Empirical mode decomposition of local field potential data from optogenetic experiments.

Introduction: This study investigated the effects of cocaine administration and parvalbumin-type interneuron stimulation on local field potentials (LFPs) recorded in vivo from the medial prefrontal cortex (mPFC) of six mice using optogenetic tools. Methods: The local network was subject to a brief 10 ms laser pulse, and the response was recorded for 2 s over 100 trials for each of the six subjects who showed stable coupling between the mPFC and the optrode. Due to the strong non-stationary and nonlinearity of the LFP, we used the adaptive, data-driven, Empirical Mode Decomposition (EMD) method to decompose the signal into orthogonal Intrinsic Mode Functions (IMFs). Results: Through trial and error, we found that seven is the optimum number of orthogonal IMFs that overlaps with known frequency bands of brain activity. We found that the Index of Orthogonality (IO) of IMF amplitudes was close to zero. The Index of Energy Conservation (IEC) for each decomposition was close to unity, as expected for orthogonal decompositions. We found that the power density distribution vs. frequency follows a power law with an average scaling exponent of ~1.4 over the entire range of IMF frequencies 2-2,000 Hz. Discussion: The scaling exponent is slightly smaller for cocaine than the control, suggesting that neural activity avalanches under cocaine have longer life spans and sizes.

Epigenetic function during heroin self-administration controls future relapse-associated behavior in a cell type-specific manner.

Opioid use produces enduring associations between drug reinforcement/euphoria and discreet or diffuse cues in the drug-taking environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OUD). Here, we sought to determine whether the epigenetic enzyme, histone deacetylase 5 (HDAC5), regulates relapse-associated behavior in an animal model of OUD. We examined the effects of nucleus accumbens (NAc) HDAC5 on both heroin- and sucrose-seeking behaviors using operant self-administration paradigms. We utilized cre-dependent viral-mediated approaches to investigate the cell-type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and medium spiny neuron (MSN) cell and synaptic physiology. We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. Moreover, overexpressing HDAC5 in the NAc suppressed context-associated and reinstated heroin-seeking behaviors, but it did not alter sucrose seeking. We also found that HDAC5 functions within dopamine D1 receptor-expressing MSNs to suppress cue-induced heroin seeking, and within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Assessing cell-type-specific transcriptomics, we found that HDAC5 reduced expression of multiple ion transport genes in both D1- and D2-MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes. These findings revealed roles for HDAC5 during active heroin use in both D1- and D2-MSNs to limit distinct triggers of drug-seeking behavior. Together, our results suggest that HDAC5 might limit relapse vulnerability through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.

Repeated methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic transmission in the prefrontal cortex.

Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.

Dopamine receptor antagonists effects on low-dimensional attractors of local field potentials in optogenetic mice.

The goal of this study was to investigate the effects of acute cocaine injection or dopamine (DA) receptor antagonists on the medial prefrontal cortex (mPFC) gamma oscillations and their relationship to short term neuroadaptation that may mediate addiction. For this purpose, optogenetically evoked local field potentials (LFPs) in response to a brief 10 ms laser light pulse were recorded from 17 mice. D1-like receptor antagonist SCH 23390 or D2-like receptor antagonist sulpiride, or both, were administered either before or after cocaine. A Euclidian distance-based dendrogram classifier separated the 100 trials for each animal in disjoint clusters. When baseline and DA receptor antagonists trials were combined in a single trial, a minimum of 20% overlap occurred in some dendrogram clusters, which suggests a possible common, invariant, dynamic mechanism shared by both baseline and DA receptor antagonists data. The delay-embedding method of neural activity reconstruction was performed using the correlation time and mutual information to determine the lag/correlation time of LFPs and false nearest neighbors to determine the embedding dimension. We found that DA receptor antagonists applied before cocaine cancels out the effect of cocaine and leaves the lag time distributions at baseline values. On the other hand, cocaine applied after DA receptor antagonists shifts the lag time distributions to longer durations, i.e. increase the correlation time of LFPs. Fourier analysis showed that a reasonable accurate decomposition of the LFP data can be obtained with a relatively small (less than ten) Fourier coefficients.

Methamphetamine Self-Administration Elicits Sex-Related Changes in Postsynaptic Glutamate Transmission in the Prefrontal Cortex.

Preclinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge, we recorded from the prelimbic area of the prefrontal cortex (PL-PFC) of male and female rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during SA; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDA receptors (NMDAR) in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.

Cocaine-Induced Changes in Low-Dimensional Attractors of Local Field Potentials in Optogenetic Mice.

Optogenetically evoked local field potential (LFP) recorded from the medial prefrontal cortex (mPFC) of mice during basal conditions and following a systemic cocaine administration were analyzed. Blue light stimuli were delivered to mPFC through a fiber optic every 2 s and each trial was repeated 100 times. As in the previous study, we used a surrogate data method to check that nonlinearity was present in the experimental LFPs and only used the last 1.5 s of steady activity to measure the LFPs phase resetting induced by the brief 10 ms light stimulus. We found that the steady dynamics of the mPFC in response to light stimuli could be reconstructed in a three-dimensional phase space with topologically similar "8"-shaped attractors across different animals. Therefore, cocaine did not change the complexity of the recorded nonlinear data compared to the control case. The phase space of the reconstructed attractor is determined by the LFP time series and its temporally shifted versions by a multiple of some lag time. We also compared the change in the attractor shape between cocaine-injected and control using (1) dendrogram clustering and (2) Frechet distance. We found about 20% overlap between control and cocaine trials when classified using dendrogram method, which suggest that it may be possible to describe mathematically both data sets with the same model and slightly different model parameters. We also found that the lag times are about three times shorter for cocaine trials compared to control. As a result, although the phase space trajectories for control and cocaine may look similar, their dynamics is significantly different.

Abstinence from Cocaine-Induced Conditioned Place Preference Produces Discrete Changes in Glutamatergic Synapses onto Deep Layer 5/6 Neurons from Prelimbic and Infralimbic Cortices.

Glutamatergic signaling in the medial prefrontal cortex (mPFC) plays a critical role in drug addiction and relapse. The mPFC is functionally subdivided into dorsal (prelimbic, PL) and ventral (infralimbic, IL) regions, and evidence suggests a differential role of these two divisions in the control of drug seeking and taking; however, there is a dearth of information on the cocaine-induced adaptations in PL- and IL-mPFC synaptic glutamate transmission and their regulation of behavioral responses to cocaine-associated stimuli. We tested male rats in a cocaine-induced conditioned place preference (CPP) paradigm. In vitro whole-cell recordings were performed at different abstinence intervals to investigate the neuroadaptations in synaptic glutamate transmission in PL- and IL-mPFC deep layer (5/6) pyramidal neurons. Our results show that in naïve animals, PL-mPFC neurons expressed higher frequency of spontaneous events (sEPSCs) than IL-mPFC neurons. Following cocaine-CPP and a short abstinence (SA) period (8 d), we observed decreases in the amplitude of sEPSCs in both mPFC regions. Longer abstinence periods (30 d), resulted in a sustained decrease in the frequency of sEPSCs and an increase in AMPA receptor rectification only in PL-mPFC neurons. In addition, PL-mPFC neurons expressed a decrease in the area under the curve of sEPSCs, suggesting altered receptor activation dynamics. Synaptic glutamate transmission was not significantly different between retested and naïve rats. These results suggest that retention of cocaine-CPP requires differential modulation of glutamate transmission between PL- and IL-mPFC neurons and that these adaptations are dependent on the abstinence interval and reexposure to the cocaine context.

Methamphetamine self-administration modulates glutamate neurophysiology.

World-wide methamphetamine (meth) use is increasing at a rapid rate; therefore, it has become increasingly important to understand the synaptic changes and neural mechanisms affected by drug exposure. In rodents, 6-h access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. There is a dearth of knowledge regarding the underlying physiological changes within this circuit following meth self-administration. We assessed pre- and postsynaptic changes in glutamate transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following daily 6-h meth self-administration. In the mPFC, meth caused postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the NAc, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. These changes in mPFC synapses and NAc activity begin to characterize the impact of meth on the corticostriatal circuitry.

Low-dimensional attractor for neural activity from local field potentials in optogenetic mice.

We used optogenetic mice to investigate possible nonlinear responses of the medial prefrontal cortex (mPFC) local network to light stimuli delivered by a 473 nm laser through a fiber optics. Every 2 s, a brief 10 ms light pulse was applied and the local field potentials (LFPs) were recorded with a 10 kHz sampling rate. The experiment was repeated 100 times and we only retained and analyzed data from six animals that showed stable and repeatable response to optical stimulations. The presence of nonlinearity in our data was checked using the null hypothesis that the data were linearly correlated in the temporal domain, but were random otherwise. For each trail, 100 surrogate data sets were generated and both time reversal asymmetry and false nearest neighbor (FNN) were used as discriminating statistics for the null hypothesis. We found that nonlinearity is present in all LFP data. The first 0.5 s of each 2 s LFP recording were dominated by the transient response of the networks. For each trial, we used the last 1.5 s of steady activity to measure the phase resetting induced by the brief 10 ms light stimulus. After correcting the LFPs for the effect of phase resetting, additional preprocessing was carried out using dendrograms to identify "similar" groups among LFP trials. We found that the steady dynamics of mPFC in response to light stimuli could be reconstructed in a three-dimensional phase space with topologically similar "8"-shaped attractors across different animals. Our results also open the possibility of designing a low-dimensional model for optical stimulation of the mPFC local network.

Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.

Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 µM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia.

Optogenetically evoked gamma oscillations are disturbed by cocaine administration.

Drugs of abuse have enormous societal impact by degrading the cognitive abilities, emotional state and social behavior of addicted individuals. Among other events involved in the addiction cycle, the study of a single exposure to cocaine, and the contribution of the effects of that event to the continuous and further use of drugs of abuse are fundamental. Gamma oscillations are thought to be important neural correlates of cognitive processing in the prefrontal cortex (PFC) which include decision making, set shifting and working memory. It follows that cocaine exposure might modulate gamma oscillations, which could result in reduced cognitive ability. Parvalbumin-positive fast-spiking interneurons play an orchestrating role in gamma oscillation induction and it has been shown recently that gamma oscillations can be induced in an anesthetized animal using optogenetic techniques. We use a knock-in mouse model together with optogenetics and in vivo electrophysiology to study the effects of acute cocaine on PFC gamma oscillation as a step toward understanding the cortical changes that may underlie continuous use of stimulants. Our results show that acute cocaine administration increases entrainment of the gamma oscillation to the optogentically induced driving frequency. Our results also suggest that this modulation of gamma oscillations is driven trough activation of D1 receptors. The acute cocaine-mediated changes in mPFC may underlie the enhancement of attention and awareness commonly reported by cocaine users and may contribute to the further use and abuse of psychostimulants.

Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice.

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein encoded by DTNBP1, dysbindin-1, is expressed in forebrain neurons where it interacts with proteins mediating vesicular trafficking and exocytosis. It has been shown that loss of dysbindin-1 results in a decrease in glutamate release in the prefrontal cortex; however the mechanisms underlying this decrease are not fully understood. In order to investigate this question, we evaluated dysbindin-1 null mutant mice, using electrophysiological recordings of prefrontal cortical neurons, imaging studies of vesicles, calcium dynamics and Western blot measures of synaptic proteins and Ca(2+) channels. Dysbindin-1 null mice showed a decrease in the ready releasable pool of synaptic vesicles, decreases in quantal size, decreases in the probability of release and deficits in the rate of endo- and exocytosis compared with wild-type controls. Moreover, the dysbindin-1 null mice show decreases in the [Ca(2+)]i,expression of L- and N-type Ca(2+)channels and several proteins involved in synaptic vesicle trafficking and priming. Our results provide new insights into the mechanisms of action of dysbindin-1.

Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance.

BACKGROUND: Schizophrenia is a heritable disorder associated with disrupted neural transmission and dysfunction of brain systems involved in higher cognition. The gene encoding dystrobrevin-binding-protein-1 (dysbindin) is a putative candidate gene associated with cognitive impairments, including memory deficits, in both schizophrenia patients and unaffected individuals. The underlying mechanism is thought to be based in changes in glutamatergic and dopaminergic function within the corticostriatal networks known to be critical for schizophrenia. This hypothesis derives support from studies of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and excitatory neurotransmission abnormalities in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate presynaptic glutamatergic transmission. METHODS: We investigated the relationship between glutamate receptor dynamics and memory performance in dysbindin mutant mice. We assessed N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor function in prefrontal cortex pyramidal neurons in vitro with whole-cell recordings, molecular quantitative analyses (reverse transcription-polymerase chain reaction) of the mandatory NMDA receptor subunit NR1, and cognitive function with a spatial working memory task. RESULTS: Decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in NR1 expression. Furthermore, the degree of NR1 expression correlates with spatial working memory performance, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression. CONCLUSIONS: These data show a significant downregulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with schizophrenia.

Methamphetamine self-administration produces attentional set-shifting deficits and alters prefrontal cortical neurophysiology in rats.

BACKGROUND: Chronic methamphetamine abusers exhibit deficits in tasks requiring intact prefrontal cortex function, and prefrontal cortex dysfunction has been implicated in the loss of control over drug use. This study used a combination of behavioral and electrophysiologic assessments in rats with a history of long access methamphetamine self-administration to determine methamphetamine-induced changes in prefrontal cortex-dependent attentional set-shifting performance, drug-seeking, and prefrontal cortex neuronal activity. METHODS: Male Long-Evans rats self-administered methamphetamine (.02 mg/infusion, intravenous) or received yoked saline infusions for 6 hours a day for 14 days. Cognitive flexibility was assessed using an attentional set-shifting task before 2 weeks of self-administration and 1 day after self-administration. Animals then underwent 11 days of abstinence, followed by three subsequent tests for context-induced drug seeking. Finally, animals were anesthetized, and single-unit in vivo extracellular recordings were performed in the dorsomedial prefrontal cortex. RESULTS: Methamphetamine-experienced rats showed escalated drug intake and context-induced drug-seeking following abstinence. During the extradimensional set-shift component, meth-experienced rats showed selective impairments that were identical to deficits produced by excitotoxic lesions of the prefrontal cortex. Rats with a history of chronic methamphetamine intake also exhibited higher basal firing frequency and a significantly greater proportion of burst-firing cells in the prefrontal cortex compared with yoked-saline controls. CONCLUSIONS: Prefrontal cortex-specific alterations in neuronal function may play a key role in methamphetamine-induced attentional deficits and drug-seeking. These data support the possibility that targeting prefrontal cortex pathology may improve treatment outcome in methamphetamine addiction.

Altered dopamine modulation of inhibition in the prefrontal cortex of cocaine-sensitized rats.

A functionally hypoactive prefrontal cortex (PFC) is thought to contribute to decreased cognitive inhibitory control over drug-seeking behavior in cocaine addicts. Alterations in PFC dopamine (DA) and γ-aminobutyric acid (GABA) transmission are involved in the development of behavioral sensitization to cocaine, and repeated exposure to cocaine decreases DA D2 receptor (D2R) function in the PFC. We used recordings in PFC slices from adult rats to investigate how repeated cocaine treatment followed by 2 weeks of withdrawal affects DA modulation of GABA transmission and interneuron firing. In agreement with previous results in drug-naïve animals we found that in saline-treated control animals DA (20 µM) modulated evoked inhibitory post-synaptic currents (eIPSCs) in a biphasic, time- and receptor-dependent manner. Activation of D2Rs transiently reduced, whereas D1 receptor activation persistently increased the amplitude of eIPSCs. In cocaine-sensitized animals the D2R-dependent modulation of eIPSCs was abolished and the time course of DA effects was altered. In both saline- and cocaine-treated animals the effects of DA on eIPSCs were paralleled by distinct changes in spontaneous IPSCs (sIPSCs). In cocaine-treated animals the alterations in DA modulation of eIPSCs and sIPSCs correlated with a lack of D2R-specific reduction in action potential-independent GABA release, which might normally oppose D1-dependent increases in GABA transmission. Recordings from interneurons furthermore show that D2R activation can increase current-evoked spike firing in saline, but not in cocaine-treated animals. Altered DA regulation of inhibition during cocaine withdrawal could disturb normal cortical processing and contribute to a hypoactive PFC.

Strong somatic stimulation differentially regulates the firing properties of prefrontal cortex neurons.

Among the brain structures involved in processing affective stimuli, the roles of the prefrontal cortex (PFC) and the mesocorticolimbic dopaminergic (DA) innervation are well established. In contrast to our understanding of the reward stimuli, less is known about how strong somatic stimulation is processed within the PFC. Here, we examined the effects of a strong pinch delivered to the rat posterior paw on spontaneous and current-evoked activity of PFC neurons using intracellular recordings in anesthetized rats. Following the paw pinch, pyramidal cells exhibited a significant decrease in spontaneous activity along with a significant increase in the current-evoked firing. The increase in current-evoked firing elicited by the paw pinch was inversely correlated with the baseline firing rate. Systemic administration of a selective dopamine D2 receptor antagonist partially blocked the effects elicited by the paw pinch on cortical excitability, whereas systemic administration of a D1 antagonist seems to facilitate paw-mediated increases in evoked firing. These results suggest that strong somatic stimuli decrease spontaneous firing while increasing depolarization-evoked firing in a DA receptor dependent manner. These mechanisms may help in the control of the signal to noise ratio or the salience of information processing in the PFC following strong somatic stimulation.

Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice.

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.

N-Acetylcysteine reverses cocaine-induced metaplasticity.

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

The ability of the mesocortical dopamine system to operate in distinct temporal modes.

BACKGROUND: This review discusses evidence that cells in the mesocortical dopamine (DA) system influence information processing in target areas across three distinct temporal domains. DISCUSSIONS: Phasic bursting of midbrain DA neurons may provide temporally precise information about the mismatch between expected and actual rewards (prediction errors) that has been hypothesized to serve as a learning signal in efferent regions. However, because DA acts as a relatively slow modulator of cortical neurotransmission, it is unclear whether DA can indeed act to precisely transmit prediction errors to prefrontal cortex (PFC). In light of recent physiological and anatomical evidence, we propose that corelease of glutamate from DA and/or non-DA neurons in the VTA could serve to transmit this temporally precise signal. In contrast, DA acts in a protracted manner to provide spatially and temporally diffuse modulation of PFC pyramidal neurons and interneurons. This modulation occurs first via a relatively rapid depolarization of fast-spiking interneurons that acts on the order of seconds. This is followed by a more protracted modulation of a variety of other ionic currents on timescales of minutes to hours, which may bias the manner in which cortical networks process information. However, the prolonged actions of DA may be curtailed by counteracting influences, which likely include opposing actions at D1 and D2-like receptors that have been shown to be time- and concentration-dependent. In this way, the mesocortical DA system optimizes the characteristics of glutamate, GABA, and DA neurotransmission both within the midbrain and cortex to communicate temporally precise information and to modulate network activity patterns on prolonged timescales.

Long-term neuroadaptations produced by withdrawal from repeated cocaine treatment: role of dopaminergic receptors in modulating cortical excitability.

Dopamine (DA) modulates neuronal activity in the prefrontal cortex (PFC) and is necessary for optimal cognitive function. Dopamine transmission in the PFC is also important for the behavioral adaptations produced by repeated exposure to cocaine. Therefore, we investigated the effects of repeated cocaine treatment followed by withdrawal (2-4 weeks) on the responsivity of cortical cells to electrical stimulation of the ventral tegmental area (VTA) and to systemic administration of DA D1 or D2 receptor antagonists. Cortical cells in cocaine- and saline-treated animals exhibited a similar decrease in excitability after the administration of D1 receptor antagonists. In contrast, cortical neurons from cocaine-treated rats exhibited a lack of D2-mediated regulation relative to saline rats. Furthermore, in contrast to saline-treated animals, VTA stimulation did not increase cortical excitability in the cocaine group. These data suggest that withdrawal from repeated cocaine administration elicits some long-term neuroadaptations in the PFC, including (1) reduced D2-mediated regulation of cortical excitability, (2) reduced responsivity of cortical cells to phasic increases in DA, and (3) a trend toward an overall decrease in excitability of PFC neurons.