Conditioned social preference and reward value of activating oxytocin-receptor-expressing ventral tegmental area neurons following repeated daily binge ethanol intake.

Background: Individuals with alcohol use disorder (AUD) exhibit a disruption of social behavior and dysregulation of oxytocin signaling in the brain, possibly reflecting decreased activation of oxytocin receptors (OxTRs) in reward pathways in response to social stimuli. We hypothesize that daily binge ethanol intake causes a deficit in social reward and oxytocin signaling in the ventral tegmental area (VTA).

Methods: After 9 weeks of daily binge ethanol intake (blood ethanol concentration >80 mg%), OxTR-cre mice underwent conditioned place preference for social reward.

Binge ethanol consumption-associated behavioral impairments in male mice using a gelatin-based drinking-in-the dark model.

Background: Acute intoxication caused by binge ethanol drinking is linked to widespread impairments in brain functions. Various alcohol administration paradigms have been used in animals to model the heterogeneous clinical manifestation of intoxication in people. It is challenging to model a procedure that produces "visible intoxication" in rodents; however, manipulation of variables such as route of alcohol administration, time of availability, frequency, and duration and amount of ethanol exposure has achieved some success.

Glutamatergic projections from homeostatic to hedonic brain nuclei regulate intake of highly palatable food.

Food intake is a complex behavior regulated by discrete brain nuclei that integrate homeostatic nutritional requirements with the hedonic properties of food. Homeostatic feeding (i.e.

Chronic Voluntary Binge Ethanol Consumption Causes Sex-Specific Differences in Microglial Signaling Pathways and Withdrawal-associated Behaviors in Mice.

Background: Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward.

Oxytocin treatment for alcoholism: Potential neurocircuitry targets.

Oxytocin (OT) has gained considerable interest in recent years as a potential treatment for alcoholism and other substance use disorders. Evidence continues to mount that OT administered either centrally, peripherally or intranasally can decrease ethanol intake in both humans and animal models. The potential mechanisms for the ability of OT to decrease ethanol reward, and importantly, cue- and stress-induced ethanol relapse, are explored by reviewing the specific neuronal circuits involved in mediating these actions and their sensitivity to OT.

Regionally Specific Effects of Oxytocin on Reinstatement of Cocaine Seeking in Male and Female Rats.

Background: Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues.

Ceftriaxone reduces alcohol intake in outbred rats while upregulating xCT in the nucleus accumbens core.

Alcohol addiction is a chronic disease characterized by an inability to regulate drinking. A critical brain region involved in alcohol consumption is the nucleus accumbens (NA). Glutamate transmission in this region regulates alcohol consumption and relapse to alcohol-seeking.

Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets.

The mesolimbic dopamine (DA) circuitry determines which behaviors are positively reinforcing and therefore should be encoded in the memory to become a part of the behavioral repertoire. Natural reinforcers, like food and sex, activate this pathway, thereby increasing the likelihood of further consummatory, social, and sexual behaviors. Oxytocin (OT) has been implicated in mediating natural reward and OT-synthesizing neurons project to the ventral tegmental area (VTA) and nucleus accumbens (NAc); however, direct neuroanatomical evidence of OT regulation of DA neurons within the VTA is sparse.

Peripheral oxytocin administration reduces ethanol consumption in rats.

The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague-Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms.

Intermittent high-dose ethanol exposure increases ethanol preference in rats.

Objective: Alcohol use disorders have both high social and economic costs and are among the leading causes of preventable death in the United States. Understanding the factors that contribute to escalation of alcohol intake is important in developing effective treatments for this problem. This study further characterizes the effects of limited intermittent exposure to high levels of alcohol on the preference for alcohol consumption over other incentives.

Serotonin-2C receptor agonists decrease potassium-stimulated GABA release in the nucleus accumbens.

The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2-N,N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons.

Alpha 1-antitrypsin therapy mitigated ischemic stroke damage in rats.

Our objective is to develop a new therapy for the treatment of stroke. Currently, the only effective therapy for acute ischemic stroke is the thrombolytic agent recombinant tissue plasminogen activator. α1-Antitrypsin (AAT), a serine proteinase inhibitor with potent anti-inflammatory, anti-apoptotic, antimicrobial, and cytoprotective activities, could be beneficial in stroke.

The serotonin-2 receptor modulator, (-)-trans-PAT, decreases voluntary ethanol consumption in rats.

Serotonin (5-HT) 5-HT2C receptor agonists have shown promise as novel alcoholism pharmacotherapies, but developing selective agonists has been problematic. Female Sprague Dawley rats were given ethanol in a palatable gel vehicle during operant sessions. 5-HT2C receptor modulators (Ro60-0175, SB242,084, and (-)-trans-PAT) were administered before operant sessions.

The protective effects of plasma gelsolin on stroke outcome in rats.

Background: To date, recombinant tissue plasminogen activator (rtPA) is the only approved drug for ischemic stroke. It is intravenously administered functioning as a thrombolytic agent and is used to obtain reperfusion of the affected area of the brain. Excitotoxicity, inflammation and apoptosis are all involved in delayed neuronal death following stroke and offer multiple opportunities to intervene with neuroprotective agents.

The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex.

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia.

Intermittent high-dose ethanol exposures increase motivation for operant ethanol self-administration: possible neurochemical mechanism.

We investigated the neurochemical mechanism of how high-dose ethanol exposure may increase motivation for ethanol consumption. First, we developed an animal model of increased motivation for ethanol using a progressive ratio (PR) schedule. Sprague-Dawley rats were trained to administer 10% ethanol-containing gelatin or plain gelatin (on alternate weeks) in daily 30-min sessions under different fixed ratio (FR) and PR schedules.

Effects of an enrichment device on voluntary alcohol consumption on single-housed rats.

We evaluated the effect of an enrichment device (that is, a polyurethane bone) on the voluntary consumption of ethanol containing gel by single-housed rats. Male Sprague-Dawley rats (n = 5 per group) were exposed for 4 d to each of the following 3 treatments: access to a new synthetic bone and ethanol gel for 1 h daily (treatment 1); a new bone was left in the cage for 24 h, with access to ethanol gel for 1 h daily (treatment 2); and both the bone and ethanol gel remained in the cage for 24 h (treatment 3). Average alcohol consumption over 4 d was 0.

High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation.

Capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF) provides 15-s temporal resolution of amino acid levels in microdialysate, which, for the first time, allows almost real time measurement of changes during episodes of behavior. We trained Sprague-Dawley rats to self-administer either 10% ethanol-containing gelatin or non-alcoholic gelatin in a typical operant chamber. After rats reached stable daily levels of responding, microdialysis probes were inserted into nucleus accumbens and samples were collected before, during and after operant sessions with on-line analysis via CE-LIF.

Microdialysis as a tool in local pharmacodynamics.

In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was first used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the field.

A murine model for human sepiapterin-reductase deficiency.

Tetrahydrobiopterin (BH(4)) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH(4) is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH(4) deficiency has been shown to be closely associated with diverse neurological psychiatric disorders.

In vivo monitoring of amino acids by microdialysis sampling with on-line derivatization by naphthalene-2,3-dicarboxyaldehyde and rapid micellar electrokinetic capillary chromatography.

An analytical method was developed to monitor amino acids collected by in vivo microdialysis. Microdialysate was continuously derivatized on-line by mixing 6 mM naphthalene-2,3-dicarboxyaldehyde (NDA) and 10 mM potassium cyanide with the dialysate stream in a fused silica capillary to form fluorescent products. Reaction time, determined by the flow rate and volume of reaction capillary, was 3 min.

Taurine-induced long-lasting potentiation in the rat hippocampus shows a partial dissociation from total hippocampal taurine content and independence from activation of known taurine transporters.

Perfusion with high millimolar levels of taurine evoked a long-lasting potentiation (LLP-TAU) of synaptic transmission in the Schaffer-collateral CA1 region of the rat hippocampus. Although LLP-TAU showed some correlations to increases in the total taurine content of hippocampal slices, it could not be blocked by the taurine transport inhibitor guanidinoethanesulfonic acid (GES), which was able to significantly reduce total slice taurine uptake. Inhibition of GABA transport by either nipecotic acid or beta-guanidinopropionate failed to abolish LLP-TAU and had no significant effect on taurine uptake.