Abstract Background: We and others have reported that glatiramer acetate promotes innate phagocytosis. Methods: In this study, we investigated the interaction between glatiramer acetate and amyloid-β (Aβ) by using circular dichroism and microscale thermophoresis. Glatiramer acetate was delivered intracerebroventricularly to 22-month-old APP/PS1 mice by using mini-osmotic pumps. Mice underwent behavioural testing for two consecutive weeks after three-weeks treatment. Five weeks after implantation, animals were sacrificed and brain samples were collected for electrophysiology, immunochemistry and histopathology studies. Intracerebroventricular delivery of glatiramer acetate to sheep was also examined. Results: Glatiramer acetate binds to amyloid-β within high affinity and antagonize its toxicity. Glatiramer acetate treatment significantly improved cognitive function, restored long-term potentiation, reduced soluble amyloid-β and amyloid-β plaques in aged APP/PS1 mice, and promoted energy metabolism in sheep. Conclusions: Our results suggest a novel treatment strategy that targets both innate phagocytosis and amyloid-β, which may prove useful for treatment of all stages of Alzheimer’s disease.

Behavioural sensitization (BS) is characterized by enhanced psychomotor responses to a dose of substance of abuse after prior repeated exposure. We previously reported that BS can be induced by a single injection of morphine in rats, whereas septal nuclei are specifically involved in the development phase of BS. Here, we demonstrated that intra-LS or intra-MS microinjections also incubated BS to a systemic morphine injection in a cross-sensitization fashion, whereas inactivation of either subdivision of septal nuclei (LS: lateral septum; MS: medial septum) can negate this ability of morphine. Then, non-selective (naloxone) and selective (μ-, δ- and κ-)opioid receptor antagonists were directly delivered into LS or MS, respectively, ahead of a morphine microinjection, whereas only μ-opioid receptors in both LS and MS play indispensable roles in mediating the BS development. Finally, there was a pronounced elevation in the levels of the monoamines (i.e. dopamine, homovanillic acid, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid) in the septum, 8 h after a morphine injection detected with a HPLC-ECD method, suggesting that dopaminergi and serotoninergic systems are implicated in the BS formation. Our studies demonstrated that septal nuclei critically participate in the BS development. Essentially, μ- instead of δ- or κ-opioid receptors in LS and MS mediate sensitization to opiates.

Deficits in hippocampal cellular and synaptic plasticity are frequently associated with cognitive and mood disorders, and indeed common mechanisms of antidepressants are thought to involve neuroplastic processes. Here, we investigate hippocampal adult-born cell survival and synaptic plasticity (long-term potentiation, LTP, and long-term depression, LTD) in serotonin transporter (5-HTT) knockout (KO) mice. From 8 weeks of age, mice either continued in standard-housing conditions or were given access to voluntary running wheels for 1 month. Electrophysiology was performed on hippocampal slices to measure LTP and LTD, and immunohistochemistry was used to assess cell proliferation and subsequent survival in the dentate gyrus. The results revealed a reduced LTP in 5-HTT KO mice that was restored to wild-type (WT) levels after chronic exercise. While LTD appeared normal in 5-HTT KO, exercise decreased the magnitude of LTD in both WT and 5-HTT KO mice. Furthermore, although 5-HTT KO mice had normal hippocampal adult-born cell survival, they did not benefit from the pro-proliferative effects of exercise observed in WT animals. Taken together, these findings suggest that reduced 5-HTT expression is associated with significant alterations to functional neuroplasticity. Interestingly, 5-HTT appeared necessary for exercise-induced augmentation of adult-born hippocampal cell survival, yet exercise corrected the LTP impairment displayed by 5-HTT KO mice. Together, our findings further highlight the salience of serotonergic signalling in mediating the neurophysiological benefits of exercise.

There is currently no disease-modifying treatment for Huntington's disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.

Down syndrome is caused by partial or total trisomy of chromosome 21 and is characterized by intellectual disability and other disorders. Although it is difficult to determine which of the genes over-expressed on the supernumerary chromosome contribute to a specific abnormality, one approach is to study each gene in isolation. This can be accomplished either by using an over-expression model to study increased gene dosage or a gene-deficiency model to study the biological function of the gene. Here, we extend our examination of the function of the chromosome 21 gene, ITSN1. We used mice in which the long isoform of intersectin-1 was knocked out (ITSN1-LKO) to understand how a lack of the long isoform of ITSN1 affects brain function. We examined cognitive and locomotor behavior as well as long term potentiation (LTP) and the mitogen-activated protein kinase (MAPK) and 3 '-kinase-C2 beta-AKT (AKT) cell signaling pathways. We also examined the density of dendritic spines on hippocampal pyramidal neurons. We observed that ITSN1-LKO mice had deficits in learning and long term spatial memory. They also exhibited impaired LTP, and no changes in the levels of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2. The amount of phosphorylated AKT was reduced in the ITSN1-LKO hippocampus and there was a decrease in the number of apical dendritic spines in hippocampal neurons. Our data suggest that the long isoform of ITSN1 plays a part in normal learning and memory.

BackgroundAlcohol use disorder places a heavy burden on global public health systems and thus is in urgent need of improved pharmacotherapies. Previously, our group has demonstrated that 30 mg/kg of the indole alkaloid brucine significantly attenuates alcohol‐drinking behavior; however, the high toxicity, poor water solubility, short half‐life, and limited therapeutic window of brucine restrain its clinical application as an antialcoholism medication. We subsequently hypothesized that the oxide of brucine (brucine N‐oxide) would produce a similar behavioral effect without the risk profile associated with brucine.MethodsMale Fawn‐Hooded rats with high innate alcohol preference underwent 2‐bottle choice procedures (Experiments 1 to 3). Experiment 1 examined the effects of 7 daily BNO injections of 0, 30, 50, or 70 mg/kg (s.c.) on voluntary alcohol consumption (n = 9/group). Experiment 2 evaluated the impact of a single dose of 0 or 70 mg/kg BNO on the increased alcohol intake induced by a 4‐day alcohol deprivation (n = 8/group). Experiment 3 tested the effect of 7 daily BNO injections of 0 or 70 mg/kg (s.c.) on sucrose preference (n = 6/group). Experiment 4 measured the median lethal dose (LD50) values of BNO and brucine to compare their acute toxicity in rats. Experiment 5 tested whether BNO (0, 30, 50, and 70 mg/kg, s.c.) affected locomotor activity using an open‐field paradigm (n = 8/group). Finally, Experiment 6 evaluated the possible conditioned rewarding effects of 0, 30, 50, and 70 mg/kg BNO using the conditioned place preference paradigm (n = 6/group).ResultsBNO administration dose‐dependently attenuated alcohol consumption without affecting food intake, total fluid consumption, or the natural preference for a sucrose solution, with 70 mg/kg BNO reducing consumption by 22.8%. A single dose of 70 mg/kg BNO significantly inhibited the alcohol deprivation effect. The LD50 values of BNO and brucine in rats were determined to be 1,103.5 ± 177.0 mg/kg and 264.6 ± 17.7 mg/kg, respectively. Finally, BNO administration did not affect spontaneous locomotor activity or induce a place preference.ConclusionsBNO may help to control excessive alcohol use and should be considered a treatment strategy for future study and development.

Background and Purpose Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. Experimental Approach Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. Key Results SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. Conclusions and Implications Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.

Although misfolding of normal prion protein (PrPC) into abnormal conformers (PrPSc) is critical for prion disease pathogenesis our current understanding of the underlying molecular pathophysiology is rudimentary. Exploiting an electrophysiology paradigm, herein we report that at least modestly proteinase K (PK)-resistant PrPSc (PrPres) species are acutely synaptotoxic. Brief exposure to ex vivo PrPSc from two mouse-adapted prion strains (M1000 and MU02) prepared as crude brain homogenates (cM1000 and cMU02) and cell lysates from chronically M1000-infected RK13 cells (MoRK13-Inf) caused significant impairment of hippocampal CA1 region long-term potentiation (LTP), with the LTP disruption approximating that reported during the evolution of murine prion disease. Proof of PrPSc (especially PrPres) species as the synaptotoxic agent was demonstrated by: significant rescue of LTP following selective immuno-depletion of total PrP from cM1000 (dM1000); modestly PK-treated cM1000 (PK+M1000) retaining full synaptotoxicity; and restoration of the LTP impairment when employing reconstituted, PK-eluted, immuno-precipitated M1000 preparations (PK+IP-M1000). Additional detailed electrophysiological analyses exemplified by impairment of post-tetanic potentiation (PTP) suggest possible heightened pre-synaptic vulnerability to the acute synaptotoxicity. This dysfunction correlated with cumulative insufficiency of replenishment of the readily releasable pool (RRP) of vesicles during repeated high-frequency stimulation utilised for induction of LTP. Broadly comparable results with LTP and PTP impairment were obtained utilizing hippocampal slices from PrPC knockout (PrPo/o) mice, with cM1000 serial dilution assessments revealing similar sensitivity of PrPo/o and wild type (WT) slices. Size fractionation chromatography demonstrated that synaptotoxic PrP correlated with PK-resistant species >100kDa, consistent with multimeric PrPSc, with levels of these species >6 ng/ml appearing sufficient to induce synaptic dysfunction. Biochemical analyses of hippocampal slices manifesting acute synaptotoxicity demonstrated reduced levels of multiple key synaptic proteins, albeit with noteworthy differences in PrPo/o slices, while such changes were absent in hippocampi demonstrating rescued LTP through treatment with dM1000. Our findings offer important new mechanistic insights into the synaptic impairment underlying prion disease, enhancing prospects for development of targeted effective therapies.

De-novo protein synthesis is required in the development of behavioural sensitization. A prior screening test from our laboratory has implicated heat shock protein 70 (Hsp70) as one of the proteins required in this behavioural plasticity. Thus, this study was designed to extend our understanding of the role of Hsp70 in the development of behavioural sensitization induced by a single morphine exposure in mice. First, by employing transcription inhibitor actinomycin D (AD) and protein synthesis inhibitor cycloheximide (CHX), we identified a protein synthesis-dependent labile phase (within 4 h after the first morphine injection) in the development of behavioural sensitization to a single morphine exposure. Second, Hsp70 protein expression in the nucleus accumbens correlated positively with locomotor responses of sensitized mice and, more importantly, the expression of Hsp70 increased within 1 h after the first morphine injection. Third, AD and CHX both prevented expression of Hsp70 and disrupted the development of the single morphine induced behavioural sensitization, which further implied Hsp70 was highly associated with behavioural sensitization. Finally, the selective Hsp70 inhibitor pifithrin-μ (PES) i.c.v. injected in mice prevented the development of behavioural sensitization and, critically, this inhibitory effect occurred only when PES was given within 1 h after the first morphine injection, which was within the labile phase of the development period. Taken together, we draw the conclusion that Hsp70 is crucially involved in the labile phase of the development of behavioural sensitization induced by a single morphine exposure, probably functioning as a molecular chaperone.

Drug addiction is a major public health issue, yet the underlying adaptation of neural networks by drugs of abuse is not fully understood. We have previously linked chaperone heat shock protein 70 (Hsp70) to drug-induced adaptations. Focusing on the NAc core and shell, the present study aims to provide further findings for our understanding of the relation between behavioural sensitization to morphine and Hsp70 at transcriptional and functional levels in rats. Firstly, we delineated the characteristics of behavioural sensitization induced by a single morphine exposure (1-10 mg/kg, s.c.). Secondly, Hsp70 protein expression in the NAc core was time- and dose-relatedly induced during the development of behavioural sensitization to a single morphine exposure in rats, and Pearson analysis indicated a positive correlation between behavioural sensitization and Hsp70 expression in NAc core. Thirdly, at the transcriptional level, intra-NAc core injection of the specific heat shock factor-I (HSF-I) inhibitor N-Formyl-3,4-methylenedioxy-benzylidine-γ-butyrolactam (KNK437) suppressed Hsp70 expression and the development of behavioural sensitization, while the HSF-I specific inducer geranylgeranylacetone (GGA) promoted both of them. Interestingly, intra-NAc shell injection of KNK437 or GGA did not affect the development of behavioural sensitization. Finally, both the functional inhibition of Hsp70 ATPase activity by methylene blue (MB), and the antagonism of Hsp70 substrate binding site (SBD) activity by pifithrin-μ (PES) impaired the development of behavioural sensitization when they were microinjected into the NAc core. Taken together, the critical involvement of chaperone Hsp70 in behavioural sensitization to morphine identifies a biological target for long-lasting adaptations with relevance to addiction.

Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.

New protein synthesis has been implicated as necessary for long-lasting changes in neuronal function. Behavioural sensitization to a single exposure to addictive drugs is a form of neuroplasticity, but little is known about the importance of new protein synthesis in the underlying mechanism. This study was designed to investigate the effects of the transcription inhibitor actinomycin D (AD) and the protein synthesis inhibitor cycloheximide (CHX) on induction of behavioural sensitization to a single morphine exposure in mice. In combination with behavioural experiments, changes in gene and protein expression in the mouse nucleus accumbens (NAc) were analysed by RT-PCR array and Western blot respectively. Behavioural sensitization was evident in mice pretreated only once with morphine at the doses of 20 and 40 mg/kg, but not 5 and 10 mg/kg. Mice pretreated with morphine (20 mg/kg) and challenged with a lower dose (5 mg/kg) after a period of 4-21 d washout showed sensitized locomotion. At the doses that did not affect locomotion in mice, AD or CHX significantly suppressed hyperactivity induced by acute treatment, but not challenge with morphine, and blocked induction of behavioural sensitization to a single morphine exposure in a dose-related manner. The results from RT-PCR array and Western blot indicated that the changes of Hsp70 expression in the NAc of mice were associated with behavioural sensitization induced by a single morphine exposure. Together, these findings suggest that induction of behavioural sensitization to a single morphine exposure requires new protein synthesis, potentially involving Hsp70 expression in the NAc of mice.

Post-translation palmitoylation is a reversible modification regulating protein trafficking and localization from different aspects. The ionotropic glutamate receptors ( GluRs) can be classified into several groups: N-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and KA receptors. The palmitoylation of the receptors contributes to stabilization of their surface distribution and internalization. The NMDA receptor subunits NR2A and NR2B have two palmitoylation sites of distinct clusters in the C-terminal region. The palmitoylation of Cys cluster Ⅰ on a membrane-proximal region increases tyrosine phosphorylation to enhance the stable surface expression of NMDA receptors and regulates their constitutive internalization in developing neurons. The Cys cluster Ⅱ site in the middle of C-terminal region is up-regulated by specific palmityl acyl transferases GODZ and leads to the accumulation of the receptors in the Glogi apparatus and reduces the receptor surface localization. Similarly,the AMPA receptor subunits GluR1-4 also have two different palmitoylation sites. The one palmtoylated by GODZ in the TMD 2 region retains the AMPA receptors in Glogi,and the other in the C-teminus affects the receptor internalization by AMPA and NMDA induction by weakening the interaction of the AMPA with the 4. 1N protein. . The different mechanisms underlying the palmitoylation- nonpalmitoylation of NMDA and AMPA receptors both influence the receptor trafficking, surface distribution and internalization.

Increasing body core temperature reflexly decreases renal blood flow (RBF), and the hypothalamic paraventricular nucleus (PVN) plays an essential role in this response. ANG II in the brain is involved in the cardiovascular responses to hyperthermia, and ANG II receptors are highly concentrated in the PVN. The present study investigated whether ANG II in the PVN contributes to the cardiovascular responses elicited by hyperthermia. Rats anesthetized with urethane (1-1.4 g/kg iv) were microinjected bilaterally into the PVN (100 nl/side) with saline (n = 5) or losartan (1 nmol/100 nl) (n = 7), an AT1 receptor antagonist. Body core temperature was then elevated from 37°C to 41°C and blood pressure (BP), heart rate (HR), RBF, and renal vascular conductance (RVC) were monitored. In separate groups losartan (n = 4) or saline (n = 4) was microinjected into the PVN, but body core temperature was not elevated. Increasing body core temperature in control rats elicited significant decreases in RBF (-48 ± 5% from a resting level of 14.3 ± 1.4 ml/min) and MVC (-40 ± 4% from a resting level of 0.128 ± 0.013 ml/min·mmHg), and these effects were entirely prevented by pretreatment with losartan. In rats in which body core temperature was not altered, losartan microinjected into the PVN had no significant effects on these variables. The results suggest that endogenous ANG II acts on AT1 receptors in the PVN to mediate the reduction in RBF induced by hyperthermia.

Increased sympathetic nerve activity is associated with obesity-related hypertension, but the underlying central neural mechanisms are not clear. We examined the role of the hypothalamic paraventricular nucleus (PVN) in the regulation of sympathetic nerve activity in rats fed a normal chow diet (controls) and rats fed a high-fat diet (36% fat) over 12 wk. The effects on blood pressure, heart rate, and lumbar sympathetic nerve activity (LSNA) induced by microinjection of the GABA(A) receptor agonist muscimol or the antagonist bicuculline were monitored in anesthetized rats. Body weight of rats fed the high-fat diet was not significantly different from controls, but a significant 80% increase in epididymal fat mass, significantly elevated fasting blood glucose, and significantly impaired glucose tolerance were observed in rats fed the high-fat diet. Resting blood pressure and heart rate were not significantly different between rats fed the high-fat diet and controls. Muscimol microinjected into the PVN elicited a greater reduction of blood pressure and LSNA in rats fed the high-fat diet than controls: -14 +/- 6 vs. -7 +/- 2 mmHg and -35 +/- 6 vs. -10 +/- 9% (P < 0.05). Microinjection of bicuculline into the PVN increased blood pressure and LSNA, but the responses were similar in rats fed the high-fat diet and controls. In conclusion, the role of the paraventricular nucleus in cardiovascular regulation can be altered by a diet high in fat, even when hypertension and obesity are absent.

Increasing body core temperature reflexly decreases mesenteric blood flow (MBF), and the hypothalamic paraventricular nucleus (PVN) plays an essential role in this response. Nitric oxide (NO) is involved in temperature regulation and is concentrated within the PVN. The present study investigated whether NO in the PVN contributes to the cardiovascular responses elicited by hyperthermia. Anesthetized rats were microinjected bilaterally in the PVN (100 nl/side) with saline or N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (100 or 200 nmol/100 nl) (n = 5/group). Body core temperature was then elevated from 37 degrees C to 39 degrees C, and blood pressure (BP), heart rate (HR), MBF, and mesenteric vascular conductance (MVC) were monitored. In separate groups, L-NAME (200 nmol) (n = 5) or saline (n = 5) was microinjected in the PVN, but body core temperature was not elevated. In control rats, increasing body core temperature resulted in no marked change of BP but an increase in HR and significant decreases in MBF (15%) and MVC. Pretreatment with 100 nmol L-NAME did not affect the responses. In contrast, 200 nmol L-NAME prevented the normal reduction in MBF and MVC but did not significantly affect the BP and HR responses. In rats in which body core temperature was not increased, L-NAME reduced MBF by 19%. The present results suggest that endogenous NO in the PVN is important in mediating the reduction of MBF induced by hyperthermia. In the absence of hyperthermia, however, endogenous NO in the PVN may play a role in maintaining mesenteric vasodilation.

BACKGROUND:Epidemiological evidence of co-use of alcohol and areca nuts suggests a potential central interaction between arecoline, a major alkaloid of areca and a muscarinic receptor agonist, and ethanol. Moreover, the central cholinergic system plays an important role in the depressant action of ethanol and barbiturates. The purpose of this study was to investigate the effects of arecoline on pentobarbital- and ethanol-induced hypnosis in mice.METHODS:Male ICR mice were tested for locomotor activity following acute systemic administration of ethanol alone, arecoline alone, or ethanol plus arecoline. For the loss of the righting reflex (LORR) induced by pentobarbital and ethanol, sleep latency and sleeping duration were evaluated in mice treated with arecoline alone or the combination of arecoline and scopolamine or methscopolamine.RESULTS:Ethanol (1.0 to 3.0 g/kg, i.p.) reduced locomotor activity significantly and a declining trend was observed after treatment with arecoline (0.25 to 1.0 mg/kg, i.p.), but there were no synergistic effects of ethanol and arecoline on locomotor activity. The experiments on LORR demonstrated that arecoline (0.125 to 1.0 mg/kg, s.c.) shortened the duration of sleeping induced by ethanol (4.0 g/kg, i.p.), but not pentobarbital (45 mg/kg, i.p.). In addition, alterations of sleep latency were not obvious in both pentobarbital- and ethanol-induced LORR. Statistical analyses revealed that scopolamine (centrally acting), but not methscopolamine (peripherally acting), could antagonize the effect of arecoline on the duration of ethanol-induced LORR in mice.CONCLUSIONS:These results suggest that central muscarinic receptor is a pharmacological target for the action of arecoline to modulate ethanol-induced hypnosis.

Drugs of abuse have the ability to instantiate plastic adaptations within the central nervous system, and this property may relate to the development and persistence of addiction. In this context, a single exposure to cocaine in rodents may induce synaptic plasticity by increasing the AMPA/NMDA receptor excitatory post-synaptic current (EPSC) amplitude ratio in dopaminergic cells of the ventral tegmental area (VTA). Here, we examine the role of the metabotropic glutamate 5 (mGlu5) receptor in this regard using a genetic mouse model. The control AMPA/NMDA EPSC ratio is reduced in mGlu5-deficient mice compared to wild-types. Moreover, cocaine-induced enhancement of this EPSC ratio is also absent in mutant mice, which suggests that mGlu5 receptors are required for single-dose cocaine-induced plasticity onto VTA cells. While the temporal profile of hyperactivity to acute cocaine is altered in mGlu5-deficient mice; these mice still develop and express sensitized psychomotor responses to cocaine. These data suggest that the mGlu5 receptor is required for cocaine-induced plasticity in VTA dopaminergic cells. In contrast, the mGlu5 receptor may not be essential for psychostimulant behavioural sensitization; although it probably impacts other aspects drug addiction, such as motivation to self-administer.

The hypothalamic paraventricular nucleus (PVN) is an important integrative center in the brain. In the present study, we investigated whether the PVN is a key region in the mesenteric vasoconstriction that normally accompanies an increase in core body temperature. Anesthetized rats were monitored for blood pressure, heart rate, mesenteric blood flow, and vascular conductance. In control rats, elevation of core body temperature to 41 degrees C had no significant effect on blood pressure, increased heart rate, and reduced mesenteric blood flow by 21%. In a separate group of rats, muscimol was microinjected bilaterally (1 nmol/side) into the PVN. Compared with the control group, there was no significant difference in the blood pressure and heart rate responses elicited by the increase in core body temperature. In contrast to control animals, however, mesenteric blood flow did not fall in the muscimol-treated rats in response to the elevation in core body temperature. In a separate group, in which muscimol was microinjected into regions outside the PVN, elevating core body temperature elicited the normal reduction in mesenteric blood flow. The results suggest that the PVN may play a key role in the reflex decrease in mesenteric blood flow elicited by hyperthermia.