Jeremy Wetzel

The shell of the nucleus accumbens has a higher dopamine response compared with the core after non-contingent intravenous ethanol administration

Dopamine increases in the nucleus accumbens after ethanol administration in rats, but the contributions of the core and shell subregions to this response are unclear. The goal of this study was to determine the effect of various doses of i.v. ethanol infusions on dopamine in these two subregions of the nucleus accumbens. Male Long-Evans rats were infused with either acute i.v. ethanol (0.5, 1.0, 1.5 g/kg), repeated i.v. ethanol (four 1.0 g/kg infusions resulting in a cumulative dose of 4.0 g/kg), or saline as a control for each condition. Dopamine and ethanol were measured in dialysate samples from each experiment. The in vivo extraction fraction for ethanol of probes was determined using i.v. 4-methylpyrazole, and was used to estimate peak brain ethanol concentrations after the infusions. The peak brain ethanol concentrations after the 0.5, 1.0 and 1.5 g/kg ethanol infusions were estimated to be 20, 49 and 57 mM, respectively. A significant dopamine increase was observed for the 0.5 g/kg ethanol group when collapsed across subregions. However, both the 1.0 g/kg and 1.5 g/kg ethanol infusions produced significant increases in dopamine levels in the shell that were significantly higher than those in the core. An ethanol dose-response effect on dopamine in the shell was observed when saline controls, 0.5, 1.0, and 1.5 g/kg groups were compared. For the cumulative-dosing study, the first, second, and fourth infusions resulted in significant increases in dopamine in the shell. However, these responses were not significantly different from one another. The results of this study show that the shell has a stronger response than the core to i.v. ethanol, that dopamine in the shell increases in a dose-dependent manner between 0.5-1.0 g/kg doses, but that the response to higher ethanol doses reaches a plateau.

The Dopamine Response in the Nucleus Accumbens Core–Shell Border Differs From That in the Core and Shell During Operant Ethanol Self‐Administration

BACKGROUND Ethanol self-administration has been shown to increase dopamine in the nucleus accumbens; however, dopamine levels in the accumbal subregions (core, shell, and core-shell border) have not yet been measured separately in this paradigm. This study was designed to determine if dopamine responses during operant ethanol self-administration are similar in the core, core-shell border, and shell, particularly during transfer from the home cage to the operant chamber and during consumption of the drinking solution. METHODS Six groups of male Long-Evans rats were trained to lever-press for either 10% sucrose (10S) or 10% sucrose + 10% ethanol (10S10E) (with a guide cannula above the core, core-shell border, or shell of the accumbens). On experiment day, 5-minute microdialysis samples were collected from the core, core-shell border, or shell before, during, and after drinking. Dopamine and ethanol concentrations were analyzed in these samples. RESULTS A significant increase in dopamine occurred during transfer of the rats from the home cage into the operant chamber in all 6 groups, with those trained to drink 10S10E exhibiting a significantly higher increase than those trained to drink 10S in the core and shell. No significant increases were observed during drinking of either solution in the core or shell. A significant increase in dopamine was observed during consumption of ethanol in the core-shell border. CONCLUSIONS We conclude that dopamine responses to operant ethanol self-administration are subregion specific. After operant training, accumbal dopamine responses in the core and shell occur when cues that predict ethanol availability are presented and not when the reinforcer is consumed. However, core-shell border dopamine responses occur at the time of the cue and consumption of the reinforcer.

Thromboelastography in patients with acute ischemic stroke.

Background Thromboelastography measures the dynamics of coagulation. There are limited data about thromboelastography in acute ischemic stroke other than a single study from 1974 suggesting that acute ischemic stroke patients are hypercoagulable. There have been no studies of thromboelastography in the thrombolytic era despite its potential usefulness as a measure of clot lysis. This study was designed to provide initial thromboelastography data in stroke patients before and after tissue plasminogen activator therapy and to provide the necessary preliminary data for further study of thromboelastographys ability to identify clot subtype and predict response to tissue plasminogen activator therapy. Methods All acute ischemic stroke patients presenting between 11/2009 and 2/2011 eligible for tissue plasminogen activator therapy were screened and 56 enrolled. Blood was drawn before (52 patients) and 10 mins after tissue plasminogen activator bolus (30 patients). Demographics, vitals, labs, 24 h National Institutes of Health Stroke Scale, and computed tomography scan results were collected. Patients were compared with normal controls. Results Acute ischemic stroke patients had shorter R (4·8 ± 1·5 vs. 6·0 ± 1·7 min, P = 0·0004), greater a Angle (65·0 ± 7·6 vs. 61·5 ± 5·9°, P = 0·01), and shorter K (1·7 ± 0·7 vs. 2·1 ± 0·7 min, P = 0·002) indicating faster clotting. Additionally, a subset formed clots with stronger platelet-fibrin matrices. Treatment with tissue plasminogen activator resulted in reduction in all indices of clot strength (LY30 = 0 (0–0·4) vs. 94·4 (15·2–95·3) P < 0·0001); however, there was considerable variability in response. Conclusions Thromboelastography demonstrates that many acute ischemic stroke patients are hypercoaguable. Thromboelastography values reflect variable clot subtype and response to tissue plasminogen activator. Further study based on these data will determine if thromboelastography is useful for measuring the dynamic aspects of clot formation and monitoring lytic therapy.

Thrombelastography Detects Possible Coagulation Disturbance in Patients With Intracerebral Hemorrhage With Hematoma Enlargement

Background and Purpose— Intracerebral hemorrhage (ICH) has high morbidity, and hematoma enlargement (HE) causes worse outcome. Thrombelastography (TEG) measures the dynamics of clot formation and dissolution, and might be useful for assessing bleeding risk. We used TEG to detect changes in clotting in patients with and without HE after ICH. Methods— This prospective study included 64 patients with spontaneous ICH admitted from 2009 to 2013. TEG was performed within 6 hours of symptom onset and after 36 hours. Brain imaging was obtained at baseline and at 36±12 hours, and HE was defined as total volume increase >6 cc or >33%. TEG was also obtained from 57 controls. Results— Compared with controls, patients with ICH demonstrated faster and stronger clot formation; shorter R and delta (P<0.0001) at baseline; and higher MA and G (P<0.0001) at 36 hours; 11 patients had HE. After controlling for potential confounders, baseline K and delta were longer in HE+ compared with HE− patients, indicating that HE+ patients had slower clot formation (P<0.05). TEG was not different between HE+ and HE− patients at 36 hours. Conclusions— TEG may detect important coagulation changes in patients with ICH. Clotting may be faster and stronger in immediate response to ICH, and a less robust response may be associated with HE. These findings deserve further investigation.

Iodinated Contrast Does Not Alter Clotting Dynamics in Acute Ischemic Stroke as Measured by Thromboelastography

Background and Purpose— Iodinated contrast agents used for computed tomography angiography (CTA) may alter fibrin fiber characteristics and decrease fibrinolysis by tissue plasminogen activator (tPA). Thromboelastography (TEG) measures the dynamics of coagulation and correlates with thrombolysis in acute ischemic stroke patients. We hypothesized that receiving CTA before tPA will not impair thrombolysis as measured by TEG. Methods— Acute ischemic stroke patients receiving 0.9 mg/kg tPA <4.5 hours of symptom onset were prospectively enrolled. For CTA, 350 mg/dL of iohexol or 320 mg/dL of iodixanol at a dose of 2.2 mL/kg was administered. TEG was measured before tPA and 10 minutes after tPA bolus. CTA timing was left to the discretion of the treating physician. Results— Of 136 acute ischemic stroke patients who received tPA, 47 had CTA before tPA bolus, and 42 had either CTA after tPA and post–tPA TEG draw or no CTA (noncontrast group). Median change in clot lysis (LY30) after tPA was 95.3% in the contrast group versus 95.0% in the noncontrast group (P=0.74). Thus, tPA-induced thrombolysis did not differ between contrast and noncontrast groups. Additionally, there was no effect of contrast on any pre–tPA TEG value. Conclusions— Our data do not support an effect of iodinated contrast agents on clot formation or tPA activity.