, 2009). Importantly, this response is regulated by two distinct signal transduction cascades, both of which are downstream of a major target of drug-induced increases in striatal

dopamine concentration: the activation of dopamine D1 receptors in the striatonigral (direct) pathway. H3S10 phosphorylation is positively regulated by the same MAPK pathways reviewed above, including phosphorylation of ERK and MSK-1-induced phosphorylation of H3 ( Bertran-Gonzalez et al., 2008 and Brami-Cherrier et al., 2005). Likewise, nuclear accumulation of 32 kDa dopamine and cyclic-AMP-regulated phosphoprotein (DARPP-32), which also occurs following D1 receptor activation, acts to inhibit PP1, thereby preventing histone dephosphorylation http://www.selleckchem.com/products/fg-4592.html ( Stipanovich et al., 2008). Critically, these pathways are instrumental in controlling behavioral responses to cocaine and morphine, as inhibition of D1 receptors, ERK, DARPP-32, and MSK-1, all diminish drug-induced locomotor responses or drug CPP ( Brami-Cherrier et al., 2009, Brami-Cherrier et al., 2005 and Stipanovich et al., 2008). Much like the emergent evidence that DNA methylation regulates hippocampal-dependent memory formation, recent reports have revealed that DNA methylation in

the striatum is associated with drug-related behaviors. For example, acute learn more cocaine administration produces rapid changes in expression of DNMT isoforms within the nucleus accumbens (Anier et al., 2010 and LaPlant et al., 2010), suggesting dynamic control of DNA methylation by drugs of abuse. Consistent with this observation, cocaine produces a hypermethylation at the promoter

region of PP1c (the catalytic subunit of PP1) in the nucleus accumbens, resulting in enhanced MeCP2 binding to the PP1c promoter ( Anier et al., 2010). Conversely, cocaine decreases methylation at the FosB Tolmetin promoter, which coincides with the transcriptional upregulation of FosB and is consistent with the observed decrease in MeCP2 binding to FosB ( Anier et al., 2010). Importantly, systemic inhibition of DNA methyltransferase activity significantly impairs the development of locomotor sensitization induced by repeated cocaine administration ( Anier et al., 2010), and site-specific DNMT inhibition in the nucleus accumbens boosts the development of cocaine CPP ( LaPlant et al., 2010). In contrast, overexpression of the DNMT3a isoform within the nucleus accumbens disrupts cocaine CPP ( LaPlant et al., 2010), whereas MeCP2 knockdown in the dorsal striatum prevents escalation of cocaine self-administration during extended access ( Im et al., 2010). Additionally, DNA methylation within the hippocampus and prelimbic cortex is also necessary for the establishment and maintenance of cocaine CPP, respectively, indicating that epigenetic changes in brain regions outside of the striatum are also key regulators of drug memories ( Han et al., 2010).

, 1981). The in vitro

methods provide means to screen rapidly for potential anthelmintic activities of different plant extracts and to analyze the possible mechanisms involved in the interactions between active compounds and parasites. C. schoenanthus showed the best anthelmintic activity in vitro. Thus, based on the LC50 of 24.66 mg/ml obtained for C. schoenanthus in LEA, an approximate dose of 1.18–2.45 g of oil/kg STI571 in vitro body weight (BW) would provide a 50% reduction in exsheathment and worm reduction considering an animal of 40 kg and 2–4l abomasal volume. However, sometimes the effect in vitro or in a different animal system can be lower than when tested in the target host. A recent illustration of this point is the work with orange emulsion oil, where 600 mg of the oil emulsion per kg BW caused 7% and PLX3397 cost 62.6% worm reduction in gerbils with a single dose or daily for five days, respectively ( Squires et

al., 2010). However, when these authors tested the emulsion with 600 mg of orange oil per kg BW in sheep infected with H. contortus, it resulted in a 97.4% reduction in fecal egg count (adult worm reduction was not evaluated). Although encouraging, these results must be interpreted with caution because of the high doses of the preparation (40% orange terpenes, 20% Valencia orange oil, 4% polysorbate 80, and 1.5% hydrogen peroxide) required for anthelmintic effects. The authors Tolmetin mentioned that few lambs presented toxicity signs such as head shaking and feed aversion. These symptoms may be aggravated if the active component(s) has(ve) a low LD50. In the case of the orange oils used, the authors ( Squires et al., 2010) reported that >95% was d-limonene, which has a high LD50 (5000 mg/kg). When a potential compound or plant extract is found, more comprehensive studies are needed

to assess its bioavailability. How much is being absorbed and metabolized versus how much is being disposed in gastrointestinal content, and which metabolites are being generated. Besides nematocidal effect, plant extracts/compounds are tested for their ability to impair egg hatching and larval development from feces of infected animals treated with those plant extracts. Desired effects can result in reduced re-infection and lighter worm loads leading to decreased pasture contamination levels (Ketzis et al., 2002 and Max, 2010). In vivo tests, problems with absorption through the gastrointestinal tract, and compound solubility and stability after oral intake are the main obstacles in developing herbal formulations with good bioavailability and anthelmintic efficacy. According to Stepek et al. (2007), given the sensitivity to pH, it is not surprising that plant enzymes for instance have lower efficacy against stomach nematodes in situ than against those residing further down the gastrointestinal tract.

Vascuri et al10 reported synthesis and characterization of related substances of paliperidone. Few impurities in paliperidone have been also reported by Jadhav et al,11 out of which two were identified as degradation products, but their degradation chemistry is not reported. In reported methods9 and 11 photolytic stress studies have been carried

out for drug in only solid state. With this background it was really necessary to characterize all possible degradation products of paliperidone under various stress conditions in accordance with regulatory guidelines.2 and 3 The present manuscript describes the (i) degradation behaviour of paliperidone under hydrolysis (acid, alkali and neutral), oxidation, photolysis and thermal stress conditions, (ii) optimization of LC conditions to separate the drug and its degradation products on a reversed PLX-4720 mw phase C18 column, (iii) method SKI-606 mouse validation, (iv) characterization of degradation products with the help LC–MS experiments and (v) proposed fragmentation

pathways of degradation products. Paliperidone was supplied by Cadila Healthcare Ltd. (Ahmedabad, India). Acetonitrile and methanol (HPLC grade) were procured from Merck (Mumbai, India) and used without purification. Analytical reagent grade (AR) hydrochloric acid, sodium hydroxide pellets, hydrogen peroxide solution were purchased from S. D. Fine Chemicals (Mumbai, India). Ultrapure water was obtained from a water purification unit (Elga Ltd., Bucks, England). Buffer materials and all other chemicals were of AR grade. High precision water bath equipped tuclazepam with MV controller (Lab-Hosp Corporation, M.S., India) capable of controlling the temperature with in ±1 °C was used for generating hydrolytic degradation products. The thermal degradation study was performed using a high precision hot air oven (Narang Scientific Works, New Delhi, India) capable of controlling temperature with in ±2 °C. Photo degradation study was carried out in a photostability chamber (GMP, Thermolab Scientific Equipments Pvt. Ltd., Mumbai, India). The analyses were carried out on

Jasco HPLC (Jasco International Co., Tokyo, Japan) equipped with binary pump (PU-2080 plus), solvent mixing module (MX-2080-31), multi-wavelength PDA detector (MD-2010 plus), an interface box (LC-NET ΙΙ/ADC), a rheodyne manual injector (7725i, USA) and chrompass data system software ver. 1.8.1.6. The separations were carried out on a Hypersil Gold C18 (4.6 × 250 mm, 5 μm) analytical column (Thermo Scientific, Japan). The LC–MS analyses were carried out on a 500-MS LC Ion Trap Mass spectrophotometer (Varian Inc., USA) in which the HPLC part comprised of an auto sampler (410, Prostar), solvent delivery module (210, Prostar), column valve module (500, Prostar), PDA Detector (355, Prostar), fraction collector (710, Prostar). The data acquisition was under the control of 500-MS workstation software.

, 2002, Miller and Bloomfield, 1983 and Vaney, 1990). In contrast to most retinal neurons, SACs display an extensive dendritic overlap (Tauchi and Masland, 1984), Everolimus which enables them to provide independent neuronal hardware for the different functional subtypes of DS cells. It has been

proposed earlier that SACs are importantly involved in the DS computation (Borg-Graham and Grzywacz, 1992, Masland et al., 1984a and Vaney et al., 1989), but experimental proof for this notion came less than 10 years ago, when it was shown that massive ablation of SACs results in a selective loss of retinal direction selectivity (Amthor et al., 2002 and Yoshida et al., 2001; but see He and Masland, 1997). Optical measurements of light-stimulus-evoked

Ca2+ concentration changes (Denk and Detwiler, 1999) in the dendrites of SACs demonstrated that stimuli moving this website from the soma to the dendritic tips, i.e., centrifugal motion, evoked larger Ca2+ responses in the distal dendrites than motion in the opposite direction, i.e., centripetal motion (Figure 5B2) (Euler et al., 2002). Because SAC output synapses are located in the distal dendrites (Famiglietti, 1991) and transmitter release from SACs is Ca2+-dependent (O’Malley et al., 1992 and Zheng et al., 2004), this indicated that SACs are able to provide DS ganglion cells with directionally tuned input. In fact, since the dendritic sectors are electrically isolated from each other, each sector can be thought of as an independent detector for centrifugal motion (Figure 5B3). Around the same time, the related long-standing question as to whether retinal direction selectivity is computed in the ganglion cells themselves or presynaptically by interneurons (reviewed in Masland, 2004) was successfully addressed. Patch-clamp studies revealed that the synaptic input to ON/OFF DS cells

is already DS TCL (Borg-Graham, 2001, Fried et al., 2002 and Taylor and Vaney, 2002): Preferred direction motion elicits more excitation and less inhibition in the ganglion cells, whereas null direction motion elicits more inhibition and less excitation. This suggested (1) that both inhibitory and excitatory inputs are DS, (2) that the Barlow-Levick model does not fully capture retinal DS computations, and (3) that the latter are indeed already performed presynaptically by interneurons. Note that the latter point does not exclude that postsynaptic, i.e., ganglion cell-intrinsic mechanisms contribute to the overall direction selectivity observed in ganglion cells (see Mechanisms at the Ganglion Cell Level). It was already known for long that blocking GABAA receptors abolishes DS responses in the ganglion cells but leaves their responsiveness intact (Caldwell et al., 1978 and Massey et al., 1997).

, 2010). A hypothetical advantage

of using GFP as a neuronal tracer rather than transported dyes is the fact that GFP reputedly moves through the cell through passive diffusion rather than axonal transport, and is not accordingly vulnerable to artifacts associated with injury-related changes in axonal transport. That is, rates of axonal transport increase after neural injury, and greater tracer labeling in an axon may reflect accelerated transport Fulvestrant mouse rather than true structural change; GFP may not be subject to this potential artifact. Viral vectors expressing GFP may also be employed elegantly to study the effects of genetic manipulation of axonal growth. For example, we have utilized an AAV vector coding for a candidate regeneration-associated gene that also expresses the GFP reporter; a neuron that incorporates the AAV vector will

both express the candidate gene and label that neuron’s axon with GFP. This ATM Kinase Inhibitor molecular weight allows specific assessment of a gene effect on growth only in transduced neurons, potentially enhancing the sensitivity to detect an effect on growth (Löw et al., 2010). Transgenic mice can be a very useful model for examining the role of specific genes in axonal growth after adult injury. Several points must be considered when interpreting results from these models, however.

First, genes that are deleted in neural development may perturb development of spinal pathways, leading to uncertainties regarding interpretation of results after adult injury. For example, early post-natal deletion of PTEN enhanced CST growth after spinal cord injury (Liu et al., 2010); however, deletion at this stage, while the CST is developing, could have altered the anatomy of its spinal projections with the result that partial lesion models in the adult failed to remove aberrant axon projections. Accordingly, a precise survey of the anatomy of the CST Idoxuridine projection in adult unlesioned PTEN-deletion mice was required to confirm that axons were not in locations that would be inadvertently spared (Liu et al., 2010). Another caveat of transgenic mouse models in regeneration research is the possibility that developmental compensation may occur for loss of the targeted gene, leading to erroneous conclusions regarding the role of the deleted gene. Finally, a caveat to studies of axon regeneration in mice is a unique wound healing response that occurs at the lesion site, which results in a contracted, cell-rich lesion (Zhang et al., 1996) rather than a large, cystic lesion cavity. Accordingly, it remains to be seen whether manipulations that enable axon growth in mice will also be effective in other species.

Ectopic activity can also contribute to central sensitization, as discussed below. What drives a normally quiet sensory axon, designed only to conduct action potentials, EGFR cancer to begin to initiate action potentials? Nerve injury drastically changes the expression, distribution,

and phosphorylation of many ion channels in sensory neurons leading to changes in intrinsic membrane properties and the generation of membrane potential oscillations resulting in rhythmic firing bursts in the absence of a stimulus. Which ion channels are modified as a direct or indirect consequence of a nerve injury or lesion? As for most neurons, the membrane potential in sensory neurons is largely determined by potassium channels. The two-pore domain

K+ channels TRESK (K2p18.1) and TREK-2 (K2p10.1) represent approximately 85% of K+ background current in DRG neurons (Dobler et al., 2007 and Kang and Kim, 2006) with TRESK being particularly highly expressed in the DRG (Allen Brain Atlas). After injury, TRESK is downregulated by 30%–40% leading to a steady depolarization of the sensory neuronal membrane potential (Tulleuda et al., 2011). However, reduction in potassium leak current cannot be the sole cause of ectopic activity. Subthreshold membrane potential oscillations, find more largely carried by the persistent component of the sodium current, INaP, are frequently seen in injured sensory neurons and may be a major contributor to ectopic spike discharge (Amir et al., 1999). Computer modeling and pharmacological inhibition support the importance of INaP for spontaneous activity in injured neurons (Kovalsky et al., 2009 and Xie et al., 2011), even if the specific molecular identity of the responsible sodium channel remains uncertain. Most likely for injured sensory neurons, this current is generated by non-inactivating Nav1.3- and Nav1.6-mediated currents; but there is also evidence

that Nav1.9 is involved enough (Dib-Hajj et al., 2010, Enomoto et al., 2007 and Herzog et al., 2001). In addition, it is possible that the persistent current is modified by changes in the expression of auxiliary sodium channel β subunits in injured and uninjured fibers, which may alter trafficking and kinetics (Pertin et al., 2005 and Zhao et al., 2011). Membrane potential oscillations, spontaneous activity, and neuropathic pain behavior have also been attributed to the mixed cation current Ih conducted by hyperpolarization-acivated cyclic nucleotide-gated (HCN) channels. Large sensory neurons mainly express HCN1, while small sensory neurons predominantly express HCN2 (Biel et al., 2009, Emery et al., 2011, Momin et al., 2008 and Moosmang et al., 2001). In rodent models of neuropathic pain, low concentrations of the nonspecific HCN antagonist ZD7288 strongly reduce pain behavior and spontaneous firing in injured fibers (Chaplan et al., 2003 and Lee et al., 2005).

This axon-specific switch primes RhoA for degradation in the axon while Par6 becomes stabilized ( Figure 1). The substrate switch of Smurf1 can be induced extracellularly via a protein kinase A (PKA)-dependent pathway. Whereas neuronal polarization happens spontaneously in vitro and is based on cell-intrinsic Venetoclax mechanisms, extracellular cues can regulate axon specification and play an important role in vivo. Previous studies have shown that the localized exposure of extracellular polarizing

factors to one neurite can transform this neurite into an axon. These factors include transforming growth factor β (TGFβ) (Yi et al., 2010), brain-derived neurotrophic factor (BDNF) or cAMP (Shelly et al., 2007). As previously shown, neurons, plated on the border of stripes coated with BDNF or cAMP, preferentially initiate their axons toward the cAMP or BDNF stripe (Shelly et al., 2007). Cheng and colleagues (2011) provide

now evidence that the extracellularly stimulated polarization involves selective degradation via the ubiquitin/proteasome system (UPS). Preferential polarization through BDNF/cAMP was blocked by LY294002 global inhibition of the UPS. Moreover, local inhibition of the UPS in only one neurite using stripes coated with proteasome inhibitors triggered axon formation mimicking BDNF or cAMP exposure. The authors then examined whether these cues differentially regulate ubiquitination and degradation of candidate polarity regulators. Importantly, they found that BDNF and the cell-permeable db-cAMP increased the stability of the polarity regulators Par6 and LKB1, whereas the growth inhibitory molecule RhoA was degraded. Consistently, db-cAMP stimulation decreased the ubiquitination of Par6 and LKB1, but enhanced RhoA ubiquitination. To better understand the pathways in this process, the authors performed a screen during to find the E3 ligases responsible for the ubiquitination of the axonal

proteins. They found that Par6 is a direct substrate of the E3 ligase Smurf1 and that only Smurf1 targets Par6 for proteasomal degradation, but not other E3 ligases, including Smurf2. Consistently, downregulation of Smurf1 or overexpression of a ligase-deficient Smurf1 mutant increased Par6 and RhoA protein levels. The most intriguing observation is the converse ubiquitination of Par6 and RhoA by Smurf1 upon BDNF/cAMP stimulation. How is this opposite ubiquitination of the two substrates achieved? Are the substrates differently primed for their ubiquitination or is the substrate specificity regulated by the ligase itself? BDNF activates PKA (Shelly et al., 2007). The observed stabilization of Par6 and LKB1 as well as the degradation of RhoA was diminished by inhibiting PKA-dependent phosphorylation. Interestingly, upon BDNF/cAMP treatment, PKA did not phosphorylate the substrates themselves, but the ligase Smurf1.

We observed that the LTP and STD induced by SO preceding

SC stimulation, which were sensitive to MLA, were entirely absent in slices from the α7 nAChR KO mice, although we observed the plasticity in the wild-type littermates (Figures 2E and 2F). Furthermore, as expected, the mAChR-dependent LTP was unchanged in the α7 nAChR KO mice (Figure 2G). Because AChRs in the hippocampus are located both presynaptically and postsynaptically, the contribution of both sites to the various forms of plasticity we have observed was examined by comparing the changes of the paired-pulse ratio (PPR); an increase in the PPR, where the second pulse is increased selleck chemicals relative to first pulse, suggests decreased presynaptic release, whereas a decreased ratio suggests increased synaptic release (Dobrunz and Stevens, 1997). For the α7 nAChR-dependent LTP (pairing SO 100 ms before SC), the PPR was decreased initially, and then returned to the

baseline (Figure 3A). This suggests that an increased presynaptic release may account for the early potentiation Galunisertib of the EPSCs, but not the late stage. For the α7 nAChR-mediated STD by pairing SO 10 ms before SC, PPR was increased transiently in a time course that fit the time course of the decrease in amplitude of the EPSCs (Figure 3B). This correlation strongly suggests that the STD was mainly mediated through presynaptic inhibition. The PPR was virtually unchanged for the mAChR-mediated LTP (pairing SO 10 ms after SC) (Figure 3C), suggesting that a postsynaptic mechanism is more likely to be mediating this particular form of LTP. The molecular mechanisms underlying the α7 nAChR-dependent LTP were further studied. Because the activation of the α7 nAChR is known to mediate calcium influx, we first tested whether intracellular calcium chelation could block this form of LTP. Intracellular dialysis of the CA1 pyramidal neuron with the calcium chelator BAPTA (10 mM) completely blocked this form

of LTP (Figure 4A), suggesting a mechanism requiring postsynaptic calcium. Thus, the α7 nAChR activation may act as a source of calcium in inducing this form of LTP. Interestingly, this LTP Sodium butyrate was also blocked by the NMDAR antagonist AP5 (50 μM) (Figure 4B). Thus, activation of either the α7 nAChR or NMDAR could serve as a source of calcium. Finally, we tested whether this LTP requires the postsynaptic insertion of GluR2-containing AMPARs, which previously have been shown to mediate LTP in hippocampal CA1 spines (Yao et al., 2008). Indeed, dialyzing pyramidal cells with pep2m (100 μM), a peptide containing the NSF (N-ethylmaleimide-sensitive fusion protein)-binding site to GluR2 and, thus, interrupting GluR2-containing AMPAR synaptic insertion, effectively blocked the late stage (about 30 min after the induction of LTP) of the α7 nAChR-dependent LTP (Figure 4C).

Morphologically, the Ruffini ending is similar to the Golgi tendon organ, it is a large (200–100 μm) and thin spindle-shaped cylinder composed

of layers of perineural tissue including Schwann cells and collagen fibers and an inner core composed of nerve terminals surrounded by a capsule space filled with fluid (Chambers et al., 1972 and Halata, 1977). In humans, each SAII axon possesses a low-threshold region, suggesting that a single Aβ fiber supplies each receptor organ (Johansson and Vallbo, 1980). Unlike the Merkel cell-neurite complex, the Aβ fibers that make up SAII-LTMRs are suggested to sense mechanical stretch applied to collagen fibers of the Ruffini ending (Maeda et al., 1999 and Rahman et al., 2011). It is unlikely, however, that in

the mouse Ruffini endings or Ruffini-like structures give rise to SAII-LTMR responses, as such structures have not been identified in rodents. Furthermore, rodent SAII-LTMRs have been observed CHIR-99021 cell line after stimulation of hairy skin in an ex vivo skin/nerve preparation in which deep structures such as muscles and associated joints are removed (Wellnitz et al., 2010 and Zimmermann et al., 2009). Therefore, the functions of SAII-LTMRs in different animal species and the morphological properties of SAII-LTMR endings remain unknown. The other physiologically defined mechanosensor is the RA receptor, which responds best to objects moving across the skin but less well to static indentation. As with SA-LTMRs, RA-LTMRs can be further divided into two categories: RAI- and RAII-LTMRs. In the simplest interpretation, L-NAME HCl they merge into a psychophysical frequency GSK-3 inhibitor review continuum, with RAI responses generally associated with small receptive fields and low-frequency vibrations, such as tapping and flutter (1–10 Hz), while RAII responses are associated with larger receptive fields and high-frequency vibrations (from 80–300 Hz) (Knibestol, 1973, Talbot et al., 1968 and Vallbo and Johansson, 1984). Anatomically, both are associated with corpuscles, which may be significant to both their rapidly adaptive properties and the tactile functions they subserve. RAI-LTMRs and Meissner Corpuscles. One of the hallmarks of rapidly adapting responses

is the firing of action potentials only at the initial and final contacts of a mechanical stimulus (Table 1). The percept initially associated with activation of RAI-LTMRs innervating the hand was the feeling of rapid skin movement or “flutter,” and, therefore, the first function ascribed to RAI-LTMRs was detection and scaling of low-frequency vibrations (Torebjörk and Ochoa, 1980). However, RAI-LTMRs possess other response properties that may be specialized for a unique function in grip control. First, in comparison to SAI-LTMRs, RAI-LTMRs are about four times more sensitive, yet respond with far less spatial acuity to stimuli moving across their receptive fields. Second, RAI-LTMRs respond consistently and with very short latencies to skin stimulation.

At the

moment, the simplicity of the neuronal activity hypothesis is most compelling and potentially testable by precise depth-dependent electrophysiological measures in these areas ( Maier et al., 2010). The authors further go on to suggest an extremely intriguing possibility: that these hemodynamics not only apply to negative activation-induced BOLD signal changes at steady state, but also to the negative BOLD signal changes that occur following cessation of activation, known as the post-stimulus undershoot (Chen and Pike, 2009). Data suggest that CBV remains elevated in middle layers while GSK126 chemical structure CBV and CBF at the surface quickly return to baseline. Might spatially adjacent as well as post-stimulus activity therefore be related to inhibitory neuronal activity? This seems quite possible, and to test this hypothesis, it would be relatively easy to collect layer-specific postundershoot

data from Palbociclib clinical trial a variety of cortical areas. As is often the case with cutting-edge work such as this, more questions are raised than answered. In this case, these questions may lead to avenues of investigation that could explain more fully the nature of the BOLD and hemodynamic response. While the initial aim of this paper, toward using laminar profile activation (Chen et al., 2012; Olman et al., 2012; Siero et al., 2011; Uğurbil, 2012) to disentangle feedforward, feedback, excitatory, and inhibitory processing, may still remain somewhat elusive until the underlying hemodynamic processes are fully resolved, the study opens up exciting new questions about the nature of the BOLD response. In terms of implications for human fMRI, while VASO is certainly an option for

human investigation, the emergence of human use of ferumoxytol (Qiu et al., 2012) potentially offers an avenue for measurement of CBV changes in humans with much higher sensitivity than previously possible. Such technical advances should allow oxyclozanide researchers to address these questions with a wider array of activation paradigms in humans. “
“Nucleus accumbens dopamine (DA) has been implicated in several behavioral functions related to motivation. Yet the specifics of this involvement are complex and at times can be difficult to disentangle. An important consideration in interpreting these findings is the ability to distinguish between diverse aspects of motivational function that are differentially affected by dopaminergic manipulations. Although ventral tegmental neurons have traditionally been labeled “reward” neurons and mesolimbic DA referred to as the “reward” system, this vague generalization is not matched by the specific findings that have been observed. The scientific meaning of the term “reward” is unclear, and its relation to concepts such as reinforcement and motivation is often ill defined.