The Journal of neuroscience : the official journal of the Society for Neuroscience
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The use of cannabis sativa preparations as recreational drugs can be traced back to the earliest civilizations. However, animal models of cannabinoid addiction allowing the exploration of neural correlates of cannabinoid abuse have been developed only recently. We review these models and the role of the CB1 cannabinoid receptor, the main target of natural cannabinoids, and its interaction with opioid and dopamine transmission in reward circuits. Extensive reviews on the molecular basis of cannabinoid action are available elsewhere (Piomelli et al., 2000; Schlicker and Kathmann, 2001).
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Addictive behavior associated with alcoholism is characterized by compulsive preoccupation with obtaining alcohol, loss of control over consumption, and development of tolerance and dependence, as well as impaired social and occupational functioning. Like other addictive disorders, alcoholism is characterized by chronic vulnerability to relapse after cessation of drinking. To understand the factors that compel some individuals to drink excessively, alcohol research has focused on the identification of brain mechanisms that support the reinforcing actions of alcohol and the progression of changes in neural function induced by chronic ethanol consumption that lead to the development of dependence. More recently, increasing attention has been directed toward the understanding of neurobiological and environmental factors in susceptibility to relapse.
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We have previously shown (Otani et al., 1999b) that bath application of (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV), the agonist of group II metabotropic glutamate receptors (mGluRs), induces postsynaptic Ca2+-dependent long-term depression (LTD) of layer I-II to layer V pyramidal neuron glutamatergic synapses of rat medial prefrontal cortex. In the present study, we examined detailed mechanisms of this DCG IV-induced LTD. First, the group II mGluR antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester blocked DCG IV-induced LTD, and another group II agonist (2S,3S,4S)-CCG/(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine-induced LTD, suggesting that LTD is indeed mediated by the activation of group II mGluRs. ⋯ Fourth, fluorescent Ca2+ analysis techniques revealed that DCG IV increases Ca2+ concentration in prefrontal layer V pyramidal neurons. These Ca2+ rises and the LTD were both blocked by postsynaptic heparin in the same cells. Taken together, these results suggest that postsynaptic group II mGluRs, linked to phospholipase C and probably also phospholipase D, induce LTD through postsynaptic PKC activation and IP3 receptor-mediated postsynaptic increases of Ca2+ concentration.
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Our goal was to investigate whether the neurokinin-1 receptor (NK1R)-expressing cells of the rostral ventrolateral medulla (RVLM) regulate respiration and arterial pressure (AP). We examined the consequences of their ablation on the cardiorespiratory responses [phrenic nerve discharge (PND) and AP] caused by injecting dl-homocysteic acid (DLH) into the ventral respiratory group (VRG). In intact rats, DLH produced tachypnea only when injected into the pre-Bötzinger complex (pre-BötC). ⋯ The hypotension produced by DLH injection into pre-BötC and rVRG of SSP-SAP-treated rats was reduced on the lesioned side only. In conclusion, NK1R-expressing cells of the rostral ventrolateral medulla control both respiratory rhythm and blood pressure. However, there is no evidence yet that these two functions are regulated by the same NK1R-expressing neurons.
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Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. ⋯ There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.