Melanin concentrating hormone (MCH) is a cyclic neuropeptide present in the hypothalamus of all vertebrates. MCH is implicated in a number of behaviors but direct evidence is lacking. To selectively stimulate the MCH neurons the gene for the light-sensitive cation channel, channelrhodopsin-2, was inserted into the MCH neurons of wild-type mice. Three weeks later MCH neurons were stimulated for 1 min every 5 min for 24 h. A 10 Hz stimulation at the start of the night hastened sleep onset, reduced length of wake bouts by 50%, increased total time in non-REM and REM sleep at night, and increased sleep intensity during the day cycle. Sleep induction at a circadian time when all of the arousal neurons are active indicates that MCH stimulation can powerfully counteract the combined wake-promoting signal of the arousal neurons. This could be potentially useful in treatment of insomnia.

The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (post-natal day 28–42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive-ratio responding for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex and hypothalamus) were significantly different in AIE exposed adults compared to litter-matched control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.

Stimulation of α 2 -noradrenergic (NA) receptors within the PFC improves working memory performance. This improvement is accompanied by a selective increase in the activity of PFC neurons during delay periods, although the cellular mechanisms responsible for this enhanced response are largely unknown. Here we used current and voltage clamp recordings to characterize the response of layer V-VI PFC pyramidal neurons to α 2 -NA receptor stimulation. α 2 -NA receptor activation produced a small hyperpolarization of the resting membrane potential, which was accompanied by an increase in input resistance and evoked firing. Voltage clamp analysis demonstrated that α 2 -NA receptor stimulation inhibited a caesium and ZD7288-sensitive hyperpolarization-activated (HCN) inward current. Suppression of HCN current by α 2 -NA stimulation was not dependent on adenylate cyclase but instead required activation of a PLC-PKC linked signalling pathway. Similar to direct blockade of HCN channels, α 2 -NA receptor stimulation produced a significant enhancement in temporal summation during trains of distally evoked EPSPs. These dual effects of α 2 -NA receptor stimulation -membrane hyperpolarization and enhanced temporal integration -together produce an increase in the overall gain of the response of PFC pyramidal neurons to excitatory synaptic input. The net effect is the suppression of isolated excitatory inputs while enhancing the response to a coherent burst of synaptic activity.

Background Chronic methamphetamine abusers exhibit deficits in tasks requiring intact prefrontal cortex (PFC) function, and PFC dysfunction has been implicated in the loss of control over drug use. The current study used a combination of behavioral and electrophysiological assessments in rats with a history of long access methamphetamine self-administration to determine methamphetamine-induced changes in PFC-dependent attentional set-shifting performance, drug-seeking, and PFC neuronal activity. Methods Male Long-Evans rats self-administered methamphetamine (0.02 mg/infusion, i.v.) or received yoked saline infusions for 6 hours/day for 14 days. Cognitive flexibility was assessed using an attentional set-shifting task prior to 2 weeks of self-administration and one day after self-administration. Animals then underwent 11 days of abstinence, followed by three subsequent tests for context-induced drug-seeking. Finally, animals were anesthetized and single-unit in vivo extracellular recordings were performed in the dorsomedial PFC. Results Methamphetamine-experienced rats showed escalated drug intake and context-induced drug-seeking following abstinence. During the extra-dimensional set-shift component, meth-experienced rats showed selective impairments that were identical to deficits produced by excitotoxic lesions of the PFC. Rats with a history of chronic methamphetamine intake also exhibited higher basal firing frequency and a significantly greater proportion of burst-firing cells in the PFC as compared to yoked-saline controls. Conclusions PFC-specific alterations in neuronal function may play a key role in methamphetamine-induced attentional deficits and drug-seeking. These data support the possibility that targeting PFC pathology may improve treatment outcome in methamphetamine addiction.

Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB. CDPPB treatment reduced active lever responding during extinction, decreased the total number of extinction sessions required to meet criteria, and attenuated cue-induced reinstatement of ethanol seeking. CDPPB facilitation of extinction was blocked by the local infusion of the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl) pyridine into the infralimbic (IfL) cortex, but had no effect when infused into the prelimbic (PrL) cortex. Analysis of dendritic spines revealed alterations in structural plasticity, whereas electrophysiological recordings demonstrated differential alterations in glutamatergic neurotransmission in the PrL and IfL cortex. Extinction was associated with increased amplitude of evoked synaptic PrL and IfL NMDA currents but reduced amplitude of PrL AMPA currents. Treatment with CDPPB prevented the extinction-induced enhancement of NMDA currents in PrL without affecting NMDA currents in the IfL. Whereas CDPPB treatment did not alter the amplitude of PrL or IfL AMPA currents, it did promote the expression of IfL calcium-permeable GluR2-lacking receptors in both abstinence-and extinction-trained rats, but had no effect in ethanol-naive rats. These results confirm changes in the PrL and IfL cortex in glutamatergic neurotransmission during extinction learning and demonstrate that manipulation of mGluR5 facilitates extinction of ethanol cues in association with neuronal plasticity.