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Patricia H Janak

Publications and source records attributed to Patricia H Janak.

At least 19 recordsLinked to original sources
PubMed2006

Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons.

Transforming growth factor beta (TGFbeta) is a potent trophic factor for midbrain dopamine (DA) neurons, but its in vivo function and signaling mechanisms are not entirely understood. We show that the transcriptional cofactor homeodomain interacting protein kinase 2 (HIPK2) is required for the TGFbeta-mediated survival of mouse DA neurons. The targeted deletion of Hipk2 has no deleterious effect on the neurogenesis of DA neurons, but leads to a selective loss of these neurons that is due to increased apoptosis during programmed cell death. As a consequence, Hipk2(-/-) mutants show an array of psychomotor abnormalities. The function of HIPK2 depends on its interaction with receptor-regulated Smads to activate TGFbeta target genes. In support of this notion, DA neurons from Hipk2(-/-) mutants fail to survive in the presence of TGFbeta3 and Tgfbeta3(-/-) mutants show DA neuron abnormalities similar to those seen in Hipk2(-/-) mutants. These data underscore the importance of the TGFbeta-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

Amphetamine↗
PubMed2006

Post-training and post-reactivation administration of amphetamine enhances morphine conditioned place preference.

Amphetamine has been shown to enhance consolidation in a variety of memory paradigms. However, it is not known if amphetamine can modulate the consolidation of the types of context-reward associations involved in drug addiction, such as those formed in the conditioned place preference (CPP) task. Also, some types of memory exhibit a second period of lability following memory reactivation, and it is not known whether amphetamine administered during this period can modulate CPP. Our study investigated whether amphetamine can enhance morphine CPP when administered during the consolidation period or the post-reactivation period. Subjects were trained in the CPP task and injected with amphetamine or vehicle immediately or 6 h after each training session. The day after the completion of training, they were tested. Amphetamine injected immediately but not 6 h after training enhanced morphine CPP. In separate experiments, subjects were first trained in the CPP task. The day following the completion of training, subjects were given a memory reactivation session and injected with amphetamine or vehicle immediately or 6 h after reactivation. Subjects were tested the next day. Amphetamine injected immediately but not 6 h after memory reactivation enhanced morphine CPP. However, amphetamine injected without memory reactivation had no effect on the expression of morphine CPP. Our results suggest that amphetamine enhances the consolidation of morphine CPP and that morphine CPP exhibits a temporally limited period of post-reactivation lability during which the memory can be modulated.

Amphetamine↗
PubMed2006

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes.

RATIONALE: Corticotropin-releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established. OBJECTIVES: We used selective CRF receptor antagonists to determine the receptor subtypes involved in the anxiogenic-like and aversive effects CRF in the BNST. MATERIALS AND METHODS: Male Long-Evans rats were bilaterally infused with CRF (0.2 or 1.0 nmol) either alone or in combination with the CRF1 receptor antagonist CP154,526 or the CRF2 receptor antagonist anti-sauvagine 30 (AS30) before behavioral testing in the elevated plus maze or place conditioning paradigms. RESULTS: Intra-BNST administration of CRF produced a dose-dependent reduction in open arm entries and open arm time in the elevated plus maze, indicating an anxiogenic-like effect. These effects were inhibited by co-infusion of CP154,526 but not of AS30, indicating that the anxiogenic-like effects of CRF in the BNST are mediated by CRF1 receptors. Place conditioning with intra-BNST administration of CRF produced a dose-dependent aversion to the CRF-paired environment that was prevented by co-infusion of either CP154,526 or AS30, indicating that both CRF receptor subtypes mediate the aversive effects of this peptide. Intra-BNST infusions of the CRF receptor antagonists alone produced no effects in either behavioral paradigm. CONCLUSIONS: CRF1 receptors in the BNST mediate the anxiogenic-like effects of CRF in this region, whereas both CRF1 and CRF2 receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST.

Animals↗
PubMed2006

The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption.

We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF). RACK1 translocates to the nucleus after exposure of neurons to ethanol and increases expression of BDNF (McGough et al., 2004). We also found that increasing the levels of BDNF via systemic administration of RACK1 expressed as a Tat-fusion protein (Tat-RACK1) reduces ethanol consumption, whereas reduction of BDNF levels augments this behavior (McGough et al., 2004). Based on these results, we hypothesized that activation of the BDNF receptor TrkB is necessary for the effects of BDNF on ethanol intake and that gene products downstream of BDNF negatively regulate ethanol consumption. Here, we show that inhibition of the BDNF receptor TrkB increases voluntary ethanol consumption in wild-type mice but not in mice lacking one copy of the BDNF gene (BDNF(+/-)). We also find that increases in the levels of BDNF, mediated by ethanol or RACK1, lead to increased dorsal striatal levels of the dopamine D3 receptor (D3R), a gene downstream of BDNF, via activation of the TrkB receptor. Finally, we show that the Tat-RACK1-mediated reduction of ethanol consumption is attenuated by coinjection with either the Trk inhibitor K252a or the dopamine D3R-prefering antagonist U-99194A [5, 6-dimethoxy-2-(di-n-propylamino)indan], suggesting that activation of the BDNF pathway via RACK1 leads to increased expression of the dopamine D3R, which in turn mediates the attenuation of ethanol consumption.

Alcohol Drinking↗
PubMed2006

Alcohol seeking in C57BL/6 mice induced by conditioned cues and contexts in the extinction-reinstatement model.

We have recently shown that the alcohol self-administration context can reinstate extinguished responding for alcohol when that extinction occurs in a different context [Burattini, C., Gill, T. M., Aicardi, G., & Janak, P. H. (2006)]. The ethanol self-administration context as a reinstatement cue: acute effects of naltrexone. Neuroscience, in press; Zironi, I., Burattini, C., Aicardi, G., & Janak, P. H. (2006). Context is a trigger for relapse to alcohol. Behav Brain Res 167, 150-155). Here, we test whether the C57BL/6 mice will also show context-induced reinstatement for alcohol, and whether presentation of an alcohol-associated cue will alter the observed responding. Male C57BL/6 mice were trained to lever press on a fixed ratio-3 schedule for a 10% ethanol solution in a context made distinctive using visual, tactile, and olfactory stimuli. Each ethanol delivery was paired with a compound tone-light stimulus. After training, extinction sessions were given in a distinct context, comprised of different visual, tactile, and olfactory stimuli; the compound cue and the alcohol were not available during these sessions. In Experiment 1, after response extinction, subjects were tested by placement into both the alcohol self-administration context and, on a subsequent test, by response-contingent presentation of the cue following placement into the alcohol self-administration context. In Experiment 2, after response extinction, subjects were tested in both of these conditions, with the addition of a test of the effects of response-contingent presentation of the cue in the extinction context. The results indicate that the alcohol self-administration context produces a mild increase in responding at the alcohol lever, and that presentation of the alcohol-associated cue in the alcohol context, but not the extinction context, strongly increases responding on the alcohol lever. These findings suggest that the power of an alcohol-associated cue can be modulated by the context. The observed effects of alcohol contexts and cues on alcohol-seeking behavior in the C57BL/6 mouse suggest that this reinstatement model may be useful for understanding the neurobiological and genetic mechanisms of relapse triggered by conditioned environmental stimuli.

Alcohol Drinking↗
PubMed2006

BIG news in alcohol addiction: new findings on growth factor pathways BDNF, insulin, and GDNF.

In recent years, it has become clear that growth factors are not only critical for the development of the central nervous system (CNS) but may also be important contributors to other neuronal functions in the adult brain. This symposium, presented at the 2005 RSA meeting, discussed evidence to support the hypothesis that alterations in growth factor pathways produce dramatic changes in the effects of alcohol on the CNS. The 4 speakers showed that the behavioral effects of alcohol in the adult are regulated by 3 growth factors, insulin, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF). Dr. Wolf from the Heberlein laboratory presented findings obtained from genetic manipulations in Drosophila melanogaster, demonstrating that the insulin pathway controls sensitivity to the intoxicating effects of alcohol. Marian Logrip from the Ron and Janak laboratories presented evidence obtained in rodents that low concentrations of alcohol increase the expression of BDNF in the brain to regulate alcohol consumption. Dr. Pandey showed that amygdalar BDNF regulates alcohol's anxiolytic effects and preference. Finally, Dr. Janak presented evidence that increases in the expression of GDNF in the midbrain reduce alcohol self-administration in rats.

Alcoholism↗
PubMed2005

Context is a trigger for relapse to alcohol.

The environment in which alcohol consumption occurs may trigger later relapse in alcohol abusers. In this study, we tested whether an alcohol-associated environment would induce alcohol-seeking behavior. Male rats were trained to lever press for oral alcohol reinforcement in a distinctive context. Responding was then extinguished in a context with different olfactory, visual and tactile properties. Placement of the rats back into the original context in which they self-administered alcohol induced, in the absence of alcohol availability, a significant increase in lever press responding on the alcohol lever as compared to extinction levels of responding. The ability of the alcohol context to support alcohol-seeking behavior was maintained over 3 weeks, with no significant diminution. A second group of rats was trained to lever press for sucrose reinforcement; this group also demonstrated context-dependent reinstatement, although the degree of reinstatement decreased over repeated tests, returning to extinction values after 3 weeks. These findings indicate that contextual conditioning has a long-term impact on ethanol-seeking behavior after ethanol withdrawal. This animal model may be useful to study the neural mechanisms underlying relapse induced by ethanol-associated contexts in humans.

Alcohol Drinking↗
PubMed2005

Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

Alcoholism↗
PubMed2005

GDNF and addiction.

Biochemical adaptations to drugs of abuse and alcohol are especially profound in midbrain dopaminergic neurons. Long-lasting molecular and structural changes in mesolimbic dopaminergic neurons that result from chronic exposure to drugs of abuse and alcohol are thought to underlie adverse behaviors such as compulsive drug seeking and relapse. Recent studies suggest that a subset of these changes is prevented/reversed by activation of the glial cell line-derived neurotrophic factor (GDNF) signaling pathway. Behavioral effects of drugs of abuse such as cocaine and alcohol are also negatively regulated by GDNF: inhibition of the endogenous GDNF pathway enhances the activity of drugs of abuse, while administration of GDNF reduces the severity of the effects. In this review, we summarize the data implicating GDNF as a negative regulator of drug and alcohol addiction. We also provide evidence to suggest that therapies that activate GDNF signaling may be useful for the treatment of drug and alcohol addiction.

Excitatory Amino Acid Antagonists↗
PubMed2004

The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism.

Glutamatergic neurotransmission plays a critical role in addictive behaviors, and recent evidence indicates that genetic or pharmacological inactivation of the type 5 metabotropic glutamate receptor (mGluR5) reduces the self-administration of cocaine, nicotine, and alcohol. Because mGluR5 is coupled to activation of protein kinase C (PKC), and targeted deletion of the epsilon isoform (PKCepsilon) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKCepsilon. Here, we show that acute administration of the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine to mice increases phosphorylation of PKCepsilon in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKCepsilon are dependent not only on mGluR5 stimulation but also on phosphatidylinositol-3 kinase (PI3K). In addition, the selective mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) reduced basal levels of phosphorylation of PKCepsilon at S729. We also show that MPEP dose dependently reduced ethanol consumption in wild-type but not in PKCepsilon-null mice, suggesting that PKCepsilon is an important signaling target for modulation of ethanol consumption by mGluR5 antagonists. Radioligand binding experiments using [(3)H]MPEP revealed that these genotypic differences in response to MPEP were not a result of altered mGluR5 levels or binding in PKCepsilon-null mice. Our data indicate that mGluR5 is coupled to PKCepsilon via a PI3K-dependent pathway and that PKCepsilon is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.

Alcohol Drinking↗
PubMed2004

RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction.

Alcoholism is a devastating disease that manifests as uncontrolled drinking. Consumption of alcohol is regulated by neurochemical systems within specific neural circuits, but endogenous systems that may counteract and thus suppress the behavioral effects of ethanol intake are unknown. Here we demonstrate that BDNF plays a role in reducing the behavioral effects of ethanol, including consumption, in rodents. We found that decreasing the levels of BDNF leads to increased behavioral responses to ethanol, whereas increases in the levels of BDNF, mediated by the scaffolding protein RACK1, attenuate these behaviors. Interestingly, we found that acute exposure of neurons to ethanol leads to increased levels of BDNF mRNA via RACK1. Importantly, acute systemic administration of ethanol and voluntary ethanol consumption lead to increased levels of BDNF expression in the dorsal striatum. Taken together, these findings suggest that RACK1 and BDNF are part of a regulatory pathway that opposes adaptations that lead to the development of alcohol addiction.

Alcohol Drinking↗
PubMed2004

Dynamics of neural coding in the accumbens during extinction and reinstatement of rewarded behavior.

Neural correlates of reward-seeking behavior are observed in the nucleus accumbens (NAC). The dependence of these correlates upon the presence of a reward was studied by comparing the behavioral correlates observed when the presence of the reward was manipulated within a single behavioral session. Rats were well-trained on a continuous reinforcement instrumental task reinforced by 0.1 ml drops of 5% sucrose. Extracellular single-unit neural activity was recorded from electrode arrays implanted into the NAC when instrumental behavior was and then was not reinforced with sucrose (within-session extinction). A variable delay between the instrumental response and the sucrose delivery allowed for separation of neural activity related to these task events. A spike activity increase around the time of the instrumental response was the most common behavioral correlate, while a decrease in spike activity upon sucrose delivery was the second most common behavioral correlate. Following removal of the reinforcer, subjects continued to perform the instrumental response, allowing for the examination of response-related spike activity under extinction conditions in which the response was no longer reinforced by sucrose. A majority of the response-related neural activity patterns were lost when sucrose was no longer available. New neural responses also were detected during this period. For some subjects, the reinforcer was again made available during the same session. Encoding of the primary behavioral events during this period of reinstated reinforcer was similar, but not identical, to that observed during the first period of reinforced responding. These findings reveal that instrumental task-associated spike activity within the NAC is partially dependent upon the presence of the reinforcer, and that encoding across the population is distinct under reinforced and extinction conditions.

Animals↗
PubMed2004

Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice.

RATIONALE: Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909. METHODS: Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), D-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined. RESULTS: MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, D-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg. CONCLUSIONS: Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, D-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.

Amphetamine↗
PubMed2004

Ethanol operant self-administration in rats is regulated by adenosine A2 receptors.

BACKGROUND: Recent findings suggest that adenosine is involved in the neural and behavioral effects of ethanol (EtOH). Studies in neural cell culture show that EtOH, via activation of adenosine A2 receptors, triggers cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling and CRE (cAMP regulatory element)-mediated gene expression and that this effect is blocked by inhibiting G-protein betagamma subunits. Recently, we reported that expression of a betagamma inhibitor in the nucleus accumbens (NAc) reduces EtOH drinking in rats. The NAc expresses high levels of the adenosine A2A receptor in GABAergic medium spiny neurons. If the reinforcing effects of EtOH are mediated through an A2 activation of cAMP/PKA signaling via betagamma, then A2 receptor blockade should attenuate EtOH consumption. Here we tested this hypothesis. Because adenosine A2 and dopamine D2 receptors are coexpressed in neurons of the NAc, we compared the effects of A2 blockade with those of D2 receptor blockade. METHODS: Male Long-Evans rats were trained to self-administer 10% EtOH in daily 30-min sessions with an active and an inactive lever. Separate groups of rats were given the D2 antagonist eticlopride (0.005, 0.007, and 0.01 mg/kg), the A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX; 1, 3, 5, 7, 10, and 20 mg/kg), and the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.125, 0.25, and 0.5 mg/kg) by systemic injection. RESULTS: Eticlopride dose-dependently reduced EtOH drinking. DMPX showed a bimodal effect: 10 and 20 mg/kg decreased, but 1 mg/kg increased, EtOH consumption. DPCPX was without effect. CONCLUSIONS: In support of our hypothesis, the A2 antagonist DMPX attenuated EtOH self-administration. Low doses of the A2 antagonist enhanced EtOH drinking, consistent with the possibility that rats increase EtOH self-administration to overcome partial A2 blockade. The D2 antagonist eticlopride also decreased EtOH self-administration. These data provide the first evidence that pharmacological modulation of adenosine A2 receptors can regulate EtOH consumption in rats.

Adenosine A2 Receptor Antagonists↗
PubMed2003

Comparison of reinstatement of ethanol- and sucrose-seeking by conditioned stimuli and priming injections of allopregnanolone after extinction in rats.

RATIONALE AND OBJECTIVES: Understanding the mechanism of relapse provoked by conditioned and unconditioned stimuli is critical to improving treatments for alcoholism. This study compared the reinstatement of alcohol- or sucrose-seeking by conditioned stimuli and priming injections of the neuroactive steroid, allopregnanolone (ALLO). METHODS: Rats were trained to lever-press for 0.1 ml of 10% ethanol or 5% sucrose solutions. Responding was then extinguished, and subjects were tested for reinstatement of lever-press responding. The effects of priming injections of 0, 1.0, 3.0 and 7.5 mg/kg ALLO were determined in subjects trained to self-administer ethanol, and the response-reinstating effects of priming injections of 3.0 mg/kg ALLO were compared with those of conditioned cue presentation in subjects trained to self-administer either ethanol or sucrose. RESULTS: Priming injections of ALLO dose-dependently reinstated previously extinguished responding for ethanol, as shown by increased responding on the active (ethanol) lever. Contingent presentation of cues previously associated with the reinforcer increased the number of active lever-presses for both ethanol- and sucrose- trained subjects. In contrast, pretreatment with 3.0 mg/kg ALLO increased the number of active lever-presses for subjects that were trained to self-administer ethanol, but not sucrose. CONCLUSIONS: ALLO promotes responding for ethanol, but not sucrose, following a period of abstinence, suggesting that GABA(A) receptor modulation may contribute to processes involved in reinstatement of ethanol-seeking behavior. In contrast, conditioned stimuli reinstate previously extinguished ethanol- and sucrose-seeking behavior, indicating that the mechanisms that subserve cue-induced reinstatement do not depend upon the nature of the positive reinforcer.

Animals↗
PubMed2003

Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose.

Behavioral effects of ethanol are mediated by actions at multiple neurotransmitter receptors and signaling systems; prominent among these is the type A gamma-aminobutyric acid (GABA(A)) receptor. Previous work has shown that the GABAergic neuroactive steroid allopregnanolone enhances ethanol-reinforced instrumental responding in rat. In the current study, we compared the effects of allopregnanolone with the direct GABA(A) agonist muscimol and the direct type B GABA (GABA(B)) agonist baclofen in male Long-Evans rats lever pressing for a 10% ethanol solution in a limited-access procedure. The effects of concurrently available sucrose were also tested to determine the selectivity of these drugs for altering ethanol self-administration when an alternate reinforcer was available. In Experiment 1, we found that presession systemic administration of both muscimol (0.3 and 1 mg/kg) and baclofen (1 and 3 mg/kg) reduced responding for ethanol. In contrast, allopregnanolone (3 and 5.6 mg/kg) enhanced responding for ethanol. In Experiment 2, we found that a 1-mg/kg dose of baclofen reduced responding for ethanol, but not for sucrose, whereas both baclofen and muscimol, administered at a higher dose of 3 mg/kg, decreased both ethanol- and sucrose-reinforced responding. Allopregnanolone, at a dose of 5.6 mg/kg, but not of 3 mg/kg, selectively increased ethanol-reinforced responding, indicating a less robust effect of allopregnanolone on responding within the concurrent reinforcement procedure than that observed when ethanol alone was available. The results support the suggestion that direct agonist action at either the GABA(A) or the GABA(B) receptor decreases ethanol self-administration. Muscimol produces a nonselective decrease in instrumental responding, whereas baclofen may selectively reduce ethanol intake at lower doses, but not higher ones, possibly limiting its potential use for treatment of alcohol abuse in human beings. In contrast, allopregnanolone can selectively enhance ethanol self-administration in the presence of a concurrently available alternate reinforcer, indicating that the direct GABA(A) agonist muscimol and the allosteric GABA(A) modulator allopregnanolone do not produce similar behavioral effects on instrumental responding for ethanol reinforcement.

Alcohol Drinking↗
PubMed2003

Fyn kinase and NR2B-containing NMDA receptors regulate acute ethanol sensitivity but not ethanol intake or conditioned reward.

BACKGROUND: The tyrosine kinase Fyn previously has been shown to play a key role in mediating acute tolerance to ethanol. Recently, we found that the compartmentalization of Fyn to the NR2B subunit of the NMDA receptor (NMDAR) in the hippocampus regulates Fyn phosphorylation of NR2B in response to ethanol, which mediates the acute tolerance of NMDAR to ethanol inhibition in hippocampal slices. In this study we determined, first, whether acute tolerance to ethanol inhibition is mediated via NR2B-containing NMDARs in vivo and, second, whether the increase in acute sensitivity to ethanol in the Fyn-/- mice influences ethanol consumption or ethanol's conditioned rewarding effects. METHODS: A loss of righting reflex test was used to study the acute/sedative effects of ethanol after intraperitoneal injections of sedative doses of ethanol. Conditioned place preference was used to study the rewarding properties of ethanol. The two-bottle choice protocol was used to measure oral ethanol self-administration and preference as described previously. RESULTS: We found that systemic injection of the NR2B-containing NMDAR selective antagonist, ifenprodil, abolished the differences between Fyn+/+ and Fyn-/- mice in sensitivity to the acute sedative effects of ethanol. Moreover, we found that Fyn-/- and Fyn+/+ mice did not differ in their voluntary ethanol consumption or in the rewarding properties of ethanol. CONCLUSIONS: Our results suggest that the interaction between Fyn and NR2B mediates the acute sedative effects of ethanol, and that alteration in acute ethanol sensitivity does not necessarily correlate with levels of ethanol consumption or the rewarding properties of ethanol.

Alcohol Drinking↗