Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress. The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates. Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse.

The possible interactions between Δ9-tetrahydrocannabinol (THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of THC administration on the somatic manifestations and the aversive motivational state associated to nicotine withdrawal in mice. Acute THC administration significantly decreased the incidence of several nicotine withdrawal signs precipitated by mecamylamine or naloxone, such as wet-dog-shakes, paw tremor and scratches. In both experimental conditions, the global withdrawal score was also significantly attenuated by acute THC administration. THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. We have then

Mice lacking the neurokinin-1 (NK1) receptor, the preferred receptor for the neuropeptide substance P (SP), do not show many of the behaviors associated with morphine reward. To identify the areas of the brain that might contribute to this effect, we assessed the behavioral effects of ablation of neurons expressing the NK1 receptor in specific regions of the mouse brain using the neurotoxin substance P-saporin. In a preliminary investigation, bilateral ablation of these neurons from the amygdala, but not the nucleus accumbens and dorsomedial caudate putamen, brought about reductions in morphine reward behavior. Subsequently, the effect of ablation of these neurons in the amygdala on anxiety behavior was assessed using the elevated plus maze (EPM), before conditioned place preference (CPP), and locomotor responses to morphine were measured. Loss of NK1 receptor-expressing neurons in the amygdala caused an increase in anxiety-like behavior on the EPM. It also brought about a reduction in morphine CPP scores and the stimulant effect of acute morphine administration relative to saline controls, without affecting CPP to cocaine. NK1 receptor-expressing neurons in the mouse amygdala therefore modulate morphine reward behaviors. These observations mirror those observed in NK1 receptor knock-out (NK1-/-) mice and suggest that the amygdala is an important area for the effects of SP and the NK1 receptor in the motivational properties of opiates, as well as the control of behaviors related to anxiety.

h Changes in nuclear Ca 2؉ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K ؉ channel interacting protein 3), is a Ca 2؉ -binding protein that binds DNA and represses transcription in a Ca 2؉ -dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca 2؉ -insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activitydependent gene expression programs that control synaptic plasticity, learning, and memory.A major challenge for neuroscience is to identify the regulatory molecules underpinning the storage of information in neurons. Activity-dependent gene expression underlies neuronal plasticity and adaptive responses to different environmental stimuli in the central nervous system (CNS) and is determinant in the formation and storage of memories. Diverse signaling pathways participate in these processes. Among them, changes in intracellular free calcium concentration are the most universal signal, and the final output, in terms of adapted gene expression, is given by a specific set of proteins that decode the calcium signal according to its frequency, subcellular location, and intensity (1-3). A nuclear tool kit of Ca 2ϩ -dependent effectors modifies the activity or the properties of specific transcription factors to regulate gene expression in response to the Ca 2ϩ signal (for reviews, see references 4 and 5). Despite extensive investigation, a detailed mechanistic description of Ca 2ϩ -dependent signaling in the expression of the late, transcription-dependent component of long-term potentiation (LTP) is far from been complete (reviewed in reference 6). Here, we examine the role of the Ca 2ϩ -dependent transcriptional repressor DREAM (downstream regulatory element antagonist modulator) in the control of activity-dependent transcription and the expression of LTP, as well as in learning and memory.The DREAM/calsenilin/KChIP-3 gene belongs to a group of four genes (encoding K ϩ channel interacting proteins 1 to 4 [KChIP-1 to -4]) that regulate the membrane expression and gating of Kv4 potassiu...