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Abstract: Lesch-Nyhan disease is a neurogenetic disorder caused bydeficiency of the purine salvage enzyme hypoxanthine-guaninephosphoribosyltransferase (HPRT). Affected individuals exhibit acharacteristic pattern of neurological and behavioral features attributable inpart to dysfunction of basal ganglia dopamine systems. In the current studies,striatal dopamine loss was investigated in five different HPRT-deficientstrains of mice carrying one of two different HPRT gene mutations.Caudoputamen dopamine concentrations were significantly reduced in all five ofthe strains, with deficits ranging from 50.7 to 61.1%. Mesolimbic dopamine wassignificantly reduced in only three of the five strains, with a range of31.6-38.6%. The reduction of caudoputamen dopamine was age dependent, emergingbetween 4 and 12 weeks of age. Tyrosine hydroxylase and aromatic amino aciddecarboxylase, two enzymes responsible for the synthesis of dopamine, werereduced by 22.4-37.3 and 22.2-43.1%, respectively. These results demonstratethat HPRT deficiency is strongly associated with a loss of basal gangliadopamine. The magnitude of dopamine loss measurable is dependent on thegenetic background of the mouse strain used, the basal ganglia sub-regionexamined, and the age of the animals at assessment. [ABSTRACT FROM AUTHOR]

The effects of four putative ethanol antagonists [thyrotropin releasing hormone (TRH), naloxone, d-amphetamine, and fenmetozole] on two distinct behavioral actions of ethanol were compared. TRH (20-40 mg/kg) reduced ethanol-induced impairment of the aerial righting reflex (ARR) but enhanced the ethanol-induced increase in punished drinking (anticonflict effect). Naloxone antagonized both actions of ethanol but only at high doses (20-60 mg/kg). Amphetamine (1-4 mg/kg) abolished the ethanol effect on punished drinking but did not alter its impairment of the ARR (1 -8 mg/kg). Conversely, fenmetozole antagonized the ethanol impairment of the ARR (15-30 mg/kg) but not ethanol's anticonflict action. The inconsistent pattern of 'antagonist' interactions of these drugs with the behavioral actions of ethanol suggests that ethanol alters several neurochemical systems to produce its behavioral effects. [ABSTRACT FROM AUTHOR]

Rationale: Mutant mice lacking the RIIbeta subunit of protein kinase A (regulatory subunit II beta(-/-)) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIbeta(-/-) and littermate wild-type (RIIbeta(+/+)) mice on multiple genetic backgrounds., Methods: Over three consecutive days, mice were given single i.p. saline injections and immediately placed in a locomotor activity apparatus to establish a composite baseline for locomotor activity. Next, mice maintained on a hybrid 129/SvEvxC57BL/6J or pure C57BL/6J genetic background were given 10 i.p. ethanol injections before being placed in the activity apparatus. Each ethanol injection was separated by 3-4 days. To determine if changes in behavior were specific to ethanol injection, naïve mice were tested following repeated daily saline injections. The effects of ethanol injection on locomotor behavior were also assessed using an alternate paradigm in which mice were given repeated ethanol injections in their home cage environment., Results: Relative to RIIbeta(+/+) mice, RIIbeta(-/-) mice, regardless of genetic background, consistently showed significantly greater ethanol-induced locomotor activation. RIIbeta(-/-) mice also showed increased sensitivity to ethanol-induced locomotor sensitization resulting from repeated administration, an effect that was dependent on genetic background and testing paradigm. Increased locomotor activity by RIIbeta(-/-) mice was specific to ethanol injections, and was not related to altered blood ethanol levels., Conclusions: These data provide novel evidence implicating an influence of protein kinase A signaling on ethanol-induced locomotor activity and behavioral sensitization. The observation that RIIbeta(-/-) mice are more sensitive to the effects of repeated ethanol administration suggests that normal protein kinase A signaling limits, or is protective against, the stimulant effects of ethanol and the plastic alterations that underlie behavioral sensitization.

Ethanol and the volatile anesthetics share many features including effects on both GABA and NMDA receptors. To determine the degree of similarity between these compounds, we examined the concentration-response curves for ethanol and isoflurane on currents gated by GABA or NMDA. The effects of isoflurane and ethanol on the righting reflex of rats were also observed. The concentration of ethanol causing loss of the righting reflex of rats was 82.3+/-2.9 mM, whereas median concentration of isoflurane exerting that effect was 0.125 mM. Both isoflurane and ethanol inhibited NMDA-gated currents in cultured cerebral cortical neurons at concentrations well below those associated with loss of the righting reflex or anesthesia. However, the effect of isoflurane was greater than that of ethanol and the slope of the concentration-response curve for isoflurane less steep than that for ethanol. Isoflurane enhanced GABA-gated currents at anesthetic concentrations but there was a sharp concentration-response curve with only minimal effects of isoflurane on GABA-gated currents at concentrations associated with loss of the righting reflex. In contrast, ethanol had no effect on GABA-gated currents even at lethal concentrations, i.e. 300 mM or 1.2%. Comparison of the concentration-response curves for the effects of isoflurane on NMDA- and GABA-gated currents has revealed both EC50 and Hill slope for the potentiation of GABA-gated currents were significantly greater than those for inhibition of NMDA-gated currents. These results support the hypothesis that isoflurane has actions on both the GABA and NMDA systems that are not shared by ethanol.

Background: Inhibition of NMDA receptor function in brain is believed to be an important action of ethanol (EtOH). To investigate EtOH inhibition of NMDA receptor responses in vivo, the interaction of these agents in brain after different routes of administration were investigated by using transcription factor Fos protein expression to follow NMDA receptor activation and EtOH inhibition of this response., Methods: The induction of Fos-like immunoreactivity (Fos-LI) in 38 regions of the rat brain was measured 2 hr after treatment with NMDA, EtOH, or both. To determine the relative contribution of abdominal drug effects on Fos induction, rats received either intraperitoneal (ip) or intragastric (ig) EtOH and ip or intravenous (iv) NMDA. Rats received EtOH (2.5 g/kg ip or 4 g/kg ig) or vehicle 15 min before NMDA (125 mg/kg ip or 60 mg/kg iv) or vehicle., Results: For the 38 forebrain regions examined, ip and iv NMDA significantly induced Fos-LI in 13 and 32 regions, respectively. These effects occurred without elicitation of tonic-clonic seizure activity and were strong after iv NMDA in the frontal, prefrontal, and cingulate cortices, supraoptic nucleus, anterior lateral septum, and dentate gyrus. For EtOH, prominent Fos-LI induction was found in the central amygdala, dorsolateral bed nucleus of the stria terminalis, Edinger-Westphal nucleus, and paraventricular hypothalamus. Despite ip and ig EtOH induction of Fos-LI in these regions, the major effect of EtOH was to block NMDA-induced Fos-LI in 8 of 13 (ip) and 27 of 32 (ig) of the NMDA-positive regions, respectively, including retrosplenial, cingulate, and medial prefrontal cortices, central amygdala, and taenia tecta., Conclusions: These results provide new evidence for the regionally specific functional interactions of EtOH on NMDA receptors in vivo. Moreover, these results support efforts to identify brain region-specific targets for EtOH and EtOH-induced changes in gene expression.

Previous work has suggested that the therapeutic efficacy of olanzapine might be partially dependent on action at the D(1)-dopamine (DA) receptor site. Because early DA loss can lead to supersensitive D(1)-DA receptors, effects of olanzapine were investigated in adult rats given lesions to DA-containing neurons as neonates. In these animals, locomotor effects of SKF-38393 (a D(1)-DA agonist) were attenuated by olanzapine, but at doses (5 and 10 mg/kg) that decreased activity when given alone. Olanzapine prevented induction of striatal Fos protein by SKF-38393 and partially attenuated the long-term "priming" effect of repeated SKF-38393 treatment. Olanzapine also antagonized the stimulant effects of quinpirole (a D(2)-type DA agonist) in animals lesioned as young adults, at doses lower than those necessary to antagonize SKF-38393-induced activity. In addition, olanzapine antagonized apomorphine-induced self-injurious behavior in neonate-lesioned rats in a dose-related fashion. Attenuation of self-injury in this animal model suggests that olanzapine should be tested against this symptom in patient populations.

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Rat lines that were selectively bred for high (high DPAT-sensitive, HDS) or low (low DPAT-sensitive, LDS) hypothermic responses to the specific 5-HT(1A) receptor agonist, 8-hydroxy-di-n-propylaminotetralin (8-OH-DPAT), differ in receptor binding and certain behaviors related to anxiety and depression. After reviewing this literature, the present communication summarizes new experiments designed to clarify and extend the nature of the pharmacological and biochemical differences between the lines. A challenge with the 5-HT(2) receptor agonist, DOI, produced similar degrees of head shakes and skin crawls in the HDS and LDS rats, suggesting similar sensitivity of 5-HT(2A) and 5-HT(2C) receptors. In contrast, DOI-induced flat body posture (FBP), which has been linked to 5-HT(1A) receptor stimulation, was observed more readily in the HDS rats. The HDS and LDS rats exhibited similar degrees of increase in 8-OH-DPAT-stimulated [35S]GTPgammaS binding in several brain regions. This result suggests that the dramatic differences in hypothermia in HDS and LDS rats cannot be related to 5-HT(1A) receptor-mediated action on G proteins. Overall, these findings indicate that the selective breeding for 5-HT(1A)-mediated hypothermia has been fairly selective, and that differences in emotionally relevant behaviors between these two rat lines can strongly be associated with an unidentified component of the 5-HT(1A) receptor signaling pathway.

Rationale: Administration of flumazenil, a benzodiazepine (BZD) antagonist, has therapeutic efficacy against some anxiogenic effects of ethanol withdrawal. This observation has led to the suggestion that anxiety associated with ethanol withdrawal is related to release in brain of an endogenous BZD inverse agonist., Objective: The present studies further tested this hypothesis by assessing the effect of flumazenil on withdrawal-induced changes in a behavioral task and on the expression of the neuronal protein, Fos., Methods: Male Sprague-Dawley rats were withdrawn from a chronic ethanol regimen and tested, with or without flumazenil pretreatment, for either ultrasonic vocalization in response to air puff or for the induction of Fos protein-like immunoreactivity (Fos-LI) in brain. In addition, flumazenil effects on Fos-LI were measured in a group of animals treated with the BZD inverse agonist DMCM (0.75 and 1.0 mg/kg)., Results: Flumazenil (5.0 mg/kg) significantly reduced the number of ultrasonic vocalizations observed following withdrawal from chronic ethanol. In contrast, flumazenil (5.0 mg/kg), given either 14 h before withdrawal from chronic ethanol, or during hours 3 and 5 following withdrawal, did not attenuate the effects of withdrawal on Fos-LI. Subsequent testing with DMCM confirmed that a benzodiazepine inverse agonist can induce Fos-LI in most of the same brain regions as observed following ethanol withdrawal, and that this change in Fos protein can be attenuated by pretreatment with flumazenil (5.0 mg/kg)., Conclusions: Overall, these results demonstrate that specific behavioral indices of anxiety, but not measures of Fos-LI, support the contribution of an endogenous BZD inverse agonist in the ethanol withdrawal syndrome.

Background: Electrophysiological recording reveals that only a portion of cerebellar Purkinje neurons are sensitive to ethanol enhancement of gamma-aminobutyric acid (GABA) responses. Although activation of beta-adrenergic receptors permits ethanol enhancement of GABA function from some cerebellar Purkinje neurons, other neurons remain insensitive to ethanol. These findings are consistent with the finding that other external neural inputs are required to allow ethanol enhancement of GABA responses from Purkinje neurons. Because of a high expression of GABA(B) receptors on Purkinje cells, we tested whether activation of GABA(B) receptors might modulate the action of ethanol on GABA responsiveness., Methods: Extracellular single-unit electrophysiological recording was used to investigate the effects of ethanol on responses to GABA and muscimol (a GABA(A) agonist) from cerebellar Purkinje neurons. Drugs tested were baclophen (a GABA(B) agonist) and CGP35348 (a GABA(B) antagonist)., Results: Ethanol did not enhance responses to GABA and muscimol from all Purkinje neurons. Systemic administration of the GABA(B) agonist, baclophen (3 mg/kg intravenously), permitted ethanol to enhance GABA inhibition from approximately 75% of cerebellar Purkinje neurons not initially enhanced by ethanol. Local iontophoretic application of baclophen to Purkinje neurons also allowed ethanol to enhance GABA and muscimol responsiveness from a portion of neurons in which ethanol initially did not affect their actions. An inhibitory action of ethanol on responses to GABA and muscimol, which was also influenced by baclophen, was observed from some Purkinje neurons. From Purkinje neurons initially sensitive to ethanol enhancement of GABA and muscimol function, administration of CGP35348, a GABA(B) antagonist, diminished the effect of ethanol on the responsiveness of these agonists from the majority (9/15) of neurons., Conclusions: The present findings demonstrated that baclophen allows ethanol enhancement of GABA and muscimol responsiveness from some, but not all, cerebellar Purkinje neurons initially not sensitive to ethanol. Likewise, a GABA(B) antagonist can diminish ethanol enhancement of GABA and muscimol responses from some ethanol-sensitive neurons. Thus, these results emphasize that GABA(B) receptors on a portion of Purkinje neurons act as an auxiliary neural input that allows ethanol enhancement of GABA responses. Consequently, receptor structure alone does not account for the action of ethanol on GABA(A) receptor function on this cell type.

Although previous in vivo electrophysiological studies demonstrated a consistent ethanol enhancement of gamma-aminobutyric acid (GABA) responsiveness from substantia nigra reticulata (SNR) neurons, ethanol applied in vitro to dissociated neurons from the SNR had an inconsistent effect on GABA function. One source for the disparity between these contrasting in vivo and in vitro results could be an endogenous factor (acting on an auxiliary site on GABA(A) receptors) that was not available to the isolated SNR neurons. Because neurosteroids are present in vivo and act on an auxiliary site, it was hypothesized that the presence of a neurosteroid was important for a consistent effect of ethanol on GABA responsiveness from neurons studied in vitro. Alone, the neurosteroid analog alphaxalone produced a significant, concentration-related enhancement of GABA responsiveness from isolated SNR neurons. In contrast to an inconsistent action of 100 mM ethanol on GABA responsiveness in the absence of alphaxalone, the presence of 30 and 100 nM alphaxalone resulted in the majority of isolated neurons responding to this ethanol level. At a concentration of alphaxalone as low as 30 nM, ethanol produced a robust concentration-related increase in GABA-gated currents from this cell type. The neurosteroid 3alpha, 5alpha-tetrahydrodeoxycorticosterone (100 nM) also permitted a reliable concentration-dependent ethanol enhancement of responses to GABA from SNR cells, indicative that the effects of alphaxalone were not unique. This consistent neurosteroid-induced ethanol enhancement of GABA responsiveness from dissociated SNR neurons supports the view that neurosteroids may play a key role in the action of ethanol on postsynaptic GABA(A) receptor function.