Comparison of K+ Channel Families.

K+ channels enable potassium to flow across the membrane with great selectivity. There are four K+ channel families: voltage-gated K (Kv), calcium-activated (KCa), inwardly rectifying K (Kir), and two-pore domain potassium (K2P) channels. All four K+ channels are formed by subunits assembling into a classic tetrameric (4x1P = 4P for the Kv, KCa, and Kir channels) or tetramer-like (2x2P = 4P for the K2P channels) architecture. These subunits can either be the same (homomers) or different (heteromers), conferring great diversity to these channels. They share a highly conserved selectivity filter within the pore but show different gating mechanisms adapted for their function. K+ channels play essential roles in controlling neuronal excitability by shaping action potentials, influencing the resting membrane potential, and responding to diverse physicochemical stimuli, such as a voltage change (Kv), intracellular calcium oscillations (KCa), cellular mediators (Kir), or temperature (K2P).

Ethanol Experience Enhances Glutamatergic Ventral Hippocampal Inputs to D1 Receptor-Expressing Medium Spiny Neurons in the Nucleus Accumbens Shell.

A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling in the reward circuit is the nucleus accumbens, more specifically, the dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) within this region, which have been implicated in the formation of dependence to many drugs of abuse including alcohol. D1-MSNs receive glutamatergic input from several brain regions; however, it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. Here, we investigate input-specific adaptations in glutamatergic transmission in response to varying levels of alcohol experience. Virally mediated expression of Channelrhodopsin in ventral hippocampal (vHipp) glutamate neurons of male mice allowed for selective activation of vHipp to D1-MSN synapses. Therefore, we were able to compare synaptic adaptations in response to low and high alcohol experience in vitro and in vivo Alcohol experience enhanced glutamatergic activity and abolished LTD at vHipp to D1-MSN synapses. Following chronic alcohol experience, GluA2-lacking AMPARs, which are Ca permeable, were inserted into vHipp to D1-MSN synapses. These findings support the reversal of alcohol-induced insertion of Ca-permeable AMPARs and the enhancement of glutamatergic activity at vHipp to D1-MSNs as potential targets for intervention during early exposure to alcohol.SIGNIFICANCE STATEMENT Given the roles of the nucleus accumbens (NAc) in integrating cortical and allocortical information and in reward learning, it is vital to understand how inputs to this region are altered by drugs of abuse such as alcohol. The strength of excitatory inputs from the ventral hippocampus (vHipp) to the NAc has been positively associated with reward-related behaviors, but it is unclear whether or how ethanol affects these inputs. Here we show that vHipp-NAc synapses indeed are altered by ethanol exposure, with vHipp glutamatergic input to the NAc being enhanced following chronic ethanol experience. This work provides insight into ethanol-induced alterations of vHipp-NAc synapses and suggests that, similarly to drugs such as cocaine, the strengthening of these synapses promotes reward behavior.

Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia.

RATIONALE: Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement. OBJECTIVE: Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats. METHODS: Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg kg(-1) infusion(-1) paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session. RESULTS: Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation. CONCLUSION: These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse.