, 1999). The implications of this kind of drug interaction are significant, potentially impacting tobacco awareness programs as well as the treatment of alcohol abuse disorders. For example, should

alcoholics be advised to abstain from tobacco as a means to reduce their drinking? Perhaps a pharmaceutical intervention could discourage excessive drinking among smokers. In pursuit of these ideas, in this issue of Neuron, Doyon et al. (2013) seek to uncover the mechanism by which tobacco use promotes alcohol consumption. They show that a single exposure to nicotine can cause drug-naive rats to self-administer more ethanol over 4 subsequent days than they otherwise would. Doyon et al. (2013) then carefully track down the mechanism underlying this effect and find the culprit to be nicotine-induced selleck chemicals llc increases in stress hormones

acting in the ventral tegmental area. At the center of this study is the regulation of synaptic inputs to dopamine neurons in the midbrain. First, Doyon et al. (2013) confirmed that nicotine and ethanol are both capable of augmenting dopamine Volasertib concentration levels in the nucleus accumbens. They also found that when administered together, the drugs produced additive effects on dopamine levels, consistent with their somewhat divergent mechanisms of regulating dopamine neuron activity (Fagen et al., 2003 and Söderpalm and Ericson, 2013). When nicotine was administered first, however, 3–40 hr prior, ethanol-induced increases in dopamine levels were significantly attenuated. Importantly, nicotine pretreatment did not alter dopaminergic responses to subsequent nicotine injections, indicating that this dopaminergic circuitry is generally capable crotamiton of responding to drugs in a consistent manner. The extended time window during which these nicotine-ethanol interactions were observed, when dopaminergic responses to ethanol were blunted, coincided with the period when nicotine-exposed animals increased their ethanol intake. This

connection is somewhat counterintuitive, that ethanol self-administration rates would rise precisely when dopamine neurons exhibit a muted response to ethanol. However, a blunted dopamine system has previously been associated with increased susceptibility to alcohol abuse (Martinez et al., 2005). There is also evidence that animals self-administer drugs of abuse at a frequency necessary to maintain a specific elevated level of dopamine (Ranaldi et al., 1999), suggesting that the nicotine-pretreated rats may have increased their drinking to compensate for the diminished potency of ethanol on dopaminergic signaling. Ethanol is believed to augment dopamine levels in the nucleus accumbens by increasing the firing rate of ventral tegmental area dopamine neurons. Using brain slice electrophysiology, Doyon et al. (2013) confirmed that bath application of ethanol increases the excitatory drive onto midbrain dopamine neurons, as well as their average firing rate.

For a detailed account of the construction of implantable optical fibers and optical patch cables, see Sparta et al. (2011). Briefly, for chronic fibers 200 μm core, 0.37 NA standard multimode

hard cladding fiber (Thor Labs) was stripped of the cladding, threaded through a Nintedanib clinical trial 230 μm multimode zirconia ferrule, polished, and cut to a length of 6 mm. They were then tested for light output and sterilized using 70% ethanol before implantation into the brain. Optical patch cables connecting the fiber optic rotary joint to the chronic fiber consisted of a 60 μm core multimode fiber (0.22 NA) were threaded through furcation tubing connected to a 127 μm ID bore ceramic zirconia ferrule and a multimode FC multimode ferrule assembly (Precision Fiber products). Optical patch cables connecting the fiber optic rotary interfaced to the laser housing consisted of FC multimode ferrule assemblies on both ends. Light transmission was measured for all implantable

optical fibers before BMN-673 implantation and after the animal was sacrificed. Only optical fibers with > 80% light transmission prior to implantation were used. Two to three weeks after AAV-Ef1a-DIO-ChR2-eYFP virus injection and fiber implantation into the VTA, male VGAT-ires-CRE mice were food restricted to 85–90% of their free-feeding bodyweight. Mice were food restricted for 3 days while also tethered to custom-made optical patch cables for 1 hr/day before they were trained

for habituation purposes. Mice were then trained in sound-attenuated mouse chambers (Med Associates) equipped with a white noise and Resminostat tone generator, cue lights, and a receptacle for sucrose delivery that could detect head entries and individual licks. Mice were trained for one session per day that lasted ∼60 min. Each session consisted of 40 trials wherein a randomized 60–120 s intertrial interval was followed by a 5 s tone/light cue presentation that terminated with delivery of 20 μl of a 10% sucrose solution. During each training session, the chronic optical fiber was connected to a patch cable that interfaced with a FC/PC fiber optic rotary joint (Doric Lenses), which then interfaced with a 473 nm solid-state laser outside the chamber. Mice were trained for 20–25 days until stable responding was observed to both cue and reward presentation. After training, mice underwent behavioral sessions where they received a 5 s laser stimulation (12 mW into the brain) starting either at the onset of the cue or the reward delivery in a counterbalanced fashion. Laser stimulation sessions were always flanked by nonstimulation sessions on the previous and following days, where the laser light was blocked from reaching the brain by a piece of material that prevented light transmission inside the connecter sleeve between the optical patch cable to the chronic fiber.