to release and regulate dopamine is unaltered by prenatal cocaine exposure. However the tissue content of dopamine in the caudate putamen was decreased, representing a diminution in the dopamine storage pool. We conclude, therefore, that behavioral changes that have previously been observed in rats that were prenatally exposed to cocaine are not mediated through alteration of presynaptic dopaminergic mechanisms in these brain regions.     

Modulation of striatal dopamine dynamics by cocaine self‐administration and amphetamine treatment in female rats

Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self‐administration and returned to pre‐cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self‐administration (1.5 mg kg^?1 inj^?1, 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast‐scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate‐putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self‐administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate‐putamen, neither cocaine self‐administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self‐administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.     

Behavioural sensitization and enhanced dopamine response in the nucleus accumbens after intravenous cocaine self-administration in mice

The behavioural effects of cocaine are enhanced in animals with a prior history of repeated cocaine administration. This phenomenon, referred to as sensitization, is also associated with an increase in cocaine-evoked extracellular dopamine levels in the nucleus accumbens. Behavioural and neurochemical sensitization has been demonstrated in rats with a prior history of cocaine self-administration and in those that had received experimenter-administered cocaine. Although it is clear that the repeated non-contingent administration also results in behavioural sensitization in the mouse, the issue of whether behavioural and neurochemical sensitization also occur in this species following intravenous cocaine self-administration has not been assessed. The present study used the technique of in vivo microdialysis in conjunction with operant self-administration to characterize cocaine-evoked locomotor activity and dopamine levels in the nucleus accumbens in mice with a prior history of intravenous cocaine self-administration or those that had received yoked infusions of cocaine. Mice that had received contingent or non-contingent infusions of cocaine exhibited an enhanced behavioural response to cocaine and increased cocaine-evoked dopamine levels in the nucleus accumbens. There was no difference between groups in the magnitude of this effect. Prior exposure to cocaine did not modify baseline dopamine levels in the nucleus accumbens. These data demonstrate that mice with previous cocaine self-administration experience show an enhanced behavioural and dopamine response to cocaine in the nucleus accumbens. Furthermore, control over cocaine infusion does not significantly alter the magnitude of the sensitized behavioural and presynaptic dopamine responses observed in response to a challenge dose of cocaine.     

Basal levels and alcohol-induced changes in nociceptin/orphanin FQ, dynorphin, and enkephalin levels in C57BL/6J mice

In order to investigate the involvement of the opioid and nociceptin/orphanin FQ (N/OFQ) system in alcohol drinking behaviour, N/OFQ and the opioid peptides dynorphin B (DYNB) and Met-enkephalin-Arg(6) Phe(7) (MEAP) were examined in the alcohol-preferring C57BL/6J mice. Basal peptide levels were compared in the brain and the pituitary gland with basal levels in the alcohol-avoiding DBA/2J mice. Furthermore, the effects of chronic alcohol self-administration on peptides were studied in the C57BL/6J mice. Compared to the DBA/2J mice, C57BL/6J mice had low immunoreactive (ir) levels of DYNB and MEAP in the nucleus accumbens, the hippocampus, and the substantia nigra, low ir-DYNB levels in the striatum and low ir-MEAP levels in the frontal cortex. Higher ir-DYNB levels in the pituitary gland and in the periaqueductal gray (PAG) and higher ir-N/OFQ levels in the frontal cortex and in the hippocampus were detected in C57BL/6J mice compared to the DBA/2J mice. After 4 weeks of voluntary alcohol consumption, only minor changes in steady-state peptide levels were identified. However, 5 days after the alcohol-drinking period, lower levels of all peptides were detected in the ventral tegmental area and ir-DYNB levels were also lower in the amygdala and in the substantia nigra. Twenty-one days after cessation of alcohol self-administration, the opioid peptides in alcohol-consuming C57BL/6J mice were lower in the PAG, the N/OFQ was lower in the frontal cortex and DYNB was higher in the amygdala and substantia nigra as compared to control C57BL/6J mice. This study demonstrates strain differences between C57BL/6J mice and DBA/2J mice that could contribute to divergent drug-taking behaviour, and it also demonstrates time- and structure-specific changes in neuropeptide levels after alcohol self-administration in the C57BL/6J mice.     

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.     

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K⁺ concentration (100 mM KCI). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K⁺ on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K⁺ infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.     

The influence of sex on extracellular dopamine and locomotor activity in C57BL/6J mice before and after acute cocaine challenge

C57BL6/J (C57) mice serve as a useful animal model of cocaine abuse because they self-administer cocaine, exhibit place conditioning to cocaine, discriminate the interoceptive cues of cocaine, and are used for backcrossing strains of genetically modified mice. The present study was to examine the influence of sex on extracellular DA and locomotor activity in C57 mice in response to acute cocaine challenge. In the first experiment, male and female mice were implanted with guide cannulae aimed at the dorsal striatum. Microdialysates were collected in three consecutive phases: baseline, post-saline injection, and post-cocaine injection. Sex did not influence DA measurements during baseline or after intraperitoneal (i.p.) saline injection. Cocaine (20 mg/kg) injections increased peak extracellular DA of both sexes, and the increase was greater for males (278%+/-14.0%) than females (182.5%+/-10.8%) (P<0.05). In the second experiment, under conditions similar to the microdialysis experiment, locomotor activity of male and female mice was assessed during baseline, after saline injection, and after cocaine injection (5, 10, 20, or 40 mg/kg). Cocaine dose-dependently increased activity; however, sex did not influence locomotor activity during baseline, after saline, or after any cocaine dose. Results of the experiments established that cocaine (20 mg/kg) increased extracellular DA in the dorsal striatum to a greater extent in male than in female mice; however, when cocaine was administered under similar experimental conditions, sex did not influence cocaine stimulation of locomotor activity over a wide range of doses.     

Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP‐, DOP‐, and KOP‐opioid receptor knockout mice of three different genetic backgrounds

We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild‐type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [³H]SCH23390, [³H]raclopride, and [³H]mazindol, respectively in triple‐opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 × 129/SvPas (B6 × 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 × 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 × 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 × 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains. Synapse 64:520–527, 2010. © 2010 Wiley‐Liss, Inc.     

Repeated cocaine injections have no influence on tyrosine hydroxylase activity in the rat nucleus accumbens core or shell

Numerous reports have demonstrated augmented cocaine-evoked release of dopamine in the nucleus accumbens of rats pre-treated with cocaine. However, the extent to which repeated cocaine injections affect basal levels of dopamine is unclear. There have been reports of increases, decreases, or no change in basal levels of extracellular accumbal dopamine resulting from repeated psychostimulant administration. The present study assessed the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the nucleus accumbens following either acute or repeated cocaine administration. The in vivo microdialysis technique was used to measure accumulation of the dopamine precursor DOPA following intra-accumbal administration of the DOPA decarboxylase inhibitor NSD 1015 through the microdialysis probe. This method provides an estimate of tyrosine hydroxylase activity within the nucleus accumbens. Results indicate that neither acute nor repeated cocaine administration produced any change in DOPA accumulation in either the nucleus accumbens shell or core. These data indicate that dopamine synthesis is not altered by cocaine administration.     

The metabolic rate and vulnerability of dopaminergic neurons,and adenosine dynamics in the cerebral cortex,nucleus accumbens,caudate nucleus,and putamen of the common marmoset

The pathophysiology of the striatum and cerebral cortex were studied from the pharmacological aspect.

Investigation of the dopamine content in the cerebral cortex revealed that the premotor and motor area showed the highest level (61±6.2 ng/g). Intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 10 mg/kg reduced the dopamine content in the caudate nucleus and putamen to 2–3% of the control level in common marmosets, while it fell to 60% in the nucleus accumbens. There was no alteration of the dopamine content in the cerebral cortex. Immunohistochemical staining for tyrosine hydroxylase in the midbrains of MPTP-treated marmosets showed almost complete disappearance of dopaminergic cells from the substantia nigra and good preservation of cells in the ventrotegmental area. Dopaminergic cells projecting to the caudate/putamen, nucleus accumbens, and cerebral cortex showed marked, moderate, and no vulnerability to MPTP, respectively.

After systemic administration of MPTP, dopaminergic neurons projecting to the caudate nucleus and putamen were damaged equally. However, the compensatory increase of dopamine turnover was more prominent in the putamen than in the caudate nucleus. Thus, nigroputaminal dopaminergic neurons may have a higher level of activity than neuron in the caudate. The neural connections and functions of the caudate nucleus and putamen have already been differentiated anatomically or physiologically. This compensatory increase of the dopamine turnover rate is another aspect of functional differences between the caudate nucleus and putamen.

Investigation of the dopamine content in the heat, body, and tail of the caudate nucleus showed no differences in the concentration of dopamine. However, a study of the metabolic rate of dopamine using α-methyl-p-tyrosine, a tyrosine hydoxylase inhibitor, showed higher metabolism of dopamine in the head of the caudate nucleus in common marmosets. Thus, dopaminergic neurons projecting to the caudate nucleus may show topographical differences in their firing rates.

A microdialysis study indicated an increase in the metabolism of adenosine in the striatum of MPTP-treated animals. Cholinergic neurons are interneurons and are one of the main sources of adenosine in the striatum. Dopaminergic input from the substantia nigra acting on cholinergic neurons was decreased following MPTP treatment. The increase of adenosine metabolism suggested that cholinergic neurons in the striatum receive inhibitory inputs from nigrostriatal dopaminergic neurons.

     

Distinct patterns of Fos expression induced by systemic amphetamine in the striatal complex of C57BL/6JICo and DBA/2JICo inbred strains of mice

Mice from the inbred strains C57BL/6 and DBA/2 are characterized by striking differences in their behavioral response to addictive drugs. We used Fos expression as a tool to reveal strain differences in the postsynaptic effects of amphetamine (AMPH; 2.5 mg/kg) within the nucleus accumbens (NAc) (core and shell) and the dorsal caudate (dorsomedial and dorsolateral). AMPH stimulated Fos expression in all striatal regions of mice from both strains. However, while C57BL/6 showed a higher Fos response than DBA/2 mice in both NAc shell and core, the opposite was true for the dorsolateral caudate. The effects of AMPH were prevented by D1 blockade in all striatal regions of both strains and mimicked by the D1 agonist, SKF82958 (0.1 mg/kg), in both regions of the caudate and in the NAc shell, but not in the core. Our results suggest that the functional heterogeneity of the striatal complex is under genetic control and that this control may implicate DA transmission and corticostriatal interactions.     

Sexual differences and estrous cycle in methamphetamine-induced dopamine and serotonin depletions in the striatum of mice

Summary. Four consecutive doses (10 mg/kg) of methamphetamine, s.c., produced a substantial striatal dopamine depletion in both sexes of BALB/c and C57BL/6J mice. Male C57BL/6J mice exhibited greater dopamine depletions in the striatum compared to female C57BL/6J mice. In contrast, male and female BALB/c mice demonstrated an equivalent magnitude of striatal dopamine depletion. Regardless of sex, C57BL/6J mice demonstrated approximately 1.4 to 2.2 times greater dopamine depletions in the striatum compared to BALB/c mice. Moreover, methamphetamine caused 4 times greater serotonin depletions in male as opposed to female BALB/c mice while sparing either sex of the C57BL/6J mice. Furthermore, female mice of both strains appeared to have the greatest basal dopamine levels during proestrus and the lowest basal dopamine levels during diestrus. Likewise, female mice of both strains exhibited the lowest dopamine depletions in the striatum when the dosing regimen of methamphetamine started at proestrus whereas the greatest dopamine depletions in the striatum occurred when the regimen started during diestrus. These results suggest that sex hormones and other modulating factors may play a role in methamphetamine-induced dopamine and serotonin neurotoxicity. Received August 3, 1999; accepted September 13, 1999     

Behavioral sensitization to binge-pattern cocaine administration is not associated with changes in protein levels of four major G-proteins

Behavioral sensitization is a characteristic sequelae of repeated cocaine exposure. It likely occurs due to long-lasting neuroadaptations produced by cocaine, although the exact nature of these adaptations has yet to be defined. The goal of the present study was to determine if behavioral sensitization to cocaine is accompanied by alterations in G-protein levels. Adult male rats were administered cocaine or saline three times daily in a binge-pattern for 1, 3, or 14 days and activity monitored. Levels of four major G-protein alpha-subunits, Galphas, Galphaolf, Galphao and Galphai1, and their mRNAs were measured in the nucleus accumbens, caudate putamen, and cingulate/frontal cortex using Western blot analysis and in situ hybridization, respectively. Fourteen days of binge-pattern cocaine administration resulted in behavioral sensitization as evidenced by increased behavioral activity over the 14 days of drug exposure. Results demonstrated that Galphaolf mRNA expression was significantly reduced in the nucleus accumbens after 1, 3 or 14 days of cocaine, whereas Galphai1 mRNA was increased following 3, but not 1 or 14 days of cocaine in the caudate putamen, nucleus accumbens and cingulate cortex. Galphas and Galphao mRNA expression were not altered in any region investigated at any time point. In contrast to gene expression, protein levels of the four G-protein alpha-subunits were not significantly different from saline-injected rats in the caudate putamen, nucleus accumbens, or frontal cortex following 1, 3, or 14 days of cocaine administration. These results suggest that alterations in the level of G-proteins are not necessary for the development of cocaine-induced sensitization.     

The frequency of cocaine administration impacts cocaine-induced receptor alterations

The present study investigated the impact of dosing schedule on cocaine-induced receptor alterations. Rats were injected with 30 mg/kg per day of cocaine given either as a single injection or in two equally divided doses for 14 days. The effects of these two dosing regimens were compared with our previous findings following administration of cocaine three times daily at 1-h intervals. Using receptor autoradiography, twice daily injections of cocaine produced an upregulation of mu opioid receptors in the rostral nucleus accumbens, rostral caudate putamen, and layer I of the rostral cingulate cortex, whereas single daily injections resulted in a significant increase in the nucleus accumbens only. Only small insignificant increases in kappa opioid receptor densities were found following either once or twice daily cocaine injections, whereas three daily injections produced an increase in kappa receptor density in the cingulate cortex, nucleus accumbens, and caudate putamen. Increased dopamine D1 receptor binding was found in the nucleus accumbens and olfactory tubercle following twice daily cocaine injections, but not after single daily injections of the same total daily dose. These results demonstrate that the same total daily dose of cocaine administered in multiple small injections produces a greater effect on receptor regulation than a single larger injection. This suggests that the interval between cocaine injections is an important variable when studying the effects of cocaine on neurochemistry.     

Differences in nociceptive behavioral performance between C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI mice

The interpretation of knockout and transgenic mouse studies in pain research critically depends on detailed knowledge of the performance profile of the background strains. Pain-related behavior was compared between four relevant mouse strains (C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI mice of both sexes) using an extended test battery that included an unusual variety of assays for thermal and mechanical acute nociception, and inflammatory and neuropathic pain. Strain- and gender-dependent differences were demonstrated in many of these nociceptive assays. Particularly, C57BL and 129 mice, which serve as the default genetic backgrounds for experiments in genetically altered mice, display quite different patterns of nociceptive performance. Compared to C57BL/6J mice, 129S6/SvEv animals are less sensitive to inflammatory pain conditions (thermal sensitivity after carrageenan subplantar injection; flinch behavior after formalin injection), while the opposite is observed in the neuropathic pain condition and the visceral pain model. These data may be of special interest for genetic studies, where issues related to the background phenotype may confound their interpretation.     

Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine

The technique of in vivo microdialysis was used to measure the extracellular levels of dopamine in the nucleus accumbens septi and medial prefrontal cortex of chloral-hydrate-anaesthetized rats following systemic administration of cocaine and amphetamine. Intravenous injection of cocaine increased the extracellular levels of dopamine in the medial prefrontal cortex and the nucleus accumbens septi in a dose-dependent manner. However, the magnitude of increase was significantly greater in nucleus accumbens than in medial prefrontal cortex. In comparison to cocaine, amphetamine increased the extracellular levels of dopamine in the nucleus accumbens and medial prefrontal cortex to the same degree. Based on the relatively small increase of extracellular dopamine levels in medial prefrontal cortex by cocaine, it is postulated that dopaminergic innervation of other structures besides medial prefrontal cortex may be involved in maintenance of cocaine self-administration.