Showing papers in "Pharmacology, Biochemistry and Behavior in 2008"
TL;DR: It is argued in line with others that animal paradigms are unlikely to model all aspects of complex psychiatric conditions such as ADHD but components of such syndromes may be amenable to investigation using sophisticated animal models based on highly-defined psychiatric endophenotypes.
Abstract: Impulsive acts and decisions are a part of everyday normal behavior. However, in its pathological forms, impulsivity can be a debilitating disorder often associated with a number of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). This article reviews recent progress in our understanding of the neurobiology of impulsivity using examples from recent investigations in experimental animals. Evidence is reviewed from several well-established paradigms with putative utility in assessing distinct forms of impulsive behavior in rodents, including the 5-choice serial reaction time (5CSRT) task and the delay discounting paradigm. We discuss, in particular, recent psychopharmacological and in-vivo neurochemical data in task-performing rats showing functional heterogeneity of the forebrain dopamine (DA), noradrenaline (NA), serotonin (5-HT) and acetylcholine (ACh) systems and identify how these systems normally function to facilitate flexible goal-directed behavior in situations that tax basic attentional functions and inhibitory response control mechanisms. We also discuss future research needs in terms of understanding the functional diversity of different sub-regions of prefrontal cortex (PFC) and how these systems normally interact with the striatum and main nuclei of origin of DA and NA neurons. Finally, we argue in line with others that animal paradigms are unlikely to model all aspects of complex psychiatric conditions such as ADHD but components of such syndromes may be amenable to investigation using sophisticated animal models based on highly-defined psychiatric endophenotypes.
453 citations
TL;DR: The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.
Abstract: ARTICLE I NFO In the last 25 years data has grown exponentially dealing with the discovery of the endocannabinoid system consisting of specific cannabinoid receptors, their endogenous ligands, and enzymatic systems of their biosynthesis and degradation. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity which should help in providing a greater understanding of the physiological role of the endocannabinoid system and perhaps also in a broad number of pathologies. This could lead to advances with important therapeutic potential of drugs modulating activity of endocannabinoid system as hypnotics, analgesics, antiemetics, antiasthmatics, antihypertensives, immunomodulatory drugs, antiphlo- gistics, neuroprotective agents, antiepileptics, agents influencing glaucoma, spasticity and other "movement disorders", eating disorders, alcohol withdrawal, hepatic fibrosis, bone growth, and atherosclerosis. The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.
417 citations
TL;DR: Specific variations in physical and social environment during early rearing lead to some behavioral and neurochemical alterations which might be relevant for understanding the role that neurodevelopmental and experiential factors could have in human depression.
Abstract: In order to determine the effect of postnatal environments on some behavioral and neurochemical depressive-like parameters, male Sprague-Dawley rats were reared from weaning in either social isolation, standard laboratory conditions, or environmental enrichment. Open-field activity was assessed at postnatal days 37, 65, 93 and 107 and 1 h before the last open-field test, a forced-swimming test was carried out. After behavioral tests, the monoamines concentrations were analyzed in prefrontal cortex and ventral striatum. Relative to control and isolation rearing, the environmental enrichment reduced open-field activity, led to antidepressive-like effects and increased serotonin concentrations in the prefrontal cortex. Social isolation, on the other hand, did not affect open-field activity, but increased depressive-like behavior and reduced the amount of norepinephrine in the ventral striatum. Those neurochemical changes induced by rearing conditions correlated with the behavioral performance in the forced-swimming test. Also, immobility behavior could be predicted by locomotor activity even from the first week of housing. Overall, specific variations in physical and social environment during early rearing lead to some behavioral and neurochemical alterations which might be relevant for understanding the role that neurodevelopmental and experiential factors could have in human depression.
243 citations
TL;DR: The influence of the interaction between ethanol and GABA(A) receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.
Abstract: Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.
232 citations
TL;DR: This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs and the pharmacological and putative biochemical basis of the Abuse-related behavior is discussed.
Abstract: Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABAA receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.
182 citations
TL;DR: Clues are beginning to emerge from studies of knock-out and knock-in mice and from genetic analysis of human alcoholics on a role for GABAergic actions in regulating alcohol consumption and, perhaps, the development of alcoholism.
Abstract: There is substantial evidence that GABAergic neurotransmission is important for many behavioral actions of ethanol and there are reports spanning more than 30 years of literature showing that low to moderate (3-30 mM) concentrations of ethanol enhance GABAergic neurotransmission. A key question is which GABA receptor subunits are sensitive to low concentrations of ethanol in vivo and in vitro. Recent evidence points to a role for extrasynaptic receptors. Another question is which behavioral actions of alcohol result from enhancement of GABAergic neurotransmission. Some clues are beginning to emerge from studies of knock-out and knock-in mice and from genetic analysis of human alcoholics. These approaches are converging on a role for GABAergic actions in regulating alcohol consumption and, perhaps, the development of alcoholism.
175 citations
TL;DR: The regression data suggest that there is some relationship between exercise, catecholamines concentrations and cognition, and delta MHPG and HVA plasma concentrations at the 1 and 3 min sampling times were strong predictors of delta RNG, response time and movement time.
Abstract: The purpose of the study was to examine the usage of norepinephrine (NE) and dopamine (DA) in the brain when exercising while simultaneously undertaking cognitive tests. Plasma concentrations of the NE metabolite 3-methoxy 4-hydroxyphenylglycol (MHPG) and the DA metabolite homovanillic acid (HVA) showed a linear increase from rest to exercising at 40% and 80% maximum power output (W.max) while simultaneously undertaking cognitive tasks (random number generation (RNG) and response time). Delta plasma concentrations of MHPG and HVA at each exercise intensity while undertaking cognitive tasks and while exercising without cognitive tasks did not differ. Taking blood samples at 0, 1, 3, and 5 min following cessation of exercise did not affect results. Regression correlations showed that delta MHPG and HVA plasma concentrations at the 1 and 3 min sampling times were strong predictors of delta RNG, response time and movement time. Reaction time at 80% W.max significantly increased, while movement time at 80% W.max significantly decreased. It was concluded that these results provide no support for a direct effect of increased catecholamines concentrations on cognitive performance during exercise. The regression data suggest that there is some relationship between exercise, catecholamines concentrations and cognition.
171 citations
TL;DR: This review focuses primarily on research linking dynamic changes in DA efflux on the timescale of minutes, with incentive motivation, as revealed by brain dialysis experiments in behaving animals.
Abstract: Dopamine (DA) activity, in the form of increased neural firing or enhanced release of transmitter from nerve terminals and varicosities, is linked to a number of important psychological processes including: movement; hedonic reactions to positive reward; provision of an error detection signal during the acquisition of new learning; response to novel stimuli; provision of reinforcement signals essential for acquisition of new action patterns; and incentive motivation. This review focuses primarily on our research linking dynamic changes in DA efflux on the timescale of minutes, with incentive motivation, as revealed by brain dialysis experiments in behaving animals. Recent experiments on sensory-specific satiety and successive positive and negative contrast are discussed along with the distinction between preparatory behaviors that precede contact with biologically significant stimuli and subsequent consummatory behaviors. The relationship between DA efflux in the medial prefrontal cortex (mPFC) and foraging for food based on working memory is also discussed in support of the conjecture that DA may serve as a link between motivation and memory functions. Evidence in support of ‘top-down’ regulation of dopaminergic activity in the mesocorticolimbic DA pathways is reviewed briefly to introduce a mechanism by which activation of ascending DA projections in this manner might optimize dopaminergic modulation of executive function within regions such as the mPFC. Collectively, these processes could ensure coordination between cognitive processes that assess current opportunities and the motivational systems that select and engage patterns of approach behavior that bring organisms into contact with the essentials for survival.
168 citations
TL;DR: It is concluded that the chromatographic conditions for the separation of this transmitter from other amino acid-derivatives are extremely critical and microdialysis and microsensors are complementary methods to study extracellular glutamate.
Abstract: GABA and glutamate sampled from the brain by microdialysis do not always fulfill the classic criteria for exocytotic release. In this regard the origin (neuronal vs. astroglial, synaptic vs. extrasynaptic) of glutamate and GABA collected by microdialysis as well as in the ECF itself, is still a matter of debate. In this overview microdialysis of GABA and glutamate and the use of microsensors to detect extracellular glutamate are compared and discussed. During basal conditions glutamate in microdialysates is mainly derived from non-synaptic sources. Indeed recently several sources of astrocytic glutamate release have been described, including glutamate derived from gliotransmission. However during conditions of (chemical, electrical or behavioral) stimulation a significant part of glutamate might be derived from neurotransmission. Interestingly accumulating evidence suggests that glutamate determined by microsensors is more likely to reflect basal synaptic events. This would mean that microdialysis and microsensors are complementary methods to study extracellular glutamate. Regarding GABA we concluded that the chromatographic conditions for the separation of this transmitter from other amino acid-derivatives are extremely critical. Optimal conditions to detect GABA in microdialysis samples--at least in our laboratory--include a retention time of approximately 60 min and a careful control of the pH of the mobile phase. Under these conditions it appears that 50-70% of GABA in dialysates is derived from neurotransmission.
151 citations
TL;DR: The hypothesis that cholinergic system activity may be important in the cognitive deficits of ADHD and may be a useful therapeutic target is supported.
Abstract: Objective The strong association between ADHD and cigarette smoking and the known effects of nicotine on cognition has lead to interest in the role of cholinergic function in ADHD cognitive deficits. We have previously demonstrated that acute nicotine improves behavioral inhibition in adolescents with ADHD. This study examined acute nicotine in young adults with ADHD-Combined type on cognitive domains including behavioral inhibition, delay aversion, and recognition memory. Methods 15 non-smoking young adults (20 ± 1.7 years) diagnosed with ADHD-C received acute nicotine (7 mg patch for 45 min) and placebo on separate days. Cognitive tasks included the Stop Signal Task, Choice Delay task, and the High–Low Imagery Task (a verbal recognition memory task). Three subjects experienced side effects and their data was excluded from analysis of cognitive measures. Results There was a significant (p Conclusions Non-smoking young adults with ADHD-C showed improvements in cognitive performance following nicotine administration in several domains that are central to ADHD. The results from this study support the hypothesis that cholinergic system activity may be important in the cognitive deficits of ADHD and may be a useful therapeutic target.
150 citations
TL;DR: It is suggested here that dopamine and glutamate receptors are, in part, segregated in specific cellular circuits in the PFC and the stimulation/blockade of these receptors would have a different net impact on PFC output projections to regulate dopamine and acetylcholine release in the NAc and in guided behaviour.
Abstract: Previous experimental studies have shown that the prefrontal cortex (PFC) regulates the activity of the nucleus accumbens (NAc), and in particular the release of dopamine in this area of the brain. In the present report we review recent microinjections/microdialysis studies from our laboratory on the effects of stimulation/blockade of dopamine and glutamate receptors in the PFC that modulate dopamine, and also acetylcholine release in the NAc. Stimulation of prefrontal D2 dopamine receptors, but not group I mGlu glutamate receptors, reduces the release of dopamine and acetylcholine in the NAc and spontaneous motor activity. This inhibitory role of prefrontal D2 receptors is not changed by acute systemic injections of the NMDA antagonist phencyclidine. On the other hand, the blockade of NMDA receptors in the PFC increases the release of dopamine and acetylcholine in the NAc as well as motor activity which suggests that the hypofunction of prefrontal NMDA receptors is able to produce the neurochemical and behavioural changes associated with a dysfunction of the corticolimbic circuit. We suggest here that dopamine and glutamate receptors are, in part, segregated in specific cellular circuits in the PFC. Thus, the stimulation/blockade of these receptors would have a different net impact on PFC output projections to regulate dopamine and acetylcholine release in the NAc and in guided behaviour. Finally, it is speculated that environmental enrichment might produce plastic changes that modify the functional interaction between the PFC and the NAc in both physiological and pathological conditions.
TL;DR: Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naive adults, and these studies provide a basis for enhanced vulnerability to Nicotine during adolescence.
Abstract: This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naive adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.
TL;DR: The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of dopamine and serotonin in multiple brain regions and the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.
Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.
TL;DR: It is established that HR females, like their male counterparts, exhibit a dramatically greater locomotor response to novelty and less anxiety-like behavior than do LR females, and female rats, like males, exhibit HR-LR phenotypes that predict rapidity of acquiring cocaine self-administration.
Abstract: Individual differences in exploratory behavior can predictably influence psychostimulant self-administration behavior. Male rats that exhibit a high degree of locomotor activity in a novel environment (High Responders, HR) will self-administer cocaine more readily than males exhibiting low levels of novelty-induced locomotion (Low Responders, LR). The present experiment investigates the combined influences of the sex of an individual and individual phenotypes in novelty-induced locomotion to predispose animals to acquire cocaine self-administration behavior, in male and female rats selectively bred for the HR–LR phenotypes. We first established that HR females, like their male counterparts, exhibit a dramatically greater locomotor response to novelty and less anxiety-like behavior than do LR females. While locomotor behavior was subtly influenced by estrous stage, with both HR and LR females showing increased activity during metestrus and diestrus compared to proestrus and estrus, the effect did not obscure HR–LR differences. When male and female HR–LR animals were trained to self-administer cocaine (2 h/day, 5 days/wk × 3 wk, 0.2 mg cocaine/kg/infusion), HR males and females acquired cocaine self-administration significantly faster than their LR counterparts. Furthermore, HR females self-administered significantly more cocaine than all other groups. In conclusion, female rats, like males, exhibit HR–LR phenotypes that predict rapidity of acquiring cocaine self-administration. Moreover, HR females self-administer more cocaine than HR males and both LR groups.
TL;DR: Findings suggest that olanzapine is not an efficacious treatment for video poker pathological gamblers, but may still be an effective treatment for a specific subset of pathologicalgamblers, including those with a co-occurring psychiatric disorder.
Abstract: Emerging evidence suggests that dopaminergic and serotonergic functioning are altered in pathological gamblers; yet, there are no FDA-approved medications for pathological gambling and there have only been a limited number of clinical trials that have been conducted. Olanzapine was identified as a candidate medication for pathological gamblers because it modifies both dopaminergic and serotonergic function. Moreover, preliminary studies have shown that olanzapine effectively reduces impulsivity in other psychiatric disorders, a pharmacological target of interest for pathological gamblers. In this study, 21 pathological gamblers, whose primary gambling activity was video poker, were enrolled in a seven-week, double-blind, placebo-controlled trial. Outcome measures included self-reported urges for gambling, frequency of gambling behavior, and self-reported mood and anxiety levels. The results revealed that all study participants reported reduced levels of gambling urges, gambling behavior, and mood and anxiety symptoms. Olanzapine administration was not associated with an incremental effect versus placebo. While these findings suggest that olanzapine is not an efficacious treatment for video poker pathological gamblers, olanzapine may still be an effective treatment for a specific subset of pathological gamblers, including those with a co-occurring psychiatric disorder.
TL;DR: The findings of the present study suggest for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.
Abstract: Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.
TL;DR: The effects of MDMA on neurochemistry and motor activity in rats are monitored and a complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner.
Abstract: (+/-)-3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is an illicit drug that evokes transporter-mediated release of monoamines, including serotonin (5-HT) and dopamine (DA). Here we monitored the effects of MDMA on neurochemistry and motor activity in rats, as a means to evaluate relationships between 5-HT, DA, and behavior. Male rats undergoing in vivo microdialysis were housed in chambers equipped with photobeams for measurement of ambulation (i.e., forward locomotion) and stereotypy (i.e., head weaving and forepaw treading). Microdialysis probes were placed into the n. accumbens, striatum or prefrontal cortex in separate groups of rats. Dialysate samples were assayed for 5-HT and DA by microbore HPLC-ECD. Rats received two i.v. injections of MDMA, 1 mg/kg followed by 3 mg/kg 60 min later; neurochemical and locomotor parameters were measured concurrently. MDMA produced dose-related elevations in extracellular 5-HT and DA in all regions, with the magnitude of 5-HT release always exceeding that of DA release. MDMA-induced ambulation was positively correlated with dialysate DA levels in all regions (P<0.05-0.0001) and with dialysate 5-HT in striatum and cortex (P<0.001-0.0001). Stereotypy was strongly correlated with dialysate 5-HT in all areas (P<0.001-0.0001) and with dialysate DA in accumbens and striatum (P<0.001-0.0001). These data support previous work and suggest the complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner.
TL;DR: The results can suggest that neuroprotective effects of vitamin C in adult rats can be the result of reduced lipid peroxidation levels and increase of catalase activity after seizures and status epilepticus induced by pilocarpine.
Abstract: In the present study, we examined the neuroprotective effects of vitamin C in adult rats after pilocarpine-induced seizures. Vitamin C is an exogenous antioxidant that can be used in treatment of seizures. It can alter oxidative stress and damage neuronal induced by seizures. Its antioxidant properties can be proved in epilepsy models, such as pilocarpine-induced seizures in adult rats. In order to investigate neuroprotective effects of vitamin C, adult male rats (2 months-old) were pretreated with vitamin C (VIT C 250 mg/kg, i.p.) 30 min before receiving pilocarpine (400 mg/kg, s.c., P400 group). The other three groups were treated with vitamin C (VIT C group) and saline 0.9 (control group) alone. The pretreatment with vitamin C increased the latency to first seizures and reduced mortality rate after pilocarpine-induced seizures. Pretreatment with vitamin C alone decrease lipid peroxidation levels when compared to pilocarpine group and P400+VIT C. In P400, P400+VIT C and VIT C groups were observed an increased hippocampal catalase activity when compared to control group. Our results can suggest that neuroprotective effects of vitamin C in adult rats can be the result of reduced lipid peroxidation levels and increase of catalase activity after seizures and status epilepticus induced by pilocarpine.
TL;DR: Reduced BDNF levels in the medial frontal cortex and hippocampal formation are identified as potential mediators of depressive disorders associated with FASD.
Abstract: Prenatal ethanol exposure is associated with an increased incidence of depressive disorders in patient populations. However, the mechanisms that link prenatal ethanol exposure and depression are unknown. Several recent studies have implicated reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampal formation and frontal cortex as important contributors to the etiology of depression. In the present studies, we sought to determine whether prenatal ethanol exposure is associated with behaviors that model depression, as well as with reduced BDNF levels in the hippocampal formation and/or medial frontal cortex, in a mouse model of fetal alcohol spectrum disorder (FASD). Compared to control adult mice, prenatal ethanol-exposed adult mice displayed increased learned helplessness behavior and increased immobility in the Porsolt forced swim test. Prenatal ethanol exposure was associated with decreased BDNF protein levels in the medial frontal cortex, but not the hippocampal formation, while total BDNF mRNA and BDNF transcripts containing exons III, IV or VI were reduced in both the medial frontal cortex and the hippocampal formation of prenatal ethanol-exposed mice. These results identify reduced BDNF levels in the medial frontal cortex and hippocampal formation as potential mediators of depressive disorders associated with FASD.
TL;DR: Results show that interference with NO-mediated neurotransmission in the DRN induced significant and complex motor and emotional effects.
Abstract: The effects of microinjection of the nitric oxide (NO) precursor l-arginine (l-Arg), the NO synthase (NOS) inhibitors N-methyl-l-arginine (l-NAME) and 7-nitroindazole (7-NI), and the cyclic guanosine 3',5'-monophosphate (cGMP) analog 8-Br-cGMP into the dorsal raphe nucleus (DRN) were assessed in rats using the elevated plus maze (EPM) and the forced swim test (FST). l-Arg (100 and 200 nmol) produced an anxiolytic-like effect in the EPM. 8-Br-cGMP (25 and 50 nmol) dose-dependently increased locomotor activity. In the FST, antidepressant-like effects were produced by l-Arg (50 and 100 nmol) and 8-Br-cGMP (12.5 and 25 nmol). Dual effects were observed with NOS inhibitors l-NAME and 7-NI in both the EPM and FST. While low doses of l-NAME (25 nmol) or 7-NI (1 nmol) induced a selective increase in EPM open arm exploration and a decrease in immobility time in the FST, high doses (l-NAME 400 nmol, 7-NI 10 nmol) decreased locomotor activity. These results show that interference with NO-mediated neurotransmission in the DRN induced significant and complex motor and emotional effects. Further studies are needed to elucidate the mechanisms involved in these effects.
TL;DR: Findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.
Abstract: On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.
TL;DR: It is described how particular GABA(A) receptor subtypes expressed in different brain regions are critical for the expression of behavioral endpoints, such as amnesia, sedation, and hypnosis.
Abstract: General anesthetics produce a constellation of behavioral responses and widespread neurodepression. Recent studies have implicated the gamma-aminobutyric acid (GABA) subtype A receptor as a primary anesthetic target. During the past decade, considerable progress has been made in dissecting the behavioral effects of anesthetics according to the subunit composition of GABA(A) receptors. In this review, we describe how particular GABA(A) receptor subtypes expressed in different brain regions are critical for the expression of behavioral endpoints, such as amnesia, sedation, and hypnosis.
TL;DR: The contribution of in vivo microdialysis studies in spontaneously hypertensive (SH) rats to the understanding of the neurochemical deficits in this rat strain and the actions of ADHD drugs on catecholaminergic function in the prefrontocortex, striatum and nucleus accumbens is explored.
Abstract: Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric condition that is effectively treated by catecholaminergic drugs with a variety of different mechanisms and the SH rat is frequently used as a model of this disorder. In vivo microdialysis in freely-moving rats has been employed extensively to provide a better understanding of the pharmacodynamics of drugs at their sites of action. In this review, these three topics are brought together to explore the contribution of in vivo microdialysis studies in spontaneously hypertensive (SH) rats to our understanding of the neurochemical deficits in this rat strain and the actions of ADHD drugs on catecholaminergic function in the prefrontocortex (PFC), striatum and nucleus accumbens. What is revealed is that basal efflux of norepinephrine in the PFC is attenuated, whilst striatal and mesolimbic dopaminergic neurotransmission is hyperfunctional; the latter observation fits closely with the hyperactive phenotype of the SH rat. Furthermore, experiments performed with the enantiomers of amphetamine and threo-methylphenidate demonstrate that pharmacodynamic effects of drugs reported from experiments in outbred rat strains, e.g. Sprague-Dawleys, do not necessarily translate to the SH rat. When the findings are compared with the clinical efficacy of drugs used in treating ADHD, they indicate that the most efficacious drugs powerfully increase both norepinephrinergic and dopaminergic neurotransmission.
TL;DR: The present data demonstrate that LIG significantly prevented chronically hypoperfused cognitive deficits and brain damage at least partly through an antioxidant effect and improved cholinergic activity and suggest that LISA may have therapeutic potential in treating vascular dementia and cerebrovascular insufficiency.
Abstract: Previous studies have demonstrated that Z-Ligustilide (LIG), a characterized phthalide constituent present in numerous medical Umbelliferae plants, has significant neuroprotective effects in transient forebrain ischemia and permanent cerebral focal ischemia. The present study further investigated the effect of LIG on chronic cerebral hypoperfusion. Male Wistar rats were subjected to permanent ligation of both common carotid arteries (2VO). On Days 8-12 postsurgery, rat cognition was assessed in the Morris water maze. Rats with significantly impaired acquisition of spatial information were randomly allocated to three groups and orally administered LIG (10 or 40 mg/kg/day) or volume-matched vehicle on Days 13-40 post-2VO surgery. The sham-operated group served as controls. After long-term treatment with LIG, the impaired animals' behavioral, biochemical, and histopathological features were examined. Compared to the sham-operated group, significant cognitive impairment was observed in the vehicle-treated group 40 days after 2VO. Shortened mean escape latency was detected in the Morris water maze in rats treated with LIG (p<0.01 vs. vehicle-treated group) during the same trial days. Chronic 2VO-induced pathological changes included neuronal loss and an increase of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the hippocampus. These effects were prevented with LIG treatment (p<0.01 vs. vehicle-treated group). LIG also significantly reduced malondialdehyde levels and increased superoxide dismutase activity in ischemic brain tissue (p<0.05 and p<0.01 vs. vehicle-treated group). In addition, LIG significantly increased choline acetyltransferase activity and inhibited acetylcholinesterase activity in ischemic brain tissues (p<0.05 and p<0.01 vs. vehicle-treated group). The present data demonstrate that LIG significantly prevented chronically hypoperfused cognitive deficits and brain damage at least partly through an antioxidant effect and improved cholinergic activity. The present findings suggest that LIG may have therapeutic potential in treating vascular dementia and cerebrovascular insufficiency.
TL;DR: Although AVP did not affect the number of attacks or duration of aggression, it increased the latency to initiate aggression on day 5, and central AVP activity modulates maternal aggression, as well as maternal behavior and grooming behavior during lactation.
Abstract: Maternal aggression is a robust type of aggression displayed by lactating female rats. Although arginine vasopressin (AVP) has been implicated in the control of male aggression, its involvement in maternal aggression has not been thoroughly investigated. Previous neuroanatomical studies suggest that AVP may mediate the display of aggression during lactation. In the current study, AVP and an AVP V1a receptor antagonist were centrally administered to primiparous rats on days 5 and 15 of lactation, and aggression, maternal behavior, and grooming were recorded. Although AVP did not affect the number of attacks or duration of aggression, it increased the latency to initiate aggression on day 5, in addition to decreasing maternal behavior and increasing grooming. Conversely, V1a antagonist treatment increased maternal aggression on both days of lactation, decreased maternal behavior on day 15, and decreased grooming on day 5. Thus, it appears that central AVP activity modulates maternal aggression, as well as maternal behavior and grooming behavior during lactation.
TL;DR: Results indicate that NPY abolishes dependence-induced elevations in alcohol drinking and implicate the recruitment of limbic NPY systems in the motivational drive to consume alcohol following the transition to dependence.
Abstract: The anxiolytic effects of neuropeptide Y (NPY) are mediated in part by the central nucleus of the amygdala (CeA), a brain region involved in the regulation of alcohol-drinking behaviors Centrally administered NPY suppresses alcohol drinking in subpopulations of rats vulnerable to the development of high alcohol-drinking behavior The purpose of the current study was to determine the role of NPY in the CeA on elevated alcohol drinking produced by alcohol dependence Adult male Wistar rats were trained to respond for 10% w/v alcohol in an operant situation with the use of a supersaccharin fading procedure Following stabilization of responding, rats were divided into two groups matched for intake and given daily access to either alcohol-containing (92% v/v) liquid diet or an isocaloric control diet Following extended access to the diet and reliable separation of operant responding between dependent and non-dependent rats during 6-h withdrawal tests, all rats were implanted bilaterally with cannulae aimed at the CeA Rats were then infused with 4 NPY doses (00, 025, 05, 10 μg/05 μl aCSF) in a within-subjects Latin-square design during acute withdrawal and tested for operant alcohol responding 30 min later Alcohol-dependent rats exhibited higher operant alcohol responding than non-dependent rats when infused with vehicle, but responding was similar in the two groups following infusion of all doses of NPY These results indicate that NPY abolishes dependence-induced elevations in alcohol drinking and implicate the recruitment of limbic NPY systems in the motivational drive to consume alcohol following the transition to dependence
TL;DR: In this paper, a method for treating or preventing a host mammal that exhibits aversive signs and symptoms present during protracted abstinence or extended discontinuation syndromes as seen after cessation of compulsive activity, behaviors, or substance use is disclosed.
Abstract: A method for treating or preventing a host mammal that exhibits aversive signs and symptoms present during protracted abstinence or extended discontinuation syndromes as seen after cessation of compulsive activity, behaviors, or substance use is disclosed. That method comprises administering to a host mammal in need a pharmaceutical composition containing an aversive sign and symptom lessening amount a compound of Formula I or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable diluent, and repeating the administration as needed, wherein W, X, Y and Z, R1 and Ar are defined within. Data are provided in rats as host mammals using behavioral models dependent on the CRFi system: defensive burying, alcohol dependence, cocaine dependence and nicotine dependence. A contemplated method also is useful for inhibiting relapse of such a behavior. A contemplated method also is useful for treating substance -related or substance- induced psychiatric disorders that include aversive signs and symptoms.
TL;DR: It can be concluded that both serotonin and GABA in the hippocampus are highly responsive to stress, but also that these responses are shaped by the exact nature of the stressor, i.e. the balance between the psychological and physical aspects of the stressful challenge.
Abstract: Aberrant functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis seems to be involved in depression and anxiety. However, the mechanisms underlying the relationship between stress and mental illness are not completely resolved yet. The therapeutical efficacy of selective serotonin re-uptake inhibitors and benzodiazepines points to a key role of serotonin and gamma-aminobutyric acid (GABA) in depression and anxiety. Thus, it can be hypothesised that stress-induced changes in serotonin and GABA contribute to a dysregulation of the HPA axis and to the development of psychiatric disorders in susceptible subjects. It will, therefore, be crucial to increase our understanding of the effects of stress on serotonin and GABA. Various refinements have made in vivo microdialysis an extremely powerful method to study the highly dynamic neurotransmitter responses in stress physiology and behaviour. Furthermore, microdialysis can also be used to measure free corticosterone levels in the brain and, thus, HPA axis activity and neurotransmission can be monitored concomitantly. Here we review the effects of acute and chronic stress on serotonin and GABA, as assessed by microdialysis, in the hippocampus; a brain structure critically involved in the behavioural and neuroendocrine responses to stress. From the microdialysis data discussed, it can be concluded that both serotonin and GABA in the hippocampus are highly responsive to stress, but also that these responses are shaped by the exact nature of the stressor, i.e. the balance between the psychological and physical aspects of the stressful challenge.
TL;DR: Dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress in rats.
Abstract: Exposure to stress is thought to play an important role in the etiology of depression. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis characterized by glucocorticoid negative feedback resistance is frequently observed in human depressives. Additionally, dysfunctions of the dopaminergic and serotonergic systems in the prefrontal cortex (PFC) are thought to be involved in the development of a depressive state. In rats, chronic stress induces a behaviorally depressive state, concomitant with dysregulation of the HPA axis and reductions in dopaminergic and serotonergic transmissions in the PFC. Considering that dysregulation of the HPA axis is associated with relapse and persistency of depression, it is possible that the chronic stress-induced depressive state persists during long-term rest after its exposure. In the present study, we examined this possibility in rats and found that the behaviorally depressive state in the rotarod test, negative feedback resistance in the dexamethasone suppression test, and a decrease in the extracellular concentration of dopamine but not serotonin in the PFC persisted for 3 months following a 4-week stress session. These results suggest that dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress.
TL;DR: This paper examined the effects of operant ethanol self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-prefering rats.
Abstract: The current study examined the effects of operant ethanol (EtOH) self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water–water, EtOH (15% v/v)–water, or saccharin (SAC; 0.0125% g/v)–water. Animals were killed 24 h after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p