Erin Brown

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.

Formation and clearance of interstitial metabolites of dopamine and serotonin in the rat striatum: an in vivo microdialysis study.

Abstract: In vivo microdialysis was employed in order to characterize the steady‐state kinetics of the turnover of specific dopamine and serotonin metabolites in the rat striaturn 48 h after surgery. Inhibitors of monoamine oxidase (MAO; pargyline) and catechol‐O‐methyltransferase (COMT; Ro 40‐7592) were administered, either separately or in conjunction, at doses sufficient to block these enzymes in the CNS. In some experiments, the acid metabolite carrier was blocked with probenecid. Temporal changes were then observed in the efflux of interstitial dopamine, 3‐methoxytyramine (3‐MT), 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5‐hydroxyindoleacetic acid (5‐HIAA). The fractional rate constants for the accumulation or disappearance of the metabolites could be determined after pharmacological blockade of catabolic enzymes or the acid metabolite carrier. Interstitial 5‐HIAA was found to be cleared with a half‐life of approximately 2 h. After blockade of either MAO or COMT, HVA disappeared with a half‐life of 17 min. Experiments employing probenecid suggested that some of the interstitial HVA was cleared by the acid metabolite carrier, the remainder being cleared by a probenecid‐insensitive process, possibly conjugation. After MAO inhibition, DOPAC disappeared with an apparent half‐life of 11.3 min. The rate of 3‐MT accumulation after pargyline indicated that the majority of interstitial HVA (>95%) is formed from DOPAC rather than 3‐MT. The formation of 3‐MT from interstitial dopamine, calculated from the accumulation rate of 3‐MT after pargyline, appeared to follow first‐order kinetics (k = 0.1 min−1).

Cocaine-induced conditioned locomotion: Absence of associated increases in dopamine release

The potent reinforcing effects of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This phenomenon is of considerable significance as intense craving can be evoked by stimuli previously associated with the effects of cocaine. It has been proposed that the reinforcing properties of these conditional stimuli are due to their ability to elicit neural events that are similar to those produced by the drug itself. Given the large body of evidence that implicates the mesolimbic dopaminergic projection in the unconditioned behavioural properties of cocaine, the present study used in vivo microdialysis to determine whether stimuli paired with cocaine elicit increases in interstitial dopamine in the nucleus accumbens that are similar to the unconditioned effects of this drug. When administered acutely, cocaine (10 mg/kg, i.p.) produced a potent unconditioned increase in interstitial dopamine concentrations (300% of basal values) in the nucleus accumbens. The results from two separate experiments indicate that the administration of cocaine (10 mg/kg for seven days) in association with a specific environment produced significant locomotion in that environment. Compared to subjects that received saline in both settings, rats that received cocaine in their home cage (pseudoconditioned group) did not exhibit increased locomotion on the test day. Although repeated pairing of cocaine with a specific environment produced conditioned locomotion, there was no concomitant conditional increase in dopamine release. Specifically, the modest increase in dopamine (10-15% above basal values) observed after exposure to the conditional environment was equal in the conditioned and pseudoconditioned groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstitial 3‐Methoxytyramine Reflects Striatal Dopamine Release: An In Vivo Microdialysis Study

Previous ex vivo studies have provided indirect evidence that the dopamine (DA) metabolite 3‐methoxytyramine (3‐MT) may be a useful index of DA release in vivo. In the present study, in vivo microdialysis was utilized to assess directly the relationship between extracellular DA and 3‐MT in the striatum of rats following a variety of pharmacological manipulations. Apomorphine, a DA receptor agonist, produced a rapid, transient decrease in both DA and 3‐MT. Conversely, the DA receptor antagonist haloperidol produced a concomitant increase in extracellular DA and 3‐MT. Increases in DA and 3‐MT were also noted following the administration of the DA uptake inhibitor, bupropion. Local application of tetrodotoxin resulted in the complete elimination of measurable amounts of DA and 3‐MT in the dialysate. γ‐Butyrolactone also greatly decreased DA and 3‐ MT. Finally, d‐amphetamine produced a large increase in DA and 3‐MT in animals that had been treated previously with γ‐butyrolactone. The Pearson correlation coefficients for DA and 3‐MT following these manipulations ranged from 0.87 to 0.97. These data indicate that interstitial 3‐MT is an accurate index of DA release. However, when compared with previous ex vivo findings, the present results also suggest that changes in tissue concentrations of 3‐MT may not reliably reflect DA release following certain pharmacological manipulations.

ECS-induced dopamine release: Effects of electrode placement, anticonvulsant treatment, and stimulus intensity ☆

Although electroconvulsive therapy (ECT) remains an important therapy for severe depression, its mechanism of action remains elusive. We previously demonstrated that there is a significant increase of interstitial dopamine of neuronal origin in the rat striatum after electroconvulsive shock (ECS) but not after chemically (flurothyl) induced seizures. The present studies examined how electrode placement, stimulus intensity, and the administration of an anticonvulsant affect ECS-induced dopamine release in the rat striatum. Bilateral electrode placement resulted in greater dopamine release than that produced by a unilaterally applied stimulus. Pretreatment with sodium pentobarbital markedly decreased seizure duration but had no effect on the magnitude of the increase in interstitial dopamine. Finally, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase in seizure duration. These data suggest that the passage of current may be directly responsible for certain ECS-induced chemical changes. These findings are discussed in the context of clinical observations that challenge the traditional view that the production of generalized seizures of adequate duration is both necessary and sufficient for a therapeutic response to ECT.

Chronic desipramine enhances the effect of locally applied amphetamine on interstitial concentrations of dopamine in the nucleus accumbens

In vivo microdialysis was used to study the effect of chronic desipramine (DMI, 5 mg/kg, twice daily for 21 days) on increases in interstitial dopamine (DA) produced by local administration of d-amphetamine (1.0, 3.3 and 10.0 microM) in the nucleus accumbens. Locally applied amphetamine increased interstitial DA in a dose-dependent manner. The amphetamine-induced increase was significantly greater in the DMI treated animals. These data suggest that chronic DMI may directly influence the functional status of the DA terminals in the nucleus accumbens.

Circulating monocytes have the capacity to be transdifferentiated into keratinocyte-like cells

Transdifferentiation is a process in which the original commitment of a cell is changed to give rise to unexpected peripheral mature cells. Our previous report showed that circulating stem cells can generate keratinocyte‐like cells (KLCs). However, it remains to be determined whether or not other peripheral blood mononuclear cells (PBMC) subsets have the potential to follow the same cell fate. In this study, the cell transdifferentiation of circulating CD14+ monocytes into KLCs and their regulatory effect on matrix metalloproteinase‐1 (MMP‐1) expression in dermal fibroblasts were evaluated. The results showed that monocytes isolated from peripheral blood mononuclear cells have the capacity to generate KLCs. These transdifferentiated cells exhibited, along with a keratinocyte‐like morphology, a characteristic profile consisting in stratifin+, cytokeratins+ (types I and II), CD14low, and involucrin+ on day 21 in culture. Similar to keratinocyte‐conditioned media, KLC‐derived conditioned media were able to induce an increase in the MMP‐1 expression in dermal fibroblasts. This effect was significantly reduced by using 14‐3‐3 protein‐depleted KLC‐conditioned media. Our findings show the potential transdifferentiation of circulating CD14+ monocytes into KLCs and their regulatory effect on MMP‐1 expression in dermal fibroblasts.

Impact of Diabetes on Outcomes in Hand Surgery

Diabetes mellitus is associated with the development of several pathologic conditions of the hand, including carpal tunnel syndrome, Dupuytren disease, trigger digits, and limited joint mobility or cheiroarthropathy. In recent years, across a variety of surgical disciplines, increased emphasis has been placed on the impact of diabetes on treatment outcomes. This review provides an overview of the current literature regarding the effect of diabetes on outcomes of hand surgery for these common diabetes-related conditions. Taken as a whole, the best current evidence supports the efficacy of surgical interventions for the management of these conditions in diabetic individuals; however, additional research is required to determine whether the treatment outcomes are equivalent to those of nondiabetic patients, and whether diabetes is associated with an increased risk of complications.

Localized controlled release of stratifin reduces implantation-induced dermal fibrosis

Localized controlled release of anti-fibrogenic factors can potentially prevent tissue fibrosis surrounding biomedical prostheses, such as vascular stents and breast implants. We have previously demonstrated that therapeutic intervention with topically applied stratifin in a rabbit ear fibrotic model not only prevents dermal fibrosis but also promotes more normal tissue repair by regulating extracellular matrix deposition. In this work, the anti-fibrogenic effect of a controlled release form of stratifin was investigated in the prevention of fibrosis induced by dermal poly(lactic-co-glycolic acid) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel implants. Pharmacodynamic effects were evaluated by histopathological examination of subcutaneous tissue surrounding implanted composites. Controlled release of stratifin from PLGA microsphere/PVA hydrogel implants significantly moderated dermal fibrosis and inflammation by reducing collagen deposition (30%), total tissue cellularity (48%) and infiltrated CD3(+) immune cells (81%) in the surrounding tissue compared with the stratifin-free implants. The controlled release of stratifin from implants markedly increased the level of matrix metalloproteinase-1 expression in the surrounding tissue, which resulted in less collagen deposition. These stratifin-eluting PLGA/PVA composites show promise as coatings to decrease the typical fibrosis exhibited around implanted biomedical prostheses, such as breast implants and vascular stents.

Necrotizing fasciitis following a motor vehicle accident with Candida species as the sole organisms.

Necrotizing soft-tissue infections exclusively due to Candida species are rare and not usually considered in the differential diagnosis of this devastating condition. When documented previously, Candida species are generally proposed to be a saprophytic component of multibacterial synergistic infection often associated with streptococcal species. We report a case of a 51-year-old man who developed necrotizing fasciitis secondary to Candida infection following a motor vehicle accident. His clinical presentation was very similar to that of clostridial gas gangrene. The only organisms isolated from tissue culture were Candida albicans and Candida tropicalis. Histopathology confirmed yeast forms and pseudohyphae within the debrided tissue specimens. No bacteria were identified on any of the wound swabs or tissue specimens. Our report is the first that reveals Candida as the sole identifiable cause for necrotizing fasciitis following trauma. Candida should be considered in the differential diagnosis of causative organisms for necrotizing fasciitis and infective myonecrosis.