Ethanol-Induced Suppression of G Protein-Gated Inwardly Rectifying K+-Dependent Signaling in the Basal Amygdala.

BACKGROUND: The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABABR (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The effect of ethanol on GABABR-dependent signaling in the BLA is unknown. METHODS: GABABR-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the basal amygdala subregion (BA) to mood-related behavior. RESULTS: The somatodendritic inhibitory effect of GABABR activation on principal neurons in the basal but not the lateral subregion of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of GIRK (G protein-gated inwardly rectifying K+) channel activity and was mirrored by a redistribution of GABABR and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal. CONCLUSIONS: The ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for the treatment of alcohol use disorder.

Pipeline embolization of MCA aneurysms in the M2-M4 segment: Dual center study and meta-analysis.

OBJECTIVE: Flow diversion of distal MCA aneurysms in the M2-M4 segments with Pipeline embolization device is promising, but further study is needed. Here, we seek to quantify the safety and efficacy of Pipeline embolization in the M2-M4 region in a dual-center cohort and comprehensive meta-analysis. METHODS: Clinical and angiographic data of eligible patients was obtained from participating centers. A systematic review was performed with searches of Pubmed, Scopus, Embase, and the Cochrane Library for articles from inception to May 2021. 86 studies were identified in systematic review. Of these, 7 studies with 46 aneurysms met the inclusion criteria and were aggregated with 8 aneurysms from our dual-center cohort for analysis. RESULTS: In our dual-center cohort, complete occlusion was observed in 88% (7/8) of aneurysms, and no patients experienced hemorrhagic or thromboembolic complications. Clinical outcomes were reported for 100% (54/54) of aneurysms included in meta-analysis and angiographic follow-up was available for 91% (49/54). The overall rate of complete aneurysm occlusion was 80% (95% CI, 69-91%), and the overall rate of clinical complication was 9% (95% CI, 2-16%). CONCLUSION: Pipeline embolization of cerebral aneurysms of the M2-M4 segments of the MCA was reasonably effective and safe in a small group of selected patients, but further study is needed to validate these preliminary results.

Pipeline embolization of proximal middle cerebral artery aneurysms: A multicenter cohort study.

BACKGROUND AND PURPOSE: Flow diversion of aneurysms located in the M1 segment and middle cerebral artery bifurcation with Pipeline embolization device is sometimes performed, but further study is needed to support its regular use in aneurysm treatment. Here, we report measures of safety and efficacy for Pipeline embolization in the proximal middle cerebral artery in a multi-center cohort. MATERIALS AND METHODS: Clinical and angiographic data of eligible patients were retrospectively obtained from participating centers and assessed for key clinical and angiographic outcomes. Additional details were extracted for patients with complications. RESULTS: In our multi-center cohort, complete aneurysm occlusion was achieved in 71% (17/24) of treated aneurysms. There were no deaths or disabling strokes, but non-disabling ischemic strokes occurred in 8% (2/24) of patients. For aneurysms in the M1 segment, complete aneurysm occlusion was observed in 75% (12/16) of aneurysms, aneurysm volume reduction was observed in 100% (16/16) of aneurysms, and non-disabling ischemic strokes occurred in 13% (2/16) of patients. For aneurysms at the middle cerebral artery bifurcation, complete aneurysm occlusion was observed in 63% (5/8) of aneurysms, aneurysm volume reduction occurred in 88% (7/8) of aneurysms, and ischemic or hemorrhagic complications occurred in 0% (0/8) of patients. CONCLUSION: Pipeline embolization of cerebral aneurysms in the M1 segment and middle cerebral artery bifurcation demonstrated a 71% rate of complete aneurysm occlusion. There were no deaths or disabling strokes, but there was an 8% rate of non-disabling ischemic strokes.

Effect of Intensive Glucose Control on Outcomes of Hyperglycemic Stroke Patients Receiving Mechanical Thrombectomy: Secondary Analysis of the SHINE Trial.

BACKGROUND: Hyperglycemia is common among patients presenting with acute ischemic stroke (AIS) and is associated with poor clinical outcomes. We studied the effects of intensive blood glucose control among AIS patients presenting with hyperglycemia treated with mechanical thrombectomy (MT). METHODS: We analyzed publicly available data from the Stroke Hyperglycemia Insulin Network Effort trial. In this nonpreplanned secondary analysis, we compared hyperglycemic AIS patients treated with MT who received intensive blood glucose control (80 to 130 mg/dL) with those who received standard blood glucose control (80 to 179 mg/dL). Outcomes included rates of favorable 90-day outcome (modified Rankin Scale score ≤2) and death. RESULTS: This analysis included 146 patients (74 in the intensive treatment group and 72 in the standard treatment group). Intensive blood glucose was not associated with higher rates of 90-day favorable outcomes (intensive 31.1% vs. standard 30.6%, P =1.0; odds ratio 1.025, 95% confidence interval 0.51 to 2.07) or a decrease in rates of death (intensive 20.3% vs. standard 22.2%, P =0.84; odds ratio 0.98, 95% confidence interval 0.40 to 1.97). CONCLUSIONS: Intensive blood glucose control among AIS patients presenting with hyperglycemia and treated with MT was not associated with lower rates of death or higher rates of long-term favorable outcomes when compared with standard treatment.

Outcomes of Homeless Ischemic Stroke Patients Receiving Intravenous Thrombolysis in the United States.

BACKGROUND: Morbidity and mortality among homeless people with cardiovascular diseases and stroke in the United States is high. Adverse outcomes within the homeless population may be the result of seeking care too late to receive time-sensitive interventions. We sought to investigate the impact of homelessness on ischemic stroke patients who received intravenous thrombolysis (IVT). METHODS: We determined rates of post-thrombolytic intracranial hemorrhage (ICH), in-hospital death, and development of moderate to severe disability among homeless ischemic stroke patients treated with IVT. Patients were identified using the Nationwide (National) Inpatient Sample between 2002 and 2017. We compared rates of the various outcomes to non-homeless ischemic stroke patients treated with IVT. RESULTS: There were 514 homeless (mean age 54.7 ± 10.2 years, 20.4% women) and 364,408 non-homeless (mean age 68.6 ± 14.7 years, 49.7% women) ischemic stroke patients who received IVT. There was no difference in post-thrombolytic ICH rates between the two groups (6.6% homeless versus 8.8% non-homeless, p = 0.09). Homeless patients were more frequently discharged to self-care (p = 0.003). Homeless patients were less likely than non-homeless patients to suffer in-hospital death (AOR 0.499 [95% CI 0.30-0.84], p = 0.009) and moderate to severe disability (AOR 0.423 [95% CI 0.29 - 0.62], p < 0.001). CONCLUSION: Homeless ischemic stroke patients who receive IVT are not at an increased risk of developing post-thrombolytic ICH or in-hospital death. Efforts are needed to encourage this unique population to seek medical attention as soon as possible for time-sensitive interventions that may decrease the risk of permanent disability or death associated with ischemic stroke.

Pipeline embolization of distal posterior inferior cerebellar artery aneurysms.

BACKGROUND AND PURPOSE: Flow diversion is commonly used to treat intracranial aneurysms in various regions of the cerebral vasculature, but is only approved for use in the internal carotid arteries. Treatment of distal PICA aneurysms with PED is sometimes performed but has not been well studied. Here, we report our experience with flow diversion of distal PICA aneurysms with PED. MATERIALS AND METHODS: Clinical and angiographic data of eligible patients was retrospectively obtained and assessed for key demographic characteristics and clinical and angiographic outcomes. Principal outcomes included rates of aneurysm occlusion, ischemic or hemorrhagic complication, technical complication, and in-stent stenosis. RESULTS: Three female and 2 male patients underwent placement of PED in the PICA for treatment of 5 distal PICA aneurysms. Clinical and angiographic follow-up was obtained for all patients. Complete aneurysm occlusion was observed in 100% (5/5) of treated aneurysms at 6 month and longest angiographic follow-up. While there were no ischemic or device-related complications, delayed hemorrhagic complications occurred in 20% (1/5) of patients. CONCLUSION: Pipeline embolization of distal PICA aneurysms can be performed in select patients. Further study is necessary in larger cohorts to better define clinical scenarios in which flow diversion in the distal PICA should be considered.

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning.

Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABAB receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice.SIGNIFICANCE STATEMENT Prolonged exposure to drugs of abuse triggers neuroadaptations that promote core features of addiction. Understanding these neuroadaptations and their implications may suggest interventions capable of preventing or treating addiction. While previous work showed that repeated cocaine exposure increased the excitability of pyramidal neurons in the prelimbic cortex (PL), the behavioral implications of this neuroadaptation remained unclear. Here, we used neuron-specific manipulations to evaluate the impact of increased PL pyramidal neuron excitability on PL-dependent behaviors. Acute or persistent excitation of PL pyramidal neurons potentiated cocaine-induced motor activity and disrupted trace fear conditioning, effects replicated by selective excitation of the PL projection to the VTA. Our work suggests that hyperexcitability of this projection drives key behavioral hallmarks of addiction.

Quality of life among ischemic stroke patients eligible for endovascular treatment: analysis of the DEFUSE 3 trial.

BACKGROUND: The endovascular treatment (ET) for acute ischemic stroke is increasing among eligible patients. Assessing patients' perspectives on quality of life (QOL) can supplement the use of formal outcome scales and enable the assessment of outcomes across multiple domains affected by stroke. METHODS: We analyzed publicly available data from the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE 3) trial. We evaluated patients who survived beyond the time of discharge from their acute hospitalizations and completed all Neuro-QOL short forms at 90-day follow-up. RESULTS: Our final analysis included 128 patients (median age 67 [range 23-90] years, 50.8% men). As modified Rankin Scale (mRS) scores increased, there was a consistent increase in the severity of Neuro-QOL measures. T-scores for mobility, cognitive function, and the ability to participate in social roles declined significantly while depression T-scores increased significantly. We found that QOL T-scores for patients with mRS 3 did not differ significantly from T-scores for patients with mRS 2 in any domain. CONCLUSIONS: Among ischemic stroke patients eligible for ET, QOL scores help validate and supplement quantitatively measured outcomes.

Dual antiplatelet therapy does not improve outcomes after aneurysmal subarachnoid hemorrhage compared with aspirin monotherapy.

BACKGROUND: The pathophysiology of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may include platelet activation and microthrombi formation. Antiplatelet therapy may reduce the incidence of DCI and improve clinical outcomes after aSAH. This study compared outcomes among aSAH patients receiving aspirin monotherapy versus dual antiplatelet therapy (DAPT). METHODS: Aneurysmal subarachnoid hemorrhage patients treated at a single institution between November 2011 and December 2017 were divided according to whether they received aspirin monotherapy or DAPT after endovascular treatment. Baseline characteristics and outcomes of the groups were compared, including incidences of delayed cerebral ischemia, bleeding complications, symptomatic vasospasm, in-hospital mortality, and functional status 6 months after discharge. RESULTS: During the study period, 142 patients met study inclusion criteria, of which 123 were treated with aspirin monotherapy (87 %) and 19 were treated with DAPT (13 %). There was no statistically significant difference between the aspirin monotherapy and DAPT groups with respect to incidences of delayed cerebral ischemia (4.9 vs 10.5 %; p = 0.32), symptomatic vasospasm (13.0 vs 15.8 %; p = 0.74), or good clinical outcome at 6-month follow up (73.3 vs 66.7 %; p = 0.56). The DAPT group experienced a higher incidence of in-hospital mortality (21 vs 5.7 %; p = 0.02), but DAPT did not remain independently predictive of this outcome on regression analysis. There was a trend toward a higher bleeding complication rate in the DAPT group (0.8 vs 5.3 %; p = 0.13). CONCLUSIONS: DAPT does not reduce the incidence of DCI or improve outcomes in aSAH patients, and may increase the risk of clinically significant bleeding complications.

Predictive value of discharge destination for 90-day outcomes among ischemic stroke patients eligible for endovascular treatment: Post-hoc analysis of DEFUSE 3.

BACKGROUND: The endovascular treatment (ET) for acute ischemic stroke (AIS) is increasing among eligible patients. To help address care quality, administrative data sets are utilized but do not usually include formal outcome scales. We explore the predictive ability of discharge destination from acute hospitalizations for long-term disability among AIS patients eligible for ET within a clinical trial. METHODS: We analyzed publicly available data from the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial. We evaluated patients who survived beyond the time of discharge from their acute hospitalizations. We calculated positive and negative predictive values and accompanying likelihood ratios for patients discharged to home, inpatient rehabilitation facility (IRF), or subacute nursing facility (SNF) for unfavorable outcome as defined by modified Rankin Scale (mRS) scores ≥3 at 90-days. RESULTS: Our final analysis included 127 patients (median age 67 [23-89] years, 51.2% men). There were 23.6% patients discharged home, 53.5% to IRF, and 22.8% to SNF. Approximately 61% of patients had 90-day post-stroke mRS scores ≥3. Patients discharged to SNF had the highest positive predictive value (93.1%) and positive likelihood ratio (8.77 [CI 95% 2.18-35.25]) for unfavorable outcome. Discharge to home had the highest negative likelihood ratio (2.09 [CI 95% 1.54-2.83]) for unfavorable outcome. CONCLUSIONS: Among AIS patients eligible for ET within the DEFUSE 3 trial, discharge destination can provide high predictive value of 90-day functional outcomes. A discharge to SNF is highly predictive of long-term unfavorable outcomes.

Weekday Versus Weekend Presentation in the Acute Management of Ischemic Stroke Through Telemedicine.

A "weekend effect" resulting in higher mortality rates for patients with stroke admitted on weekends has been reported. We examine this phenomenon for patients with acute ischemic stroke (AIS) presenting to telestroke (TS) sites to determine its effect on stroke alert process times and outcomes. From October 2015 to June 2017, we reviewed patients with AIS receiving intravenous alteplase within our TS network. We compared patients presenting to TS sites on weekdays (Monday 07:00 to Friday 18:59) to those presenting on weekends (Friday 19:00 to Monday 06:59). We analyzed door-to-alert activation, alert activation-to-TS evaluation, door-to-imaging, and door-to-needle times. Rates of favorable outcome (modified Rankin Scale score ≤2) and death at 90 days were compared. We identified 89 (54 weekday and 35 weekend) patients (mean age: 71.8 ± 13.3 years, 47.2% women) during the study period. Median door-to-alert activation (P = .01) and door-to-needle (P = .004) times were significantly longer for patients presenting on weekends compared to weekdays. There were no significant differences in median door-to-imaging (P = .1) and alert activation-to-TS evaluation (P = .07) times. Rates of favorable outcome (P = .19) and death (P = .56) at 90 days did not differ. While there were no significant differences in outcomes, patients presenting on weekends had longer door-to-alert activation and door-to-needle times. Efforts to improve methods in efficiency of care on weekends should be considered.

Conivaptan for the Reduction of Cerebral Edema in Intracerebral Hemorrhage: A Safety and Tolerability Study.

BACKGROUND: Perihematomal edema (PHE) growth in intracranial hemorrhage (ICH) is a biomarker for worse outcomes. Although the management of PHE is potentially beneficial for ICH patients, there is currently no proven clinical therapy that both reduces PHE and improves outcomes in this population. OBJECTIVE: To examine the safety and tolerability of conivaptan, a non-peptide vasopressin (AVP) receptor antagonist, for the management of PHE in ICH patients. METHODS: We performed a single-center, open-label, phase I study in seven patients with ICH at risk for developing PHE. Conivaptan (20 mg) was administered every 12 h for 2 days, along with the standard ICH management. Electrolyte levels, renal and cardiac function, and vital signs were monitored throughout treatment. Neurological status, ICH, and PHE volumes were assessed at study baseline, 24 h, 72 h, and 7 days from the first conivaptan administration, as well as at the 3-month follow-up. RESULTS: Conivaptan was well tolerated in our patients. We observed the expected increase in sodium levels following conivaptan administration (p = 0.01), with no change in cardiac or renal function. All patients survived to follow-up, and adverse event rates were comparable with those of the neurocritical care unit overall. CONCLUSIONS: These data indicate that conivaptan can be safely administered to ICH patients and support further clinical investigation into the efficacy of this drug for ICH treatment. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT03000283, 22 December 2016.

Utility of procalcitonin for diagnosis of bacterial infection-related systemic inflammatory response in the acute neurologic injury population.

OBJECTIVE: Inflammation and bacterial infection are common complicating factors in the treatment of patients with stroke. Inflammatory responses can manifest as systemic inflammatory response syndrome (SIRS), a condition with both infectious and non-infectious etiologies. Accurately identifying patients with infection-related SIRS is important for determining the correct treatment plan. Here, we investigated the use of the glycopeptide procalcitonin (PCT) as a potential biomarker for identifying patients with bacterial infections in the setting of SIRS. PATIENTS AND METHODS: A retrospective chart review was performed for adult patients admitted to United Hospital with an admission or discharge diagnosis of stroke for whom PCT testing was ordered between January 2011 and December 2014. Medical records were searched for the timing of PCT tests, and the previous 24 h was assessed for markers of SIRS, inflammation, and disease severity. RESULTS: PCT levels were negatively correlated with Glasgow Coma Scale scores (ρ=-0.27, p < 0.0001) and glomerular filtration rates (ρ=-0.22, p < 0.001), but demonstrated a positive correlation with white blood cell (WBC) count (ρ = 0.13, p = 0.031) and creatinine levels (ρ = 0.33, p < 0.0001). PCT levels were significantly higher in samples that corresponded to the presence of at least one infection (p < 0.0001) and in SIRS + samples (p < 0.001). However, even with the addition of a SIRS + diagnosis, the predictive value of PCT did not reach levels that would indicate clinical utility for the identification of patients with bacterial infections. CONCLUSIONS: PCT was not a viable biomarker for distinguishing between infectious and non-infections etiologies of SIRS in acute brain injury in this population. However, our results do indicate potential utility for PCT as an indicator for the cessation of antibiotic use in acute brain injury patients with bacterial infections.

Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning.

The basolateral amygdala complex, which contains the lateral (LA) and basal (BA) subnuclei, is a critical substrate of associative learning related to reward and aversive stimuli. Auditory fear conditioning studies in rodents have shown that the excitation of LA pyramidal neurons, driven by the inhibition of local GABAergic interneurons, is critical to fear memory formation. Studies examining the role of the BA in auditory fear conditioning, however, have yielded divergent outcomes. Here, we used a neuron-specific chemogenetic approach to manipulate the excitability of mouse BA neurons during auditory fear conditioning. We found that chemogenetic inhibition of BA GABA neurons, but not BA pyramidal neurons, impaired fear learning. Further, either chemogenetic stimulation of BA GABA neurons or chemogenetic inhibition of BA pyramidal neurons was sufficient to generate the formation of an association between a behavior and a neutral auditory cue. This chemogenetic memory required presentation of a discrete cue, and was not attributable to an effect of BA pyramidal neuron inhibition on general freezing behavior, locomotor activity, or anxiety. Collectively, these data suggest that BA GABA neuron activation and the subsequent inhibition of BA pyramidal neurons play important role in fear learning. Moreover, the roles of inhibitory signaling differ between the LA and BA, with excitation of pyramidal neurons promoting memory formation in the former, and inhibition of pyramidal neurons playing this role in the latter.

GIRK2 splice variants and neuronal G protein-gated K+ channels: implications for channel function and behavior.

Many neurotransmitters directly inhibit neurons by activating G protein-gated inwardly rectifying K+ (GIRK) channels, thereby moderating the influence of excitatory input on neuronal excitability. While most neuronal GIRK channels are formed by GIRK1 and GIRK2 subunits, distinct GIRK2 isoforms generated by alternative splicing have been identified. Here, we compared the trafficking and function of two isoforms (GIRK2a and GIRK2c) expressed individually in hippocampal pyramidal neurons lacking GIRK2. GIRK2a and GIRK2c supported comparable somato-dendritic GIRK currents in Girk2 -/- pyramidal neurons, although GIRK2c achieved a more uniform subcellular distribution in pyramidal neurons and supported inhibitory postsynaptic currents in distal dendrites better than GIRK2a. While over-expression of either isoform in dorsal CA1 pyramidal neurons restored contextual fear learning in a conditional Girk2 -/- mouse line, GIRK2a also enhanced cue fear learning. Collectively, these data indicate that GIRK2 isoform balance within a neuron can impact the processing of afferent inhibitory input and associated behavior.

Identification and characterization of heptapeptide modulators of the glycine receptor.

The glycine receptor is a member of the Cys-loop receptor superfamily of ligand-gated ion channels and is implicated as a possible therapeutic target for the treatment of diseases such as alcoholism and inflammatory pain. In humans, four glycine receptor subtypes (α1, α2, α3, and ß) co-assemble to form pentameric channel proteins as either α homomers or αß heteromers. To date, few agents have been identified that can selectively modulate the glycine receptor, especially those possessing subtype specificity. We used a cell-based method of phage display panning, coupled with two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes, to identify novel heptapeptide modulators of the α1ß glycine receptor. This involved a panning procedure in which the phage library initially underwent subtractive panning against Human Embryonic Kidney (HEK) 293 cells expressing alternative glycine receptor subtypes before panning the remaining library over HEK 293 cells expressing the target, the α1ß glycine receptor. Peptides were identified that act with selectivity on α1ß and α3ß, compared to α2ß, glycine receptors. In addition, peptide activity at the glycine receptor decreased when zinc was chelated by tricine, similar to previous observations of a decrease in ethanol's enhancing actions at the receptor in the absence of zinc. Comparisons of the amino acid sequences of heptapeptides capable of potentiating glycine receptor function revealed several consensus sequences that may be predictive of a peptide's enhancing ability.

G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward.

BACKGROUND: G protein-gated inwardly rectifying potassium (GIRK) channels contribute to the effects of a number of drugs of abuse, including ethanol. However, the roles of individual subunits in the rewarding effects of ethanol are poorly understood. METHODS: We compare conditioned place preference (CPP) in GIRK3 subunit knock-out (GIRK3(-/-)), heterozygote (GIRK3(+/-)), and wild-type (WT) mice. In addition, the development of locomotor tolerance/sensitization and the effects of EtOH intoxication on associative learning (fear conditioning) are also assessed. RESULTS: Our data show significant EtOH CPP in GIRK3(-/-) and GIRK3(+/-) mice, but not in the WT littermates. In addition, we demonstrate that these effects are not due to differences in EtOH metabolism, the development of EtOH tolerance/sensitivity, or associative learning abilities. While there were no consistent genotype differences in the fear conditioning assay, our data do show a selective sensitization of the impairing effects of EtOH intoxication on contextual learning, but no effect on cued learning. CONCLUSIONS: These findings suggest that GIRK3 plays a role in EtOH reward. Furthermore, the selectivity of this effect suggests that GIRK channels could be an effective therapeutic target for the prevention and/or treatment of alcoholism.

GIRK Channels: A Potential Link Between Learning and Addiction.

The ability of drug-associated cues to reinitiate drug craving and seeking, even after long periods of abstinence, has led to the hypothesis that addiction represents a form of pathological learning, in which drugs of abuse hijack normal learning and memory processes to support long-term addictive behaviors. In this chapter, we review evidence suggesting that G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels are one mechanism through which numerous drugs of abuse can modulate learning and memory processes. We will examine the role of GIRK channels in two forms of experience-dependent long-term changes in neuronal function: homeostatic plasticity and synaptic plasticity. We will also discuss how drug-induced changes in GIRK-mediated signaling can lead to changes that support the development and maintenance of addiction.

Acute ethanol withdrawal impairs contextual learning and enhances cued learning.

BACKGROUND: Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. METHODS: We assess the effects of acute ethanol withdrawal (6 hours postinjection with 4 g/kg ethanol) on 2 forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post training withdrawal exposure; foreground/background processing; training strength; and nonassociative effects) is also investigated. RESULTS: Acute ethanol withdrawal during training had a bidirectional effect on fear-conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. CONCLUSIONS: Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes.

Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance.

Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus (CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures.