Biomedical subjects

B Ladenheim

Publications and source records attributed to B Ladenheim.

At least 19 recordsLinked to original sources

PubMed2001

Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.

Palatable food stimulates neural systems implicated in drug dependence; thus sugar might have effects like a drug of abuse. Rats were given 25% glucose solution with chow for 12 h followed by 12 h of food deprivation each day. They doubled their glucose intake in 10 days and developed a pattern of excessive intake in the first hour of daily access. After 30 days, receptor binding was compared to chow-fed controls. Dopamine D-1 receptor binding increased significantly in the accumbens core and shell. In contrast, D-2 binding decreased in the dorsal striatum. Binding to dopamine transporter increased in the midbrain. Opioid mu-1 receptor binding increased significantly in the cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus, intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like some drugs of abuse.

Animals↗

PubMed2001

Methamphetamine increases expression of the apoptotic c-myc and L-myc genes in the mouse brain.

To clarify the possible mechanisms by which the recreational drug, methamphetamine (METH), induces apoptosis, we investigated its effects on the expression of Myc apoptotic genes. This paper presents the characterization of c-myc and L-myc gene transcription in the striatum and the cortex. In addition, the expression of the corresponding proteins was also evaluated. Our observations reveal that c-myc and L-myc were up-regulated by METH at both the mRNA and protein levels. Thus, myc transcription factors might be responsible for some aspects of METH-induced apoptotic processes.

Animals↗

PubMed2001

Delta opioid peptide [D-Ala2, D-Leu5]enkephalin causes a near complete blockade of the neuronal damage caused by a single high dose of methamphetamine: examining the role of p53.

The delta opioid peptide [D-Ala2, D-Leu5]enkephalin (DADLE) has been reported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). We examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice. The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content (a approximately 50% blockade). DADLE did not affect the changes of rectal temperature induced by the administration of the high dose of METH. METH increased p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE abolished the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked both the increase of p53 mRNA and the decrease of p53 protein caused by METH. These results demonstrate a neuroprotective effect of DADLE against the neuronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance between the protein level of p53 and the neurotoxicity caused by a high dose of METH. Synapse 39:305-312, 2001. Published 2001 Wiley-Liss, Inc.

Animals↗

PubMed2001

Temporal profiling of methamphetamine-induced changes in gene expression in the mouse brain: evidence from cDNA array.

Methamphetamine (METH) is a neurodegenerative drug of abuse. Its toxicity is characterized by destruction of monoaminergic terminals and by apoptosis in cortical and striatal cell bodies. Multiple factors appear to control METH neurotoxicity, including free radicals and transcription factors. Here, using cDNA arrays, we show the temporal profile of gene expression patterns in the cortex of mice treated with this drug. We obtained two patterns of changes from 588 genes surveyed. First, an early pattern is characterized by upregulation of transcription factors, including members of the jun family. Second, a delayed pattern includes genes related to cell death and to DNA repair. A number of trophic factors were also activated at the later timepoint. These observations suggest that METH can activate a multigene machinery that participates in the production of its toxic effects. The resulting degenerative effects of the drug are thus the result of a balance between protoxic and antiapoptotic mechanisms triggered by its administration to these animals. These observations are of clinical relevance because of the recent identification of degenerative changes in the brains of METH abusers.

Animals↗

PubMed2001

Characterization of human cleaved N-CAM and association with schizophrenia.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule involved in cellular migration, synaptic plasticity, and CNS development. A 105- to 115-kDa isoform of N-CAM (cleaved N-CAM or cN-CAM) is increased in schizophrenia in hippocampus, prefrontal cortex, and CSF. We purified and partially characterized cN-CAM, a putative novel isoform, and confirmed that the first 9 amino acids were identical to exon 1 of N-CAM, without the signal sequence. Analysis of trypsin-digested cN-CAM fragments by matrix-assisted laser desorption ionization on a time-of-flight mass spectrometer (MALDI-TOF) yielded peptides that could be identified as being derived from the first 548 amino acid residues of the expected N-CAM amino acid sequence. Immunological identification with four specific N-CAM antisera directed toward cytoplasmic, secreted, variable alternative spliced exon, or GPI epitopes failed to indicate other known splice variants. Neuraminidase treatment of cN-CAM produced a minor alteration resulting in a faster migrating immunoreactive band, indicating partial glycosylation of cN-CAM. Membranous particles from cytosolic brain extract containing cN-CAM were obtained by ultracentrifugation; however, CSF contained few such particles. cN-CAM and synaptophysin were colocalized on these particles. Both cN-CAM and N-CAM 180 were present in synaptosomal preparations of human brain. Following incubation of synaptosomes or brain tissue without protease inhibitors, N-CAM 180 was degraded and cN-CAM was increased. A cN-CAM-like band was present in human fetal neuronal cultures, but not in fetal astrocyte cultures. Thus, cN-CAM represents a protease- and neuraminidase-susceptible fragment possibly derived by proteolytic cleavage of N-CAM 180. An enlargement in ventricular volume in a group of adult patients with schizophrenia over a 2-year interval was found to be correlated with CSF cN-CAM levels as measured at the time of the initial MRI scan (r = 0.53, P = 0.01). cN-CAM is associated with ventricular enlargement; thus, the release of N-CAM fragments may be part of the pathogenic mechanism of schizophrenia in vulnerable brain regions such as the hippocampus and prefrontal cortex. Alternatively, the increases in cN-CAM in schizophrenia may be a reflection of a more general abnormality in the regulation of proteolysis or of extracellular matrix stability.

Adult↗

PubMed2001

Amphetamine-induced toxicity in dopamine terminals in CD-1 and C57BL/6J mice: complex roles for oxygen-based species and temperature regulation.

In order to examine differential strain susceptibility to neurotoxic effects of amphetamine and to assess the potential role of superoxide radicals in amphetamine-induced dopaminergic damage, the drug was injected to mice with different levels of copper/zinc superoxide dismutase (Cu/Zn SOD) enzyme. Administration of amphetamine (10 mg/kg, i.p., given every 2 h, a total of four times) to wild-type CD-1 and C57BL/6J mice caused significant decreases in dopamine and 3,4-dihydroxyphenylacetic acid levels, in [(125)I]RTI-121-labeled dopamine transporters as well as a significant depletion in the concentration of dopamine transporter and vesicular monoamine transporter 2 proteins. The amphetamine-induced toxic effects were less prominent in CD-1 mice, which have much higher levels of Cu/Zn SOD activity (0.69 units/mg of protein) in their striata than C57BL/6J animals (0.007 units/mg of protein). Transgenic mice on CD-1 and C57BL/6J background, which had striatal levels of Cu/Zn SOD 2.57 and 1.67 units/mg of protein, respectively, showed significant protection against all the toxic effects of amphetamine. The attenuation of toxicity observed in transgenic mice was not caused by differences in amphetamine accumulation in wild-type and mutant animals. However, CD-1-SOD transgenic mice showed marked hypothermia to amphetamine whereas C57-SOD transgenic mice did not show a consistent thermic response to the drug. The data obtained demonstrate distinctions in the neurotoxic profile of amphetamine in CD-1 and C57BL/6J mice, which show some differences in Cu/Zn SOD activity and in their thermic responses to amphetamine administration. Thus, these observations provide evidence for possible complex interactions between thermoregulation and free radical load in the long-term neurotoxic effects of this illicit drug of abuse.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.

Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.

Amphetamine↗

PubMed1999

Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity.

Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms involved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a methamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this issue further, the present study was thus undertaken to assess the toxic effects of methamphetamine in heterozygous and homozygous c-fos knock-out as well as wild-type mice. Administration of methamphetamine caused significant reduction in [(125)I]RTI-121-labeled dopamine uptake sites, dopamine transporter protein, and tyrosine hydroxylase-like immunohistochemistry in the striata of wild-type mice. These decreases were significantly exacerbated in heterozygous and homozygous c-fos knock-out mice, with the homozygous showing greater loss of striatal dopaminergic markers. Moreover, in comparison with wild-type animals, both genotypes of c-fos knock-out mice showed more DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demonstrated a greater number of glial fibrillary acidic protein-positive cells than did c-fos knock-out mice. These data suggest that c-fos induction in response to toxic doses of methamphetamine might be involved in protective mechanisms against this drug-induced neurotoxicity.

Animals↗

PubMed1999

Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine.

Continuous infusion of cocaine produces partial behavioral tolerance to its locomotor activating effects, while daily injections produce sensitization. Methylphenidate binds with a similar affinity to cocaine at the dopamine transporter, but has a much lower affinity for the serotonin transporter than does cocaine. This study was done to compare the effects of chronic methylphenidate with chronic cocaine. The pattern of locomotor activity over a 7 day treatment period was significantly different from cocaine. Methylphenidate elevated activity on each day, compared to saline, yet neither tolerance to a continuous infusion of the drug, nor sensitization to repeated daily injections was produced. We have previously shown that neither of these treatments with cocaine produces significant alterations in dopamine transporter density 1 day after the end of treatment. In contrast, methylphenidate injections significantly decreased dopamine transporters in rostral caudate putamen, with no change in nucleus accumbens. Continuous infusion of methylphenidate had no effect on dopamine transporters in either brain region. These findings provide further evidence that different classes of dopamine uptake inhibitors may interact with the dopamine transporter in qualitatively different manners. Furthermore, it is possible that the inhibition of serotonin uptake by cocaine may contribute to the adaptations in behavioral activity that are seen during chronic treatment.

Animals↗

PubMed1999

Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine.

Methamphetamine is a strong and long-lasting stimulant that can be easily synthesized and is effective when taken either orally, intravenously, or smoked as 'ice'. Due to it's escalating abuse, a clear need exists for laboratory procedures to evaluate motivational components of methamphetamine abuse and their underlying neurobiological mechanisms. In the present experiment, we utilized a 'yoked' procedure in which rats were run simultaneously in groups of three, with two rats serving as yoked controls which received an injection of either 0.1 mg/kg methamphetamine or saline which was not contingent on responding each time a response-contingent injection of 0.1 mg/kg methamphetamine was self-administered by the third paired rat. Rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptors levels in the ventral tegmental area (34%) and medial (31%) and dorsal (21%) part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens (15%), as measured by in vitro quantitative autoradiography. Since the decreases in levels of dopamine D1 and D2 receptors which occurred in rats self-administering methamphetamine did not occur in littermates that received either yoked injections of methamphetamine or saline, these changes likely reflect motivational states that were present when methamphetamine injection depended on active drug self-administration behavior.

Animals↗

PubMed1999

Overexpression of human copper/zinc superoxide dismutase in transgenic mice attenuates oxidative stress caused by methylenedioxymethamphetamine (Ecstasy).

Administration of 3,4-methylenedioxymethamphetamine (4 x 20 mg/kg) to non-transgenic CD-1 mice caused marked depletion in dopamine, 3,4-dihydroxyphenylacetic acid and 5-hydroxytryptamine in the caudate-putamen. There were no significant changes in serotonergic markers in the hippocampus and frontal cortex. Homozygous and heterozygous copper/zinc superoxide dismutase transgenic mice show partial protection against the toxic effects of 3,4-methylenedioxymethamphetamine on striatal dopaminergic markers. In addition, 3,4-methylenedioxymethamphetamine injections caused marked decreases in copper/zinc superoxide dismutase activity in the frontal cortex, caudate-putamen and hippocampus of wild-type mice. Moreover, there were concomitant 3,4-methylenedioxymethamphetamine-induced decreases in catalase activity in the caudate-putamen and hippocampus, decreases in glutathione peroxidase activity in the frontal cortex as well as increases in lipid peroxidation in the frontal cortex, caudate-putamen, and hippocampus of wild-type mice. In contrast, administration of 3,4-methylenedioxymethamphetamine to homozygous superoxide dismutase transgenic mice caused no significant changes in antioxidant enzyme activities nor in lipid peroxidation. These results provide further substantiation of a role for oxygen-based radicals in 3,4-methylenedioxymethamphetamine-induced neurotoxicity. The present data also suggest that free radicals generated during 3,4-methylenedioxymethamphetamine administration may perturb antioxidant enzymes. Consequently, there might be further overproduction of free radicals with associated peroxidative damage to cell membranes and associated terminal degeneration.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice.

The present study was conducted to investigate the effects of methamphetamine (METH)-induced toxicity on brain cortical and striatal antioxidant defense systems. Because METH-induced toxicity is attenuated in copper/zinc-superoxide dismutase transgenic (Cu/Zn-SOD-Tg) mice, we sought to determine if METH had differential effect on antioxidant enzymes on these mice in comparison to non-Tg mice. METH (4 x 1) mg/kg) induced a significant decrease in Cu/Zn-SOD activity in the cortical region without altering striatal enzymatic activity in non-Tg mice; whereas homozygous SOD-Tg mice showed a significant increase in the striatum. In addition, METH caused decrease in catalase (CAT) activity in the striatum of non-Tg mice and significant increase in the cortex of homozygous SOD-Tg mice. METH also induced decreases in glutathione peroxidase (GSH-Px) in both cortical and striatal regions of non-Tg mice and in the striatum of heterozygous SOD-Tg mice. Lipid peroxidation was increased in both cortices and striata of non-Tg and heterozygous SOD-Tg, mice, whereas the homozygous SOD-Tg mice were not affected. These results are discussed in terms of their substantiation of a role for oxygen-based radicals in METH-induced toxicity in rodents.

Animals↗

PubMed1998

Effects of toxic doses of methamphetamine (METH) on dopamine D1 receptors in the mouse brain.

Methamphetamine (METH) is a drug of abuse that causes marked DA depletion in the mammalian dopaminergic systems. These are characterized by marked decreases in presynaptic markers including dopamine (DA) levels and DA transporters. Very little research has been carried out to evaluate possible postsynaptic effects of this drug. In the present study, we assessed the status of METH on striatal DA D1 receptors labeled with [3H]SCH23390 after toxic doses of METH that were shown to cause marked depletion of various markers of presynaptic DA systems in mice [J. Neurochem. 69 (1997) 780]. Our results show that these doses of METH caused 30% decrease in striatal DA D1 receptors. In contrast, p53 knockout mice that show protection against the toxic effects of METH show no significant decreases in DA D1 receptors. These results suggest that toxic doses of METH that cause loss of presynaptic DA markers might also affect postsynaptic elements. We discuss the possibility that these changes might be secondary to toxic effects of METH on intrinsic striatal cell bodies.

Animals↗

PubMed1998

Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species.

Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.

Animals↗

PubMed1997

Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice.

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked. decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar changes in both strains of mice. In contrast to METH, MDMA caused greater percentage decreases in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) caused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood-brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH into the brain.

Animals↗

PubMed1997

Comparison of measures of visual acuity in infants: Teller acuity cards and sweep visual evoked potentials.

PURPOSE: This study compares the development of acuity in the same infants during one testing session using Teller acuity cards (TAC) and sweep visual evoked potentials (sVEP). We asked whether different testing methods in two centers would produce different developmental time courses. METHODS: Forty-eight infants were tested in two centers. The standard procedure for TAC was used. For sVEP acuity, the amplitude response curve derived from time-locked cortical activity was used to extrapolate to zero response, giving an acuity estimate for each infant. RESULTS: sVEP acuity was generally higher than TAC acuity. The rate of development was steeper for TAC than sVEP acuity with TAC starting at a much lower level. The ratio of sVEP to TAC acuity decreased exponentially with age reaching an asymptote of about 1.44 at 6 months. CONCLUSIONS: Results were indistinguishable between centers suggesting that comparison of acuity measures obtained using variations of these methods across centers is possible.

Aging↗

PubMed1997

Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine.

Inhibition of dopamine (DA) transporter function is thought to be the principal mechanism underlying cocaine's addictive effects. In contrast to cocaine, several other inhibitors of DA transporter function are not considered to possess abuse liability. One of the neuroadaptive changes to chronic cocaine self-administration is the up-regulation of DA transporters. In the present study, we investigated the reinforcing and neuroadaptive effects of two other DA reuptake inhibitors, namely bupropion and nomifensine. Drug-naive rats readily acquired and subsequently maintained consistent self-administration of 3 and 1 mg/kg/infusion doses of bupropion and nomifensine, respectively, during 2-hr daily sessions over a prolonged period. Similarly, self-administration responding at low doses of bupropion (0.75 and 1.5 mg/kg/infusion) and nomifensine (0.1 and 0.3 mg/kg/infusion) showed some consistency during the initial weeks of testing which gradually declined or tended to decline to levels similar to that of the water control group during the later weeks of testing. Bupropion self-administration dose-dependently up-regulated DA transporters in caudate putamen and nucleus accumbens. In contrast, nomifensine self-administration did not alter DA transporter levels. These data provide evidence for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response.

Animals↗

PubMed1996

Differential reinforcing effects of cocaine and GBR-12909: biochemical evidence for divergent neuroadaptive changes in the mesolimbic dopaminergic system.

The dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure, in vitro autoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 +/- 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.

Adaptation, Physiological↗