Abstract
Chronic use of alcohol is associated with structural and functional alterations in brain areas that subserve cognitive processes. Of particular importance is the prefrontal cortex (PFC) that is involved in higher order behaviors such as decision making, risk assessment and judgment. Understanding the mechanisms that underlie alcohol's effects on PFC function is important for developing strategies to overcome the cognitive deficits that may predispose individuals to relapse. Our previous studies showed that acutely applied ethanol inhibits network activity in slices of prefrontal cortex and that exogenous and endogenous cannabinoids modulate up-state dynamics. In the present study, we examined the effects of repeated alcohol exposure on cannabinoid regulation of up-states in slice cultures of the prefrontal cortex. Compared to controls, up-state duration, but not amplitude was enhanced when measured 4 days after a 10 day ethanol exposure (44 mM ethanol; equivalent to 0.2% blood ethanol). Administration of the CB1 agonist WIN 55,212-2 enhanced the amplitude of up-states in control cultures but not in those treated previously with ethanol. This lack of effect occurred in the absence of any noticeable change in CB1 receptor protein expression. Chronic ethanol treatment and withdrawal also blunted WIN's inhibition of electrically evoked GABA IPSCs in layer II/III pyramidal neurons but not those in layer V/VI. WIN inhibited the amplitude of spontaneous GABA IPSCs in both layers and the magnitude of this effect was not altered by ethanol treatment. However, in layer V/VI neurons, WIN's effect on sIPSC frequency was greater in ethanol treated cultures. WIN also inhibited electrically evoked NMDA EPSCs in both layer II/III and V/VI neurons but this action was unaffected by ethanol treatment and withdrawal. Overall, these results suggest that ethanol's down-regulation of cannabinoid signaling results in altered network activity in the prefrontal cortex.
Highlights
Addictive disorders are associated with cognitive deficits that often persist into abstinence and may arise from dysfunction of the prefrontal cortex (PFC; Koob and Volkow, 2010; Lundqvist, 2010)
In order to determine if chronic EtOH treatment (CET) altered CB1 function, the effect of the CB1 agonist, WIN 55,212-2 (WIN; 1 μM), on up-state parameters was examined in CET cultures after 4 days of withdrawal (Figure 2A)
Measurements of excitatory PSCs (EPSCs) area indicate that currents recorded from layer II/III were inhibited to a greater extent that those recorded from layer V/VI [main effect of cortical layer, two-way analysis of variance (ANOVA), F(1, 32) = 7.51, p = 0.0099], but again there was no effect of CET [F(1, 32) = 0.51, p = 0.48]. These results show that CET does not alter CB1 signaling at glutamatergic synapses onto layer II/III or layer V/VI pyramidal neurons
Summary
Addictive disorders are associated with cognitive deficits that often persist into abstinence and may arise from dysfunction of the prefrontal cortex (PFC; Koob and Volkow, 2010; Lundqvist, 2010). One form of cortical network activity that contributes to slow frequencies in the delta band (0–1 Hz) and predominates in deep-stage slow-wave sleep is the slow-oscillation (Amzica and Steriade, 1998) This EEG rhythm arises from the bi-stable membrane potential of cortical neurons (Steriade et al, 1993a,b,c) that spontaneously oscillates between a quiescent, hyperpolarized “down-state” and periods of depolarization called “up-states” that are crowned with robust synaptic activity and action potentials. The shift between upand down-states is a network event because the transitions into and out of these phases are synchronized across large populations of neurons in the cortex (Sanchez-Vives and McCormick, 2000; Seamans et al, 2003; Woodward and Pava, 2009, 2012) This large-scale network activation is generated through the effects of mixed glutamatergic and GABAergic synaptic transmission with glutamate-activated currents serving as a depolarizing force moderated by GABA-mediated conductance that provides a clamp near the Cl− reversal potential (≈ −55 mV). Upstates are dependent upon NMDA, AMPA, and GABAA currents, and up-state parameters are significantly altered by inhibition of Frontiers in Integrative Neuroscience www.frontiersin.org
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