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Marina E Wolf

Publications and source records attributed to Marina E Wolf.

At least 19 recordsLinked to original sources
PubMed2006

Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons.

Considerable evidence indicates that neuroadaptations leading to addiction involve the same cellular processes that enable learning and memory, such as long-term potentiation (LTP), and that psychostimulants influence LTP through dopamine (DA)-dependent mechanisms. In hippocampal CA1 pyramidal neurons, LTP involves insertion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors into excitatory synapses. We used dissociated cultures to test the hypothesis that D1 family DA receptors influence synaptic plasticity in hippocampal neurons by modulating AMPA receptor trafficking. Brief exposure (5 min) to a D1 agonist increased surface expression of glutamate receptor (GluR)1-containing AMPA receptors by increasing their rate of externalization at extrasynaptic sites. This required the secretory pathway but not protein synthesis, and was mediated mainly by protein kinase A (PKA) with a smaller contribution from Ca2+-calmodulin-dependent protein kinase II (CaMKII). Prior D1 receptor stimulation facilitated synaptic insertion of GluR1 in response to subsequent stimulation of synaptic NMDA receptors with glycine. Our results support a model for synaptic GluR1 incorporation in which PKA is required for initial insertion into the extrasynaptic membrane whereas CaMKII mediates translocation into the synapse. By increasing the size of the extrasynaptic GluR1 pool, D1 receptors may promote LTP. Psychostimulants may usurp this mechanism, leading to inappropriate plasticity that contributes to addiction-related behaviors.

Animals↗
PubMed2006

Repeated amphetamine administration decreases D1 dopamine receptor-mediated inhibition of voltage-gated sodium currents in the prefrontal cortex.

Adaptations in dopamine (DA) transmission in the prefrontal cortex (PFC) are thought to be critical to the development and persistence of drug addiction. Our previous findings showed that medial PFC (mPFC) neurons in rats treated repeatedly with amphetamine exhibit a decreased inhibitory response to iontophoretically applied DA, demonstrating altered DA receptor transmission. To determine the role postsynaptic DA D1 receptors play in this effect, we used whole-cell patch-clamp recordings of acutely dissociated pyramidal mPFC neurons and inhibition of transient voltage-sensitive sodium current (INaT) as a measure of D1 receptor function. After 3 d of withdrawal, neurons recorded from amphetamine-treated rats (5 mg/kg for 5 d) demonstrated a significant decrease in whole-cell INaT density and in the ability of D1 receptor stimulation to inhibit INaT. Application of a protein kinase A (PKA) inhibitor blocked the ability of D1 receptor activation to inhibit INaT and increased the current density of both groups to similar values. These results suggest that repeated amphetamine exposure results in subsensitivity of the INaT to D1 receptor-mediated inhibition because of a possible increase in basal PKA activity. This adaptation may contribute to perseverative behaviors in animals that self-administer psychostimulants as well as compromised PFC-dependent behaviors in human addicts.

Amphetamine↗
PubMed2005

Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens.

Regulation of AMPA receptor trafficking is important for many forms of neuronal plasticity. In this study, a protein cross-linking assay was used to evaluate the contribution of AMPA receptor trafficking to plasticity associated with behavioral sensitization, an animal model of drug addiction. Cross-linking was used to distinguish between cell surface and intracellular AMPA receptors in nucleus accumbens (NAc) tissue obtained from rats treated repeatedly with saline or cocaine. Surface/intracellular (S/I) ratios for glutamate receptor 1 (GluR1) and GluR2/3 subunits were increased 21 d after the last injection in cocaine-sensitized rats but not rats that failed to sensitize, and the magnitude of the S/I ratio for cocaine-sensitized rats was positively correlated with the magnitude of behavioral sensitization. At the 1 d withdrawal time, cocaine did not alter S/I ratios, and there was no correlation between S/I ratios and behavioral sensitization. The majority of surface-expressed GluR1 detected with this assay was associated with synapses, based on coimmunoprecipitation with postsynaptic density protein of 95 kDa. These findings suggest that behavioral sensitization to cocaine is associated with a slowly developing redistribution of AMPA receptors to the surface of NAc neurons. Motor execution of drug-seeking responses depends on activation of AMPA receptors on NAc neurons by glutamate afferents originating in cortical and limbic regions. We propose that drug-seeking responses are more effectively triggered in cocaine-sensitized rats because of increased cell surface expression of AMPA receptors.

Analysis of Variance↗
PubMed2005

Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons.

Addiction is believed to involve glutamate-dependent forms of synaptic plasticity that promote the formation of new habits focused on drug seeking. We used primary cultures of rat prefrontal cortex (PFC) neurons to explore mechanisms by which dopamine-releasing psychomotor stimulants such as cocaine and amphetamine influence synaptic plasticity, focusing on AMPA receptor trafficking because of its key role in long-term potentiation (LTP). Brief stimulation of D1 dopamine receptors increased surface expression of glutamate receptor 1 (GluR1)-containing AMPA receptors through a protein kinase A-dependent mechanism, by increasing their rate of externalization at extrasynaptic sites. Newly externalized GluR1 remained extrasynaptic under basal conditions but could be translocated into synapses by subsequent NMDA receptor activation. These results suggest that D1 receptors may facilitate LTP by increasing the AMPA receptor pool available for synaptic insertion. However, stimulation of D2 receptors decreased surface and synaptic GluR1 expression. These findings are discussed in the context of evidence that D1 and D2 receptors act independently rather than antagonistically in the intact PFC. D1 receptor facilitation of AMPA receptor synaptic insertion helps explain D1 receptor-dependent facilitation of LTP and learning in the normal brain. Abnormal engagement of this mechanism during unregulated dopamine release may account for maladaptive plasticity after repeated exposure to cocaine or amphetamine.

Animals↗
PubMed2004

Psychomotor stimulants and neuronal plasticity.

Considerable evidence suggests that neuroadaptations leading to addiction involve the same glutamate-dependent cellular mechanisms that enable learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) have therefore become an important focus of addiction research. This article reviews: (1) basic mechanisms underlying LTP and LTD, (2) the properties of LTP and LTD in ventral tegmental area, nucleus accumbens, dorsal striatum and prefrontal cortex, (3) studies demonstrating that psychomotor stimulants influence LTP or LTD in these brain regions. In addition, we discuss our recent work on cellular mechanisms by which dopamine may influence LTP and LTD. Based on evidence that AMPA receptors are inserted into synapses during LTP and removed during LTD, we investigated the effects of D1 receptor stimulation on AMPA receptor trafficking using primary cultures prepared from nucleus accumbens and prefrontal cortex. Our results suggest that activation of the D1 receptor-protein kinase A signaling pathway leads to externalization of AMPA receptors and promotes LTP. This provides a mechanism to explain facilitation of reward-related learning by dopamine. When this mechanism is activated in an unregulated manner by psychostimulants, maladaptive forms of neuroplasticity may occur that contribute to the transition from casual to compulsive drug use.

Animals↗
PubMed2004

D1 dopamine receptor stimulation increases the rate of AMPA receptor insertion onto the surface of cultured nucleus accumbens neurons through a pathway dependent on protein kinase A.

Trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors is an important determinant of synaptic strength. Our prior work suggests that D1 dopamine (DA) receptors regulate AMPA receptor trafficking. This is a possible mechanism by which amphetamine and cocaine, which indirectly stimulate D1 receptors, may alter synaptic strength in addiction-related neuronal circuits. Post-natal rat nucleus accumbens (NAc) cultures were used to study the role of protein kinase A (PKA) in D1 receptor regulation of the surface expression of the AMPA receptor subunit GluR1. Using an immunocytochemical assay that selectively detects newly externalized GluR1, we found that the rate of GluR1 externalization is enhanced by the D1 agonist SKF 81297 (100 nm-1 microm). This was blocked by a D1 receptor antagonist (SCH 23390; 10 microm) and by two different cell-permeable PKA inhibitors, KT5720 (2 and 10 microm) and RpcAMPS (10 microm). Conversely, the PKA activator SpcAMPS increased the rate of GluR1 externalization in a concentration-dependent manner. A maximally effective concentration of SpcAMPS (10 microm) occluded the effect of SKF 81297 (1 microm) on GluR1 externalization. Using similar cultures, we showed previously that D1 receptor stimulation increases GluR1 phosphorylation at the PKA site. Together, our findings suggest that PKA phosphorylation of GluR1 is required for GluR1 externalization in response to D1 receptor stimulation.

Animals↗
PubMed2004

Stimulation of N-methyl-D-aspartate receptors, AMPA receptors or metabotropic glutamate receptors leads to rapid internalization of AMPA receptors in cultured nucleus accumbens neurons.

In hippocampus and other regions, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are inserted into synapses during long-term potentiation and removed during long-term depression. However, little is known about regulation of AMPA receptor trafficking in the nucleus accumbens (NAc), despite growing evidence that glutamate-dependent forms of plasticity in the NAc contribute to drug addiction. Using postnatal rat NAc cultures and an immunocytochemical method that selectively detects newly internalized GluR1, we studied the regulation of AMPA receptor internalization in NAc neurons by glutamate agonists. Newly internalized GluR1 was detected during 15 or 30 min of incubation at room temperature, indicating a basal rate of GluR1 turnover. The rate of GluR1 internalization was increased by glutamate (50 microM) within 5 min of its addition. Glutamate-induced GluR1 internalization was partially blocked by either an AMPA receptor antagonist (CNQX; 20 microM) or an N-methyl-D-aspartate (NMDA) receptor antagonist (APV; 50 microM). Both NMDA (50 microM) and AMPA (50 microM) increased GluR1 internalization in a Ca(2+)-dependent manner. The NMDA effect was blocked by APV while the AMPA effect was blocked by APV or CNQX. We interpret these findings to suggest that NMDA and AMPA ultimately trigger GluR1 internalization through the same NMDA receptor-dependent pathway. The effect of glutamate was also partially blocked by the group 1 metabotropic glutamate receptor antagonist N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 50 microM), while the group 1 agonist 3,5-dihydroxyphenylglycine (DHPG; 50 microM) stimulated GluR1 internalization. These data suggest that AMPA receptors on NAc neurons may be subject to rapid regulation of their surface expression in response to changes in the activity of glutamate inputs from cortical and limbic regions.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2003

Impaired DRL 30 performance during amphetamine withdrawal.

Repeated administration of psychomotor stimulants may produce an impulsive state that could contribute to the cycle of drug abstinence and relapse seen in human drug addicts. We have previously reported that the inhibitory effects of dopamine (DA) on the firing rate of medial prefrontal cortex (mPFC) neurons were reduced in rats after repeated amphetamine treatment suggesting impaired mPFC DA function. Here, we used a differential reinforcement of low rates of responding (DRL) operant conditioning task, which is dependent on mPFC DA, to test impulsivity and inhibitory control. Food-restricted rats were trained to inhibit a nose poke response for 30s before a subsequent nose poke would result in a food reward (DRL 30). Once training was completed, rats received 5 days of no treatment, daily i.p. saline injections or daily i.p. injections of 5mg/kg amphetamine. Nine days of DRL 30 test performance began following a 3-day withdrawal from treatment. The percent of training active hole nose pokes was significantly increased and the percent of training efficiency was significantly decreased in rats withdrawn from repeated amphetamine administration as compared to saline or nai;ve rats. This suggests that impulsivity is increased during amphetamine withdrawal, which we hypothesize is associated with disrupted DA function in the mPFC.

Animals↗
PubMed2003

LTP may trigger addiction.

Differing classes of abused drugs utilize different mechanisms of molecular pharmacological action yet the overuse of these same drugs frequently leads to the same outcome: addiction. Similarly, episodes of stress can lead to drug-seeking behaviors and relapse in recovering addicts. To overcome the labor-intensive headache of having to design a specific addiction-breaking intervention tailored to each drug it would be expedient to attack the cycle of addiction at targets common to such seemingly disparate classes of drugs of abuse. Recently, encouraging observations were made whereby stressful conditions and differing classes of drugs of abuse were found to impinge upon the same excitatory synapses on dopamine neurons in the midbrain. These findings will increase our understanding of the intricacies of addiction and LTP, and may lead to new interventions for breaking addiction.

Animals↗
PubMed2003

Mechanisms by which dopamine receptors may influence synaptic plasticity.

While dopamine (DA) receptors mediate acute effects of amphetamine and cocaine, chronic drug administration produces many glutamate-dependent adaptations, including LTP in reward-related neuronal circuits. An important question presents itself: How do DA receptors influence glutamate-dependent synaptic plasticity? Alterations in AMPA receptor phosphorylation and trafficking are critical for LTP. We hypothesize that D1 DA receptors modulate these processes, that chronic drug-induced adaptations in D1 receptor signaling, therefore, trigger compensatory changes in AMPA receptor function, and that this ultimately contributes to inappropriate plasticity in addiction-related neuronal circuits. Postnatal rat nucleus accumbens (NAc) cultures were used to study D1 receptor regulation of the AMPA receptor subunit GluR1. We found that D1 receptor stimulation enhances phosphorylation of GluR1 at the protein kinase A (PKA) site. Furthermore, D1 receptor stimulation increases GluR1 surface expression by increasing the rate of GluR1 externalization. The latter effect is prevented by the PKA inhibitors KT5720 and RpcAMPS, whereas the PKA activator SpcAMPS increases the rate of GluR1 externalization. These findings indicate that PKA phosphorylation is important in determining AMPA receptor surface expression and suggest a mechanism by which DA-releasing drugs of abuse may directly tap into fundamental mechanisms that enable synaptic plasticity. A limitation of our current model is that there are no intrinsic glutamate neurons in the NAc and thus no glutamate synapses in NAc cultures. To address this problem, we have restored excitatory synaptic inputs to NAc neurons by co-culturing them with prefrontal cortex (PFC) neurons. We are also studying GluR1 trafficking in PFC cultures. In both systems, synaptic AMPA receptors can be defined based on colocalization of GluR1 and the synaptic marker synaptobrevin. Preliminary results suggest that D1 receptor stimulation or PKA activation leads to increased surface GluR1 expression in PFC neurons but not to insertion into synaptic sites.

Animals↗
PubMed2002

Extracellular glutamate levels in prefrontal cortex during the expression of associative responses to cocaine related stimuli.

We conducted studies to examine the potential role of glutamate in the prefrontal cortex (PFC) during conditioned responses to stimuli (flashing light and metronome) previously associated with cocaine administration. During training, PAIRED subjects received cocaine injections (15 mg/kg) during stimuli sessions while UNPAIRED subjects received saline injections (but received cocaine in the home cage an hour later). We showed previously that PAIRED subjects exhibit conditioned locomotion when tested with the stimuli alone. In this study, we further demonstrated that the expression of behavioral sensitization in response to cocaine challenge is under conditioned control in PAIRED subjects. Then, we used microdialysis to examine extracellular levels of glutamate in the PFC in response to presentation of the conditioned stimuli alone and challenge with cocaine in the presence of the conditioned stimuli. Although PAIRED subjects demonstrated conditioned locomotion and conditioned control of sensitization during the microdialysis experiment, PFC glutamate levels were unaltered during the tests and did not differ between the PAIRED and UNPAIRED subjects.

Acoustic Stimulation↗
PubMed2002

Repeated administration of amphetamine or cocaine does not alter AMPA receptor subunit expression in the rat midbrain.

We previously reported that ventral tegmental area (VTA) dopamine neurons are supersensitive to AMPA when recorded three days after discontinuing repeated amphetamine or cocaine administration. By increasing dopamine cell activity, this may contribute to the induction of behavioral sensitization. The goal of this study was to determine if increased sensitivity to AMPA reflects increased AMPA receptor expression in the midbrain. Immunolabeling for GluR1, GluR2, GluR2/3, and GluR4 was quantified by immunohistochemistry with 35S-labeled secondary antibodies in VTA, substantia nigra, and a transitional area. First, rats were treated for five days with saline or amphetamine (5 mg/kg) and killed three or 14 days after the last injection. No significant changes in immunolabeling were observed for any subunit at either withdrawal time. GluR1 immunolabeling was further examined in rats killed 16-18 hrs or 24 hrs after a single injection of amphetamine or repeated injections of saline, amphetamine (5 mg/kg x 5 days) or cocaine (20 mg/kg x 7 days). No significant differences were observed in any region. Finally, neither repeated amphetamine or cocaine administration significantly altered GluR1 mRNA levels as quantified by reverse transcriptase-polymerase chain reaction. Our results suggest that enhanced responsiveness of VTA dopamine neurons to AMPA after withdrawal from repeated stimulant administration involves mechanisms more complex than increased expression of AMPA receptor subunits.

Amphetamine↗
PubMed2002

Conditioned locomotion is not correlated with behavioral sensitization to cocaine: an intra-laboratory multi-sample analysis.

Pre-clinical and clinical studies have demonstrated the importance of associative factors in regulating craving for drugs of abuse. To model these conditioned effects, we have examine cue-induced conditioned locomotion in rodents. The present study involved analysis of several of our prior studies to evaluate the relationship between conditioned locomotion and behavioral sensitization using a within-subjects analysis. Both are animal models used to study addiction, so it is important to know if one is predictive of the other, and more generally, if drug effects are predictive of conditioned effects. In all of our studies, Paired subjects received cocaine during presentation of conditioned stimuli while Unpaired subjects received saline with the stimuli and cocaine at the home cages an hour later. Paired subjects typically displayed behavioral sensitization over the course of training. After the completion of training, all subjects were tested with the conditioned stimuli in the absence of drug and conditioned locomotion was measured. The response of Unpaired subjects on the last training day was positively correlated with their response on test day, as expected since both days were nearly identical (stimuli presented without cocaine). However, for Paired subjects, the magnitude of conditioned locomotion on the drug-free test day was not positively correlated with the magnitude of behavioral sensitization. These results underscore the importance of focusing research on drug-free conditioned behaviors when attempting to model conditioned responses to drug related cues in human addicts.

Animals↗
PubMed2002

D(1) dopamine receptor stimulation increases GluR1 phosphorylation in postnatal nucleus accumbens cultures.

Postsynaptic interactions between dopamine and glutamate receptors in the nucleus accumbens are critical for acute responses to drugs of abuse and for neuroadaptations resulting from their chronic administration. We tested the hypothesis that D(1) dopamine receptor stimulation increases phosphorylation of the AMPA receptor subunit GluR1 at the protein kinase A phosphorylation site (Ser845). Nucleus accumbens cell cultures were prepared from postnatal day 1 rats. After 14 days in culture, GluR1 phosphorylation was measured by western blotting using phosphorylation site-specific antibodies. The D(1) receptor agonist SKF 81297 increased Ser845 phosphorylation in a concentration- dependent manner, with marked increases occurring within 5 min. This was prevented by the D(1) receptor antagonist SCH 23390 and the protein kinase A inhibitor H89, and reproduced by forskolin. The D(2) receptor agonist quinpirole attenuated the response to D(1) receptor stimulation. Neither D(1) nor D(2) receptor agonists altered GluR1 phosphorylation at Ser831, the site phosphorylated by protein kinase C and calcium/calmodulin-dependent protein kinase II. In other systems, phosphorylation of GluR1 at Ser845 is associated with enhancement of AMPA receptor currents. Thus, the present results suggest that AMPA receptor transmission in the nucleus accumbens may be augmented by concurrent D(1) receptor stimulation.

Animals↗
PubMed2002

D1 dopamine receptor stimulation increases GluR1 surface expression in nucleus accumbens neurons.

The goal of this study was to understand how dopamine receptors, which are activated during psychostimulant administration, might influence glutamate-dependent forms of synaptic plasticity that are increasingly recognized as important to drug addiction. Regulation of the surface expression of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR1 plays a critical role in long-term potentiation, a well-characterized form of synaptic plasticity. Primary cultures of rat nucleus accumbens neurons were used to examine whether dopamine receptor stimulation influences cell surface expression of GluR1, detected using antibody to the extracellular portion of GluR1 and fluorescence microscopy. Surface GluR1 labeling on processes of medium spiny neurons and interneurons was increased by brief (5-15 min) incubation with a D1 agonist (1 microm SKF 81297). This effect was attenuated by the D1 receptor antagonist SCH 23390 (10 microm) and reproduced by the adenylyl cyclase activator forskolin (10 microm). Labeling was decreased by glutamate (10-50 microm, 15 min). These results are the first to demonstrate modulation of AMPA receptor surface expression by a non-glutamatergic G protein-coupled receptor. Normally, this may enable ongoing regulation of AMPA receptor transmission in response to changes in the activity of dopamine projections to the nucleus accumbens. When dopamine receptors are over-stimulated during chronic drug administration, this regulation may be disrupted, leading to inappropriate plasticity in neuronal circuits governing motivation and reward.

Animals↗