Chronic methamphetamine exposure prior to middle cerebral artery occlusion increases infarct volume and worsens cognitive injury in Male mice.

Emerging evidence indicates that methamphetamine (MA) abuse can impact cardiovascular disease. In humans, MA abuse is associated with an increased risk of stroke as well as an earlier age at which the stroke occurs. However, little is known about how chronic daily MA exposure can impact ischemic outcome in either humans or animal models.

Local changes in neurosteroid levels in the substantia nigra reticulata and the ventral tegmental area alter chronic ethanol withdrawal severity in male withdrawal seizure-prone mice.

Background: Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAA Rs) that affects ethanol (EtOH) withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters EtOH sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during EtOH withdrawal and that intrahippocampal FIN significantly increased EtOH withdrawal severity.

A genetic animal model of differential sensitivity to methamphetamine reinforcement.

Sensitivity to reinforcement from methamphetamine (MA) likely influences risk for MA addiction, and genetic differences are one source of individual variation. Generation of two sets of selectively bred mouse lines for high and low MA drinking has shown that genetic factors influence MA intake, and pronounced differences in sensitivity to rewarding and aversive effects of MA play a significant role. Further validation of these lines as a unique genetic model relevant to MA addiction was obtained using operant methods to study MA reinforcement.

Acetylcholine from the mesopontine tegmental nuclei differentially affects methamphetamine induced locomotor activity and neurotransmitter levels in the mesolimbic pathway.

Methamphetamine (MA) increases dopamine (DA) levels within the mesolimbic pathway and acetylcholine (ACh), a neurotransmitter known to increase DA cell firing and release and mediate reinforcement, within the ventral tegmental area (VTA). The laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei provide cholinergic input to the VTA; however, the contribution of LDT- and PPT-derived ACh to MA-induced DA and ACh levels and locomotor activation remains unknown. The first experiment examined the role of LDT-derived ACh in MA locomotor activation by reversibly inhibiting these neurons with bilateral intra-LDT microinjections of the M2 receptor agonist oxotremorine (OXO).

Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine.

Rationale: Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants.

Objectives: We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg).

Conditioned taste aversion from neostigmine or methyl-naloxonium in the nucleus accumbens.

An opioid antagonist injected in the nucleus accumbens of a morphine-dependent rat will lower extracellular dopamine and release acetylcholine (ACh), as also seen in opiate withdrawal. It was hypothesized that raising extracellular ACh experimentally would be aversive as reflected by the induction of a conditioned taste aversion. Rats were implanted with cannulas aimed above the nucleus accumbens (NAc) for injection of the opiate antagonist methyl-naloxonium in morphine-dependent animals or neostigmine to increase ACh in drug naïve animals.

Cholinergic modulation of mesolimbic dopamine function and reward.

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating.

The influence of selection for ethanol withdrawal severity on traits associated with ethanol self-administration and reinforcement.

Background: Several meta-analyses indicate that there is an inverse genetic correlation between ethanol preference drinking and ethanol withdrawal severity, but limited work has characterized ethanol consumption in 1 genetic animal model, the Withdrawal Seizure-Prone (WSP) and-Resistant (WSR) mouse lines selected for severe or mild ethanol withdrawal, respectively.

Methods: We determined whether line differences existed in: (i) operant self-administration of ethanol during sucrose fading and under different schedules of reinforcement, followed by extinction and reinstatement of responding with conditioned cues and (ii) home cage drinking of sweetened ethanol and the development of an alcohol deprivation effect (ADE).

Results: Withdrawal Seizure-Prone-1 mice consumed more ethanol than WSR-1 mice under a fixed ratio (FR)-4 schedule as ethanol was faded into the sucrose solution, but this line difference dissipated as the sucrose was faded out to yield an unadulterated 10% v/v ethanol solution.

The influence of mecamylamine on ethanol and sucrose self-administration.

Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol. However, discernment of nAChR contribution to ethanol reinforcement and consumption remains incomplete. The current studies examined the influence of the nAChR antagonist mecamylamine (MEC) on operant ethanol self-administration using a procedure that independently assessed appetitive and consumptive processes, and compared these findings to effects of MEC on sucrose self-administration.

CRF enhancement of GIRK channel-mediated transmission in dopamine neurons.

Dopamine neurons in the ventral midbrain contribute to learning and memory of natural and drug-related rewards. Corticotropin-releasing factor (CRF), a stress-related peptide, is thought to be involved in aspects of relapse following drug withdrawal, but the cellular actions are poorly understood. This study investigates the action of CRF on G-protein-linked inhibitory postsynaptic currents (IPSCs) mediated by GIRK (Kir3) channels in dopamine neurons.

The neurosteroid environment in the hippocampus exerts bi-directional effects on seizure susceptibility in mice.

The progesterone derivative allopregnanolone (ALLO) rapidly potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor mediated inhibition. The present studies determined whether specific manipulation of neurosteroid levels in the hippocampus would alter seizure susceptibility in an animal model genetically susceptible to severe ethanol (EtOH) withdrawal, Withdrawal Seizure-Prone (WSP) mice. Male WSP mice were surgically implanted with bilateral guide cannulae aimed at the CA1 region of the hippocampus one week prior to measuring seizure susceptibility to the convulsant pentylenetetrazol (PTZ), given via timed tail vein infusion.

Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice.

Rationale: Recent work in our laboratory documented that the "sipper" method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction "burst" in responding under nonreinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model.

Objectives: Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on the reinstatement of extinguished ethanol-seeking behavior and compared this effect to the reinstatement of responding for sucrose reward.

Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats.

Cocaine- and amphetamine-regulated transcript (CART) peptides appear to modulate various effects of psychostimulant drugs. Injections of CART peptide into the nucleus accumbens (NAcc) inhibit locomotion produced by systemic injections of the psychostimulants cocaine and amphetamine. Intra-NAcc injections of CART peptide also inhibit locomotion produced by microinfusions of dopamine into the NAcc, suggesting that the effects of CART peptides may be due to an interaction with the dopaminergic system in the NAcc.

Decreased vesicular somatodendritic dopamine stores in leptin-deficient mice.

An increasing number of studies indicate that leptin can regulate the activity of the mesolimbic dopamine system. The objective of this study was to examine the regulation of the activity of dopamine neurons by leptin. This was accomplished by examining the dopamine D2 receptor-mediated synaptic current that resulted from somatodendritic release of dopamine in brain slices taken from mice that lacked leptin (Lep(ob/ob) mice).

The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access.

Rationale: Escalation from moderate to excessive drug intake is a hallmark of human addiction that can be modeled in rats by giving them longer daily access time to self-administer cocaine. Nicotine and cocaine are commonly coabused drugs in humans and recent work in animals suggests that activation of nicotinic acetylcholine receptors (nAChR) can increase cocaine self-administration.

Objectives: Determine the role of nAChR in the escalation of cocaine self-administration.

Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice.

Ethanol reinforcement should ideally be evaluated in animals that are not food deprived to ensure that the motivation behind its consumption is pharmacological, and not caloric, in nature. The objective of this work was to assess the influence of reinforcement schedule on ethanol intake in nondeprived mice. Male C57BL/6J mice were trained to respond on an ethanol-reinforced lever on a fixed ratio 4 reinforcement schedule for 10% ethanol (10E).

M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion.

The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth.

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice.

Although systemic allopregnanolone (ALLO; a positive modulator of GABA(A) receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food- and water-satiated mice, with a procedure designed to estimate ALLO's influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution.

Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats.

Mesencephalic dopamine neurons form synapses with acetylcholine (ACh)-containing interneurons in the nucleus accumbens (NAcc). Although their involvement in drug reward has not been systematically investigated, these large aspiny interneurons may serve an important integrative function. We previously found that repeated activation of nicotinic cholinergic receptors enhanced cocaine intake in rats but the role of muscarinic receptors in drug reward is less clear.

Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location.

The mesolimbic dopamine system, which mediates the rewarding properties of nearly all drugs of abuse, originates in the ventral tegmental area (VTA) and sends major projections to both the nucleus accumbens (NAc) and the basolateral amygdala (BLA). To address whether differences occur between neurons that project to these separate areas, retrograde microspheres were injected to either the BLA or the NAc of DBA/2J mice. Whole-cell recordings were made from labeled VTA dopamine neurons.

Locomotor activity predicts acquisition of self-administration behavior but not cocaine intake.

The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward.

Self-administration enhances excitatory synaptic transmission in the bed nucleus of the stria terminalis.

Understanding the neurobiology of motivation might help in reducing compulsive behaviors such as drug addiction or eating disorders. This study shows that excitatory synaptic transmission was enhanced in the bed nucleus of the stria terminalis of rats that performed an operant task to obtain cocaine or palatable food. There was no effect when cocaine or food was delivered passively, suggesting that synaptic plasticity in this area is involved in reward-seeking behaviors.

Cocaine self-administration selectively decreases noradrenergic regulation of metabotropic glutamate receptor-mediated inhibition in dopamine neurons.

Stimulant drugs of abuse have several effects on neural activity, including altering the excitability of dopamine neurons via the noradrenergic and glutamatergic systems. Thus, an interaction between noradrenergic and glutamatergic systems may play a role in drug-seeking behavior. Although many of the direct pharmacological effects of psychostimulants on dopamine neuron physiology are well established, the neurophysiological bases of drug-seeking behavior have yet to be fully elucidated.