Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR)-mediated synaptic transmission in the brain has been proposed as a cellular substrate for learning and memory. The expression of LTD in the nucleus accumbens (NAc) required clathrin-dependent endocytosis of postsynaptic AMPARs. NAc LTD was blocked by a dynamin-derived peptide that inhibited clathrin-mediated endocytosis or by a GluR2-derived peptide that blocked regulated AMPAR endocytosis. Systemic or intra-NAc infusion of the membrane-permeable GluR2 peptide prevented the expression of amphetamine-induced behavioral sensitization in the rat.
Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N-methyl-D-aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stressinduced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.glutamate transporter ͉ interference peptide ͉ synaptic plasticity ͉ water maze ͉ corticosterone C ognitive functions such as learning and memory are greatly affected by stress. Memory retrieval in humans is especially vulnerable to acute psychological stress (1) or cortisol treatment (2), effects caused in part by alterations in medial temporal lobe function (3). In rodents, acute stress or administration of glucocorticoids disrupts the retrieval of hippocampal-dependent spatial memory (4). Furthermore, stress and glucocorticoids have a profound influence on the physiology of the hippocampal CA1 region by inhibiting long-term potentiation (LTP) (5-7) and enabling long-term depression (LTD) (7,8), the two most well characterized forms of synaptic plasticity and proposed cellular substrates for learning and memory (9, 10). However, it remains to be established whether the alterations in either LTP or LTD caused by stress contribute to the stress-induced impairment of spatial memory retrieval.Considerable experimental evidence supports the role of hippocampal LTP in spatial memory (11)(12)(13)(14), and theoretical accounts of associative memory, based on neural network models, suggest that a balance between LTP and LTD may underlie efficient memory storage (10, 15). By using two recently developed specific inhibitors of LTD (16, 17), the present experiments assess the role of LTD in the spatial memory retrieval deficits induced by acute stress and provide strong evidence for a role of hippocampal LTD in mediating this aspect of acute stress-induced impairment of cognitive function in adult rats. ResultsBlocking the Induction of LTD Prevents the Stress-Induced Impairment of Spatial Memory Retrieval. It is well accepted that the induction of hippocampal CA1 homosynaptic LTD depends on the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) (10), which are heteromeric complexes of NR1 subunits and at least one type of NR2 subunit (NR2A-D) (18). Converging evidence supports the hypothesis that the subunit composition of NMDARs may c...
Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines.
Systematic clinical studies of GABA(B) agonists are needed to determine the extent to which these drugs might serve as tools to promote abstinence in cocaine users seeking treatment for their addiction. Several areas must still be addressed, including potential side-effects that may limit compliance and whether GABA(B) agonists interfere with other, non-drug-related behaviours.
The proinflammatory cytokines interleukin-1  (IL-1  ), IL-6, and tumor necrosis factor-alpha (TNF-␣ Dopamine; Monoamines; Neurochemical; Norepinephrine; Serotonin; Synergism; It is clear that interactions occur between the immune, endocrine, central, and autonomic nervous systems. Immunological manipulations (or products of an activated immune system, e.g., cytokines) may affect neuroendocrine and central neurotransmitter processes, and conversely, neuroendocrine and central neurotransmitter alterations may impact on immune activity (Blalock 1994;Dunn 1990;Rivier 1993;Rothwell et al. 1997). It has been posited that, among other things, the immune system acts like a sensory organ informing the brain of antigenic challenge (Blalock 1994) and that immune activation may be interpreted by the CNS as a stressor Dunn 1990). Further, cytokines may be part of a regulatory loop that, by virtue of effects on CNS functioning, might influence behavioral outputs and may even contribute to the symptoms of behavioral pathologies, including mood and anxietyrelated disorders . Indeed, in humans, depression was associated with variations of plasma cytokines, including interleukin-1  (IL-1  ), IL-1 receptor antagonist (IL-1Ra), IL-2, soluble IL-2 receptors, IL-6, and soluble IL-6 receptors Maes 1995;Maes et al. 1995;Muller and Ackenheil 1998).From the Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada (KB, SH, RZ, HA); and School of Psychology and Department of Cellular and Molecular Medicine (ZM), University of Ottawa, Ottawa, Ontario, Canada.Address correspondence to: Hymie Anisman, Ph.D., Life Sciences Research Building, Carleton University. Ottawa, Ontario K1S 5B6, Canada.Received January 28, 1999; revised May 10, 1999; accepted December 6, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 6 Synergistic Effects of Cytokines 567Cytokines and bacterial endotoxins, such as lipopolysaccharide (LPS), induce a constellation of apparently adaptive behavioral changes, collectively referred to as "sickness behaviors" . For instance, these agents induce fever, reduce social exploration, sexual behaviors, and food consumption (Bluthe et al. 1992;Johnson et al. 1996;Plata-Salaman 1988;Plata-Salaman et al. 1988;O'Reilly et al. 1987). In addition, endotoxins may induce anxiogenic-like effects ) and disrupt responding for rewarding brain stimulation (Borowski et al. 1998), possibly reflecting anhedonic effects elicited by the immune challenge. The behavioral effects of endotoxin and cytokine treatment are paralleled by increased hypothalamic-pituitary-adrenal (HPA) activity, as reflected by increased activity of corticotropin releasing hormone (CRH) and elevated plasma ACTH and corticosterone levels (Kakucksa et al. 1993;Tilders et al. 1993). Inasmuch as cytokines elicit several effects similar to those of LPS, it has been assumed that at least some of the endotoxin effects involve IL-1  , or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a; Ebisui et al. 1994;Long et...
The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule.
In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.
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