Do Peer Recovery Specialists Improve Outcomes for Individuals with Substance Use Disorder in an Integrative Primary Care Setting? A Program Evaluation.

Peer recovery specialists (PRSs) combine their personal experiences with substance use and recovery with clinical skills to support patients in treatment for or recovery from substance use. This paper provides evaluation findings from a SAMHSA-funded program that integrated a PRS team into a primary care clinic to assess the efficacy of PRS support on patients' substance use, healthcare involvement, and criminal justice involvement. PRSs provided a range of services to patients with histories of incarceration and substance use, including facilitating support groups, providing one-on-one individualized support, and navigating services. Data were collected from PRS-supported patients at intake, discharge, and 6 months post-intake. Results revealed reductions in the percentage of patients using substances in the past 30 days, decreased number of days using alcohol, increased engagement in more medical services after program enrollment, increased school enrollment, and increased rates of employment for PRS-supported patients.

Towards real-time topical detection and characterization of FDG dose infiltration prior to PET imaging.

PURPOSE: To dynamically detect and characterize 18F-fluorodeoxyglucose (FDG) dose infiltrations and evaluate their effects on positron emission tomography (PET) standardized uptake values (SUV) at the injection site and in control tissue. METHODS: Investigational gamma scintillation sensors were topically applied to patients with locally advanced breast cancer scheduled to undergo limited whole-body FDG-PET as part of an ongoing clinical study. Relative to the affected breast, sensors were placed on the contralateral injection arm and ipsilateral control arm during the resting uptake phase prior to each patient's PET scan. Time-activity curves (TACs) from the sensors were integrated at varying intervals (0-10, 0-20, 0-30, 0-40, and 30-40 min) post-FDG and the resulting areas under the curve (AUCs) were compared to SUVs obtained from PET. RESULTS: In cases of infiltration, observed in three sensor recordings (30 %), the injection arm TAC shape varied depending on the extent and severity of infiltration. In two of these cases, TAC characteristics suggested the infiltration was partially resolving prior to image acquisition, although it was still apparent on subsequent PET. Areas under the TAC 0-10 and 0-20 min post-FDG were significantly different in infiltrated versus non-infiltrated cases (Mann-Whitney, p < 0.05). When normalized to control, all TAC integration intervals from the injection arm were significantly correlated with SUVpeak and SUVmax measured over the infiltration site (Spearman ρ ≥ 0.77, p < 0.05). Receiver operating characteristic (ROC) analyses, testing the ability of the first 10 min of post-FDG sensor data to predict infiltration visibility on the ensuing PET, yielded an area under the ROC curve of 0.92. CONCLUSIONS: Topical sensors applied near the injection site provide dynamic information from the time of FDG administration through the uptake period and may be useful in detecting infiltrations regardless of PET image field of view. This dynamic information may also complement the static PET image to better characterize the true extent of infiltrations.

Optimization of 7-T chemical exchange saturation transfer parameters for validation of glycosaminoglycan and amide proton transfer of fibroglandular breast tissue.

PURPOSE: To (a) implement simulation-optimized chemical exchange saturation transfer (CEST) measurements sensitive to amide proton transfer (APT) and glycosaminoglycan (GAG) hydroxyl proton transfer effects in the human breast at 7 T and (b) determine the reliability of these techniques for evaluation of fibroglandular tissue in the healthy breast as a benchmark for future studies of pathologic findings. MATERIALS AND METHODS: All human studies were institutional review board approved, were HIPAA compliant, and included informed consent. The CEST parameters of saturation duration (25 msec) and amplitude (1 µT) were chosen on the basis of simulation-driven optimization for APT contrast enhancement with the CEST effect quantified by using residuals of a Lorentzian fit. Optimized parameters were implemented at 7 T in 10 healthy women in two separate examinations to evaluate the reliability of CEST magnetic resonance (MR) imaging measurements in the breast. CEST z-spectra were acquired over saturation offset frequencies ranging between ±40 ppm by using a quadrature unilateral breast coil. The imaging-repeat imaging reliability was assessed in terms of the intraclass correlation coefficient, which indicates the ratio of between-subject variation to total variation. RESULTS: Simulations were performed of the Bloch equations with chemical exchange-guided selection of optimal values for pulse duration and amplitude, 25 msec and 1 µT, respectively. Reliability was evaluated by using intraclass correlation coefficients (95% confidence intervals), with acceptable results: 0.963 (95% confidence interval: 0.852, 0.991) and 0.903 (95% confidence interval: 0.609, 0.976) for APT and GAG, respectively. CONCLUSION: Simulations were used to derive optimal CEST preparation parameters to elicit maximal CEST contrast enhancement in healthy fibroglandular breast tissue due to APT at 7 T. By using these parameters, reproducible values were obtained for both the amide and hydroxyl protons from CEST MR imaging at 7 T and are feasible in the human breast.

Rescue of dopamine transporter function in hypoinsulinemic rats by a D2 receptor-ERK-dependent mechanism.

The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.

Amide proton transfer imaging of the human breast at 7T: development and reproducibility.

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal), and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7T while mitigating these issues. Adequate signal-to-noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared with results obtained at 3T, the standard deviation of the measured APT effect was reduced by a factor of four at 7T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7T.

Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine.

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level-dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

Health Implications of Incarceration and Reentry on Returning Citizens: A Qualitative Examination of Black Men's Experiences in a Northeastern City.

While a great deal of research captures the lived experiences of Black men as they navigate through the criminal legal system and onto reentry, very little research is grounded in how those processes are directly connected to their health. Although some research argues that mass incarceration is a determinant of poor health, there is a lack of qualitative analyses from the perspective of Black men. Black men face distinct pathways that lead them into the criminal legal system, and these same pathways await them upon reentry. This study aims to examine the health implications associated with incarceration and reentry of Black men. While adopting a phenomenological approach alongside interviews, our findings show both race- and gender-specific outcomes for the men in our sample. For example, health and wellness appears to be a significant theme that governs their (in)ability to matriculate society. Moreover, their contact with the criminal legal system appears to exacerbate health concerns and hindrances toward reentry. Other themes include mental health and the role of masculinity. We conclude with implications on policy and future research.

Quantitative Comparison of Prone and Supine PERCIST Measurements in Breast Cancer.

Positron emission tomography (PET) is typically performed in the supine position. However, breast magnetic resonance imaging (MRI) is performed in prone, as this improves visibility of deep breast tissues. With the emergence of hybrid scanners that integrate molecular information from PET and functional information from MRI, it is of great interest to determine if the prognostic utility of prone PET is equivalent to supine. We compared PERCIST (PET Response Criteria in Solid Tumors) measurements between prone and supine FDG-PET in patients with breast cancer and the effect of orientation on predicting pathologic complete response (pCR). In total, 47 patients were enrolled and received up to 6 cycles of neoadjuvant therapy. Prone and supine FDG-PET were performed at baseline (t0 ; n = 46), after cycle 1 (t1 ; n = 1) or 2 (t2 ; n = 10), or after all neoadjuvant therapy (t3 ; n = 19). FDG uptake was quantified by maximum and peak standardized uptake value (SUV) with and without normalization to lean body mass; that is, SUVmax , SUVpeak , SULmax , and SULpeak . PERCIST measurements were performed for each paired baseline and post-treatment scan. Receiver operating characteristic analysis for the prediction of pCR was performed using logistic regression that included age and tumor size as covariates. SUV and SUL metrics were significantly different between orientation (P < .001), but were highly correlated (P > .98). Importantly, no differences were observed with the PERCIST measurements (P > .6). Overlapping 95% confidence intervals for the receiver operating characteristic analysis suggested no difference at predicting pCR. Therefore, prone and supine PERCIST in this data set were not statistically different.

Brief exposure to obesogenic diet disrupts brain dopamine networks.

OBJECTIVE: We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). METHODS: We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). RESULTS: We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. CONCLUSION: These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.

MR Imaging Biomarkers in Oncology Clinical Trials.

The authors discuss eight areas of quantitative MR imaging that are currently used (RECIST, DCE-MR imaging, DSC-MR imaging, diffusion MR imaging) in clinical trials or emerging (CEST, elastography, hyperpolarized MR imaging, multiparameter MR imaging) as promising techniques in diagnosing cancer and assessing or predicting response of cancer to therapy. Illustrative applications of the techniques in the clinical setting are summarized before describing the current limitations of the methods.

Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) has been implicated in the development of behavioral sensitization, which is the progressive enhancement of locomotor activity that occurs with repeated administration of psychostimulants. Previous data suggest that mPFC dopamine (DA) transmission may be attenuated in cocaine-sensitized animals, but the onset and duration of this effect have not been investigated. After recovery from stereotaxic surgeries, animals were given four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) and were subsequently challenged with saline or cocaine after 1, 7 or 30 d of withdrawal, on which days in vivo microdialysis of the mPFC was conducted simultaneously with monitoring of locomotor activity. Compared to acutely administered controls, the results in cocaine-pretreated animals were as follows: 1d of withdrawal was associated with a significant attenuation in cocaine-induced locomotion and mPFC DA overflow; after 7d, behavioral sensitization was accompanied by a significant attenuation in cocaine-induced elevations in mPFC DA levels; 30 d of withdrawal led to the expression of sensitized behaviors paralleled by an augmentation in cocaine-induced mPFC DA. These data suggest that repeated cocaine produces temporally distinct behavioral effects associated with alterations in mPFC DA responsiveness to cocaine that may be involved in the development of behavioral sensitization.

Effects of repeated inhalation of toluene on ionotropic GABA A and glutamate receptor subunit levels in rat brain.

Toluene is a commonly abused solvent found in many industrial and commercial products. The neurobiological effects of toluene remain unclear, but many of them, like those of ethanol, may be mediated by gamma-aminobutyric acid (GABA) and glutamate receptors. Chronic ethanol administration has been shown to alter levels of specific subunits for GABA type A (GABA(A)), N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. However, little is known about the effects of toluene on subunit levels of these receptors. To examine this, rats were exposed to toluene vapors (8000 ppm) or air for 10 days (30 min/day), and afterwards GABA(A) alpha1, NR1 and NR2B (NMDA) and GluR1 and GluR2/3 (AMPA) receptor subunit levels were determined in discrete brain regions of these animals by Western blotting. Toluene increased GABA(A) alpha1, NR1, NR2B and GluR2/3 subunits in the medial prefrontal cortex and decreased GABA(A) alpha1 and NR1 subunits in the substantia nigra compacta. Toluene inhalation produced modest increases in GABA(A) alpha1 subunits in the striatum, as well as slight decreases in this subunit in the ventral tegmental area. NR2B subunit levels were also slightly increased within the nucleus accumbens by toluene. These studies show that toluene differentially alters the levels of specific GABAergic and glutamatergic receptor subunits in a regionally selective manner.

Comparison of prone versus supine 18F-FDG-PET of locally advanced breast cancer: Phantom and preliminary clinical studies.

PURPOSE: Previous studies have demonstrated how imaging of the breast with patients lying prone using a supportive positioning device markedly facilitates longitudinal and/or multimodal image registration. In this contribution, the authors' primary objective was to determine if there are differences in the standardized uptake value (SUV) derived from [(18)F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in breast tumors imaged in the standard supine position and in the prone position using a specialized positioning device. METHODS: A custom positioning device was constructed to allow for breast scanning in the prone position. Rigid and nonrigid phantom studies evaluated differences in prone and supine PET. Clinical studies comprised 18F-FDG-PET of 34 patients with locally advanced breast cancer imaged in the prone position (with the custom support) followed by imaging in the supine position (without the support). Mean and maximum values (SUVpeak and SUVmax, respectively) were obtained from tumor regions-of-interest for both positions. Prone and supine SUV were linearly corrected to account for the differences in 18F-FDG uptake time. Correlation, Bland-Altman, and nonparametric analyses were performed on uptake time-corrected and uncorrected data. RESULTS: SUV from the rigid PET breast phantom imaged in the prone position with the support device was 1.9% lower than without the support device. In the nonrigid PET breast phantom, prone SUV with the support device was 5.0% lower than supine SUV without the support device. In patients, the median (range) difference in uptake time between prone and supine scans was 16.4 min (13.4-30.9 min), which was significantly-but not completely-reduced by the linear correction method. SUVpeak and SUVmax from prone versus supine scans were highly correlated, with concordance correlation coefficients of 0.91 and 0.90, respectively. Prone SUVpeak and SUVmax were significantly lower than supine in both original and uptake time-adjusted data across a range of index times (P < < 0.0001, Wilcoxon signed rank test). Before correcting for uptake time differences, Bland-Altman analyses revealed proportional bias between prone and supine measurements (SUVpeak and SUVmax) that increased with higher levels of FDG uptake. After uptake time correction, this bias was significantly reduced (P < 0.01). Significant prone-supine differences, with regard to the spatial distribution of lesions relative to isocenter, were observed between the two scan positions, but this was poorly correlated with the residual (uptake time-corrected) prone-supine SUVpeak difference (P = 0.78). CONCLUSIONS: Quantitative 18F-FDG-PET/CT of the breast in the prone position is not deleteriously affected by the support device but yields SUV that is consistently lower than those obtained in the standard supine position. SUV differences between scans arising from FDG uptake time differences can be substantially reduced, but not removed entirely, with the current correction method. SUV from the two scan orientations is quantitatively different and should not be assumed equivalent or interchangeable within the same subject. These findings have clinical relevance in that they underscore the importance of patient positioning while scanning as a clinical variable that must be accounted for with longitudinal PET measurement, for example, in the assessment of treatment response.

Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex.

Accumulating evidence suggests that dopamine (DA) uptake into mesocortical neurons may be regulated through mechanisms that are markedly different from those observed in nigrostriatal or mesoaccumbens systems. The current studies were conducted to develop a rapid and sensitive DA uptake assay in crude synaptosomes prepared from the medial prefrontal cortex (mPFC) of a single animal. Uptake of DA into the mPFC was saturable, linear with respect to protein concentration, time dependent, and sensitive to the effects of monoamine transport inhibitors. Saturation analysis revealed the K(m) and V(max) values for DA transport in the mPFC were approximately 60 nM and 6.5 pmol/min mg protein, respectively. A significant amount of DA uptake in the mPFC was more sensitive to inhibition by nisoxetine compared to GBR12909, fluoxetine (FLX), and cocaine (COC), suggesting the norepinephrine transporter (NET) plays an important role in the clearance of DA within this region. The described assay conditions would be useful in examining DA uptake within specific brain regions obtained from a single animal.

Longitudinal, intermodality registration of quantitative breast PET and MRI data acquired before and during neoadjuvant chemotherapy: preliminary results.

PURPOSE: The authors propose a method whereby serially acquired DCE-MRI, DW-MRI, and FDG-PET breast data sets can be spatially and temporally coregistered to enable the comparison of changes in parameter maps at the voxel level. METHODS: First, the authors aligned the PET and MR images at each time point rigidly and nonrigidly. To register the MR images longitudinally, the authors extended a nonrigid registration algorithm by including a tumor volume-preserving constraint in the cost function. After the PET images were aligned to the MR images at each time point, the authors then used the transformation obtained from the longitudinal registration of the MRI volumes to register the PET images longitudinally. The authors tested this approach on ten breast cancer patients by calculating a modified Dice similarity of tumor size between the PET and MR images as well as the bending energy and changes in the tumor volume after the application of the registration algorithm. RESULTS: The median of the modified Dice in the registered PET and DCE-MRI data was 0.92. For the longitudinal registration, the median tumor volume change was -0.03% for the constrained algorithm, compared to -32.16% for the unconstrained registration algorithms (p = 8 × 10(-6)). The medians of the bending energy were 0.0092 and 0.0001 for the unconstrained and constrained algorithms, respectively (p = 2.84 × 10(-7)). CONCLUSIONS: The results indicate that the proposed method can accurately spatially align DCE-MRI, DW-MRI, and FDG-PET breast images acquired at different time points during therapy while preventing the tumor from being substantially distorted or compressed.

Chronic exposure to manganese alters brain responses to amphetamine: a pharmacological magnetic resonance imaging study.

The parkinsonian symptoms and increased Mn accumulation in dopaminergic (DAergic) neurons of the basal ganglia implicate impaired dopamine signaling in the neurotoxic effects of chronic manganese overexposure. Using blood oxygenation level-dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), we mapped brain responses to acute amphetamine (AMPH; 3 mg/kg, ip), which stimulates midbrain DAergic systems, in male Sprague-Dawley rats following 6 weeks of chronic MnCl(2) (5 mg Mn/kg, one per week, iv) or saline treatment. Plasma Mn content, measured immediately following phMRI, was elevated twofold in Mn-treated animals (p < 0.05), but the twofold increase in mean striatal Mn content did not reach significance. In saline-treated animals, AMPH stimulated robust positive BOLD responses throughout the basal ganglia and their reciprocally innervated connections. In contrast, acute AMPH stimulated a negative BOLD response in many of these structures in the Mn-treated group, resulting in significant differences between saline- and Mn-treated AMPH-evoked BOLD responses within caudate putamen, globus pallidus, substantia nigra, mediodorsal thalamic nucleus, and somatosensory cortex. These results demonstrate the utility of AMPH-evoked phMRI as readout of the DAergic signaling in vivo and confirm the vulnerability of DAergic systems to Mn.

Effects of repeated cocaine on the release and clearance of dopamine within the rat medial prefrontal cortex.

Previous data suggest that cocaine-induced dopamine (DA) transmission within the medial prefrontal cortex (mPFC) undergoes time-dependent changes during withdrawal from repeated cocaine administration. The current studies assessed two potential mechanisms that may underlie this neuroadaptation. One set of experiments examined alterations in DA clearance in the mPFC of rats that had been pretreated with four administrations of cocaine (15 mg/kg, i.p.; once per day for 4 days) and were withdrawn 1, 7, or 30 days. No significant changes in mPFC DA uptake into crude mPFC synaptosomes or in mPFC DA transporter levels were observed at any of the time points examined. Uptake assay and Western blotting sensitivity was confirmed with prefrontal 6-hydroxydopamine lesions, which significantly reduced [3H]DA uptake and DA transporter immunoreactivity in mPFC synaptosomes. To evaluate temporal changes in DA release resulting from repeated cocaine, additional experiments utilized in vivo microdialysis to locally infuse KCl (10, 30, or 100 mM) into the mPFC over the same withdrawal time course used in the uptake studies. After 1-7 days of withdrawal, KCl-stimulated DA release was significantly reduced in the mPFC of cocaine-pretreated animals. However, after 30 days of withdrawal the evoked release of DA in the mPFC of saline- and cocaine-pretreated animals was similar. These data suggest that previously reported modulation of cocaine-induced mPFC DA transmission occurring upon withdrawal from repeated cocaine might arise from transient changes in DA releasability rather than clearance. The relevance of these findings is discussed in relation to mPFC involvement in psychostimulant sensitization.

Site-specific polymer attachment to a CCL-5 (RANTES) analogue by oxime exchange.

A synthetic strategy that allows for the site-specific attachment of polymers such as poly(ethylene glycol) (PEG) to protein pharmaceuticals is described. PEG was attached to a 67-amino acid fully synthetic CCL-5 (RANTES) analogue at its GAG binding site both to reduce aggregation and to increase the circulating lifetime. Effective protection of an Aoaa chemoselective linker during peptide assembly, total chemical protein synthesis, and protein folding was achieved with an isopropylidene group. Mild deprotection of the resulting folded synthetic protein and subsequent polymer attachment occur without interference with the native folded structure and activity.

Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study.

Excitatory amino acid transmission within mesocorticolimbic brain pathways is thought to play an important role in behavioural sensitization to psychomotor stimulants. The current studies evaluated a time course of the effects of cocaine on extracellular glutamate levels within the medial prefrontal cortex (mPFC) following increasing periods of withdrawal from repeated cocaine exposure. Male Sprague-Dawley rats underwent stereotaxic surgeries and were pretreated daily with saline (1 mL/kg/day x 4 days, i.p.) or cocaine (15 mg/kg/day x 4 days, i.p.) and withdrawn for 1, 7 or 30 days. After withdrawal rats were challenged with the same dose of saline or cocaine and in vivo microdialysis of the mPFC was conducted with concurrent analysis of locomotor activity. Animals that were withdrawn from repeated daily cocaine for 1 day and 7 days displayed an augmentation in cocaine-induced mPFC glutamate levels compared to saline and acute control subjects, which were similarly unaffected by cocaine challenge. At the 7 day time point, a subset of animals that received repeated cocaine did not express behavioural sensitization, nor did these animals exhibit the enhancement in mPFC glutamate in response to cocaine challenge. In contrast to these early effects, 30 days of withdrawal resulted in no significant changes in cocaine-induced mPFC glutamate levels regardless of the pretreatment or behavioural response. These data suggest that repeated cocaine administration transiently increases cocaine-induced glutamate levels in the mPFC during the first week of withdrawal, which may play an important role in the development of behavioural sensitization to cocaine.