Ethanol inhibits spontaneous activity of central nucleus of the amygdala neurons but does not impair retention in the passive-avoidance task.

BACKGROUND: Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation-a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single-unit activity of CeA neurons and retention in the passive-avoidance task. METHODS: The effect of ethanol (0.35, 0.75, 1.5, 2.5 g/kg) was determined on spontaneously firing neurons in the CeA in urethane-anesthetized rats by use of standard in vivo single-unit electrophysiological recording techniques. Additionally, the effect of ethanol when administered immediately after training in a standard passive-avoidance task was determined on retention the following day. RESULTS: Ethanol profoundly inhibited spontaneous CeA firing rates in urethane-anesthetized rats at all doses tested. Maximal inhibition was related to dose. Each dose of ethanol significantly inhibited CeA activity within 15 min of administration; within 35 min of administration, 0.75 g/kg of ethanol inhibited CeA activity by 65.2%, and the highest dose (2.5 g/kg) produced nearly complete suppression of CeA activity (81.3%). Although ethanol markedly inhibited CeA activity, these same doses of ethanol failed to impair retention in the passive-avoidance task: 0.35, 0.75, 1.5, and 2.5 g/kg of ethanol, administered immediately after training, failed to alter latency to step-through the following day. CONCLUSIONS: These results show that ethanol profoundly inhibits spontaneous CeA activity and suggest that inhibition of the CeA is not sufficient to impair retention in the passive-avoidance task.

Dose-sensitive excitation and inhibition of spontaneous amygdala activity by propranolol.

The effect of systemically administered propranolol was determined on spontaneous activity of neurons in the central nucleus (CeA) of the amygdala, a brain site implicated in fear-related learning and memory. Extracellular recordings of single units in the CeA were obtained in vivo from rats administered saline or the centrally and peripherally acting beta-adrenergic receptor blocker propranolol (4, 7, 10 mg/kg i.p.). The high dose (10 mg/kg) of propranolol markedly increased spontaneous activity of CeA neurons. In contrast, the low (4 mg/kg) and intermediate (7 mg/kg) doses of propranolol significantly decreased spontaneous CeA activity, with the suppressant effect of propranolol on CeA firing rates weakening as the dosage increased from 4 to 7 mg/kg. These results suggest that (1) spontaneous activity of CeA neurons is tonically influenced by competing excitatory and inhibitory modulatory circuits, and (2) propranolol's effect on the two modulatory circuits is dose dependent: the high dose increasing spontaneous CeA activity by preferentially blocking an inhibitory circuit, the low dose decreasing spontaneous CeA activity by preferentially blocking an excitatory circuit, and the intermediate dose weakly suppressing CeA activity by blocking both the excitatory and inhibitory modulatory circuits. Disinhibition of CeA activity by the high dose of propranolol may explain the enhancement of retention observed in the passive-avoidance task when this dose of the drug is administered systemically, and may have implications for the use of propranolol clinically in treating aversive-memory-related anxiety disorders such as posttraumatic stress syndrome.

Blockade of alpha2-adrenergic receptors markedly potentiates glutamate-evoked activity of locus coeruleus neurons.

The locus coeruleus (LC) is a small pontine nucleus with widely distributed efferents that supply the majority of norepinephrine in brain. Evidence from our laboratory has implicated alpha2-adrenergic receptors on LC neurons in regulating the magnitude of the bursting response of LC neurons to both sensory stimulation and systemically administered drugs. Sub-stimulation of alpha2-adrenergic receptors in the LC and the resulting hyper-responsiveness of LC neurons is thought to at least partially mediate depression in an animal model. The present study extends previous work in our laboratory by demonstrating that blockade of alpha2-adrenergic receptors also markedly augments the bursting response of LC neurons to locally-via microiontophoresis-applied glutamate.

Beta-adrenergic receptor blockade by propranolol enhances retention in a multitrial passive-avoidance procedure.

The effect of beta-adrenergic receptor blockade on retention in a mildly aversive passive-avoidance procedure was investigated. Rats were given passive-avoidance training--1 trial per day for 4 days-and were administered saline, the centrally and peripherally acting beta-adrenergic blocker propranolol (4 or 10 mg/kg ip), or the peripherally acting beta-adrenergic blocker sotalol (4 or 10 mg/kg ip) immediately or 2 hr after the 1st trial. Enhanced retention occurred only with the higher dose (10 mg/kg) of propranolol and only when it was administered immediately after training. The enhanced retention produced by propranolol is discussed in terms of opposing, regionally specific actions of beta-adrenergic receptor-mediated neural circuits on modulation of memory.

Prenatal exposure to ethanol disrupts spatial memory: effect of the training-testing delay period.

The present study investigated how variations in the period of delay between training and testing in the Morris water maze task affect the use of spatial memory in adult rats that were prenatally exposed to ethanol. Previous results utilizing the Morris water maze task have shown that prenatal, or early postnatal, exposure to ethanol produces deficits in the use of spatial memory, a type of memory that is dependent on an intact hippocampus. However, in these prior studies the delay period between the training of animals and the testing of spatial memory is typically fixed at only 1 day. In the current study, which utilized a revised training procedure within the Morris water maze task, the period of delay between training and testing was altered such that it was either 1 day or 3 days. Following the 3-day delay, different levels of prenatal exposure to ethanol impaired the use of spatial memory. In contrast, following the 1-day delay, prenatal exposure to ethanol failed to impair the use of spatial memory. The present study thus shows that prenatal exposure to ethanol differentially affects spatial memory in the Morris water maze task depending on the period of delay between training and testing.

Comparison between the effects of ethanol and diazepam on spatial working memory in the rat.

The present study compared the effects of ethanol and diazepam on a task that allows for the assessment of both spatial working memory and the acquisition of spatial information within each day. During the first trial of each day, subjects were shown the spatial location of a food reward on a six-arm radial-arm maze. During nine subsequent free-choice trials, subjects were reinforced for returning to that same spatial location. The location of the food reward varied across days. Thus, choosing correctly on any given trial required subjects to remember where food had been received during the previous trials of that day. The effects of ethanol and diazepam on working memory were assessed by analyzing the overall number of errors committed during the nine free-choice trials of each day. The effects of ethanol and diazepam on within-day acquisition were assessed by comparing the number of errors committed during the first three trials of each day to the number of errors committed during the last three trials of each day. Ethanol and diazepam both produced dose-dependent increases in working memory errors, and both did so without impairing within-day acquisition. The results of the present study provide further evidence of the similarities between the effects of ethanol and benzodiazepine receptor agonists on learning and memory, and are consistent with the hypothesis that ethanol's potentiation of GABA at GABAA receptors contributes to the learning and memory impairments produced by ethanol.

Evidence for a selective effect of ethanol on N-methyl-d-aspartate responses: ethanol affects a subtype of the ifenprodil-sensitive N-methyl-d-aspartate receptors.

An extracellular electrophysiological approach was used to determine the effect of ethanol on responses to N-methyl-D-aspartate (NMDA) across several brain regions in urethane-anesthetized rats. The results indicated that, in most brain regions, ethanol inhibited the NMDA-induced increases in firing rate for some, but not all, spontaneously active neurons. Ethanol functioned as an NMDA antagonist for some neurons in the medial septum, red nucleus, deep mesencephalic nucleus, substantia nigra reticulata, ventral tegmental area and cerebellum. In the hippocampus, ethanol inhibited NMDA responses from all neurons. However, ethanol was not found to be active against NMDA responses in the lateral septum, suggesting that there is a degree of regional specificity for ethanol inhibition of NMDA responses. It was then established in unanesthetized rats that ethanol also antagonized responses to NMDA in some, but not all, neurons in the medial septum and cortex, indicating that the differential action of ethanol on NMDA responses obtained in the urethane-anesthetized rats was not due to the anesthetic. Based on an earlier study showing that the effects of ifenprodil and ethanol on NMDA responses were correlated, the ability of ethanol to inhibit NMDA responses was compared with changes produced by ifenprodil on the same neurons, where ethanol did or did not affect NMDA responses. In the several brain regions investigated, ethanol inhibited NMDA responses in a subgroup of neurons in which ifenprodil inhibited NMDA-induced increases in firing. For all neurons investigated, if a cell was insensitive to ifenprodil antagonism of NMDA responses then ethanol also was ineffective against the response to NMDA. These results suggest that ethanol acts on an ifenprodil-sensitive NMDA receptor subtype. Given that previous investigations have suggested that the NMDA receptor type 2B subunit is essential for the action of ifenprodil, the positive relationship between the actions of ifenprodil and ethanol on responses to NMDA is consistent with the hypothesis that the combination of specific receptor subunits forming an NMDA receptor on a neuron determines the ability of ethanol to antagonize an NMDA response.

Ethanol alters spatial processing of hippocampal place cells: a mechanism for impaired navigation when intoxicated.

This study describes a new mechanism by which ethanol alters brain function and may impair performance on tasks requiring spatial navigation. Recording electrophysiological activity from single neurons in the awake, freely behaving animal, the present study shows that ethanol impairs the ability of place cells in the hippocampus to process spatial information. The impairment by ethanol in spatial processing of place cells was remarkably similar to the impairment produced by lesions of afferents to the hippocampus, except that the effect of ethanol was reversible. Since lesions to hippocampal afferents that alter spatial processing of place cells concomitantly impair spatial navigation, the present results suggest that ethanol similarly impairs spatial navigation by altering spatial processing of place cells. The present results have implications for the observation that ethanol impairs performance on navigational tasks that require spatial processing, such as automobile driving.

Acute ethanol impairs spatial memory but not stimulus/response memory in the rat.

The present studies investigate how acutely administered ethanol (ETOH) affects the use of spatial memory. Previous electrophysiological results have shown that acutely administered ETOH alters the firing of hippocampal neurons and that prenatal or chronic exposure to ETOH produces deficits on spatial learning tasks, tasks dependent on the hippocampus. In contrast, it has also been demonstrated that acutely administered ETOH does not impair spatial localization. In the current studies, rats were trained to perform a spatial or stimulus/response task under saline. After training, rats were injected with ETOH, and the use of spatial or stimulus/response memory was tested. Acutely administered ETOH impaired the use of spatial memory, but not the use of stimulus/response memory. Because the use of spatial memory requires an intact hippocampus, the present studies suggest that acutely administered ETOH selectively impairs behaviors dependent on the hippocampus.

Effect of zolpidem on gamma-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions.

Previous investigations have suggested a relationship between zolpidem binding within specific brain regions and the ability of ethanol or zolpidem to enhance gamma-aminobutyric acid (GABA)-induced inhibition. The purpose of the present study was to extend our electrophysiological analysis to additional brain sites with high levels of zolpidem binding. In the brain regions chosen, red nucleus and globus pallidus, GABA-induced inhibition was shown to be enhanced by either ethanol or zolpidem on some, but not all, neurons. These findings led to the hypothesis that the effect of zolpidem on GABA-induced inhibition would predict the action of ethanol on responses to GABA for that neuron. When zolpidem and ethanol were applied individually to the same neurons in the red nucleus and globus pallidus, those neurons sensitive to zolpidem enhancement of GABA also were sensitive to ethanol. Conversely, if zolpidem did not enhance responses to GABA, ethanol did not enhance responses to GABA at these brain sites. A similar relationship between the abilities of zolpidem and ethanol to enhance GABA-induced inhibition was obtained in 90% of the neurons studied in the medial septum/diagonal band and ventral pallidum. These studies provide further support for the contention that the zolpidem-sensitive GABAA-benzodiazepine isoreceptor also responds to ethanol. Finally, the expression of GABAA subunit mRNAs was analyzed by polymerase chain reaction from micropunches of several brain regions that contain zolpidem binding sites and exhibit sensitivity to ethanol. Polymerase chain reaction analysis proved more sensitive than in situ hybridization in the detection of receptor subunit mRNAs. Several subunits (alpha 1, alpha 2, alpha 3, beta 2, beta 3 and gamma 2) were common to all brain regions in which ethanol and zolpidem enhanced GABA responses. GABAA receptor alpha 4/5, alpha 6, beta 1, gamma 1, gamma 3 and delta subunits were not consistently expressed in association with the presence of zolpidem binding. These data are consistent with the view that one native GABAA receptor to which zolpidem binds, and on which ethanol acts, contains the GABAA receptor subunits alpha 1, beta 2 and gamma 2; however, the present investigation did not preclude the possibility that other subunit combinations can contribute to ethanol and zolpidem enhancement of responses to GABA.

Effects of ethanol, MK-801, and chlordiazepoxide on locomotor activity in different rat lines: dissociation of locomotor stimulation from ethanol preference.

Several lines of research have suggested a link between the reward value of a drug and its ability to stimulate locomotion. One goal of the present study was to determine whether ethanol preferentially stimulates locomotor activity in lines of rat that show a preference for ethanol. A secondary goal was to determine the extent to which the benzodiazepine-like and NMDA antagonistic action of ethanol accounted for its effect on locomotor activity. To meet these goals, the effects of varying doses of ethanol (0.125-1.0 g/kg), MK-801 (0.1-0.3 mg/kg), and chlordiazepoxide (0.3-3 mg/kg) on locomotor activity were studied in several lines of rats that had been habituated to the testing procedure. The effect of low doses of ethanol on motor activity in the Alcohol-Preferring (P) and Fawn-Hooded rats, which show a strong ethanol preference, were similar to those of the alcohol-nonpreferring (NP), Flinders Sensitive Line, and Flinders Resistant Line rats. Only the Flinder Resistant Line rats showed a small, but significant increase in locomotor activity after the administration of ethanol. The highest dose of ethanol (1.0 g/kg) produced locomotor depression in all lines except the P and NP lines, which were not tested at this dose. These findings do not support a link between locomotor stimulation by ethanol and ethanol preference. In contrast, all lines exhibited locomotor stimulation after moderate (0.1-0.3 mg/kg) doses of MK-801, but did not exhibit increases in activity following any dose of chlordiazepoxide. These data indicate that the profiles of activity after MK-801 and chlordiazepoxide were distinct from that of ethanol in the various rat lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal destruction of dopaminergic neurons.

Rats treated as neonates with 6-hydroxydopamine are proposed to model the dopamine deficiency associated with Lesch-Nyhan syndrome (LNS). To understand the neurobiological basis of specific behaviors in LNS, investigations were undertaken in these neonatally lesioned rats. Several new findings resulted from these studies. The first was that D1-dopamine receptors are essential for the action of D2-dopamine receptors, a phenomenon called "coupling" of receptor function. Another finding was that D1-dopamine receptors must be repeatedly stimulated before maximal behavioral sensitivity can be observed. This has been referred to as "priming" of D1-dopamine receptor responsiveness. This priming action by repeated administration of a D1-dopamine agonist was antagonized by NMDA antagonists indicating a potential role of glutamate in this sensitization. Ongoing work suggests that DARPP-32 is not involved in priming of D1-dopamine receptor responsiveness. However, we have observed an accumulation of GFAP in brain following repeated administration of a D1-dopamine agonist. In addition, immunoblots employing an antibody to phospho-DARPP-32 revealed a protein present in lesioned rats that was not present in control rats. Studies in these lesioned rats are expected to continue to contribute to our basic understanding of adaptive changes caused by lesioning of dopaminergic neurons during development.

Molecular basis for regionally specific action of ethanol on gamma-aminobutyric acidA receptors: generalization to other ligand-gated ion channels.

The present investigation provides evidence that there is neuroanatomical specificity for ethanol enhancement of gamma-aminobutyric acid (GABA)-induced inhibition in mammalian brain and that the expression of a specific GABAA isoreceptor is associated with this regional action of ethanol. Ethanol enhanced responses to iontophoretically applied GABA in the medial septum, inferior colliculus, substantia nigra reticulata, ventral pallidum and the diagonal band of Broca. In contrast to these results, responses to GABA applied to cells in the lateral septum, ventral tegmental area and the hippocampus were not affected by ethanol. In those brain regions where ethanol enhanced responses to GABA, a high concentration of zolpidem binding was found, whereas zolpidem binding was much lower or absent in brain regions where ethanol did not enhance GABA. These observations support the hypothesis that ethanol enhances GABA within specific regions of brain by affecting a GABAA receptor with specific structural components. From data obtained with in situ hybridization, there was a strong relationship between the regional distribution of zolpidem binding and the expression of specific mRNAs for the alpha-1, beta-2 and gamma-2 GABAA receptor subunits at sites where ethanol enhanced responses to GABA. The mRNA for the long and short variants of the gamma-2 subunit were found in brain regions both sensitive and insensitive to the action of ethanol on GABA-induced inhibition. These data were not able to address whether the gamma-2 long variant in combination with the alpha-1 and beta-2 subunits is essential for ethanol enhancement of responses to GABA. However, the observation that the long version of the gamma-2 subunit is present in brain areas where ethanol did not affect GABA function suggests that the presence of the long variant of the gamma-2 subunit alone is not sufficient for ethanol's action to enhance responses to GABA. Rather it is concluded that the appropriate combination of GABAA receptor subunits is critical for this action of ethanol. Because the GABAA receptor belongs to a superfamily of ligand-gated ion channels, the action of ethanol was examined on responses to agonists acting on receptors linked to other ion channels. As noted for GABA, local application of ethanol altered responses to NMDA, nicotine and glycine when applied to some, but not all, neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of NMDA-evoked electrophysiological activity by ethanol in selected brain regions: evidence for ethanol-sensitive and ethanol-insensitive NMDA-evoked responses.

Our laboratory has previously shown that systemically administered ethanol inhibits NMDA-evoked electrophysiological activity in some, but not all, neurons in the medial septum. In the present report, it was found that ethanol, when applied locally via electro-osmosis, potently inhibited NMDA-evoked neuronal activity in a current-dependent manner in the inferior colliculus and hippocampus. In contrast, locally applied ethanol failed to inhibit NMDA-evoked activity in the lateral septum. The inhibition by ethanol of NMDA-evoked activity in the inferior colliculus was specific, in that ethanol failed to inhibit neuronal activity of the inferior colliculus evoked by the excitatory neurotransmitter glutamate. These findings indicate that ethanol can specifically inhibit NMDA-evoked activity in vivo via a local action, and that the ability of ethanol to inhibit NMDA-evoked activity varies regionally in brain. The possibility that these results are explained by the existence of two types of NMDA receptors, one sensitive to ethanol, the other insensitive to ethanol, is discussed.

The neuroanatomical specificity of ethanol action on ligand-gated ion channels: a hypothesis.

The studies described will demonstrate that the subunit composition of a GABAA receptor allows ethanol to enhance responses to GABA. Since we have determined that ethanol will influence responses to glycine, nicotine and NMDA in some, but not all, neurons with receptors to these agonists, we hypothesize that specific receptor subtypes of these ligand-gated ion channels will be affected by ethanol.

Augmented sensitivity of D1-dopamine receptors in lateral but not medial striatum after 6-hydroxydopamine-induced lesions in the neonatal rat.

Lesioning of neonatal rats with the neurotoxin 6-hydroxydopamine (6-OHDA) reduced striatal dopamine (DA) levels to 3% of control levels and produced marked increases in the behavioral effects of the selective D1-DA receptor agonist SKF-38393 in these animals when tested as adults. However, no differences were observed, either in basal or D1-DA-stimulated striatal cAMP formation or in forskolin-stimulated or GTP-stimulated cAMP production, between control and lesioned animals. C-fos-like immunoreactivity after SKF-38393 was significantly greater in dorsolateral vs. ventromedial aspects of the striatum in lesioned animals. Like the c-fos response, augmented electrophysiological responsiveness to SKF-38393 occurred in lesioned rats in lateral, but not medial, portions of the striatum. No differences were found in nucleus accumbens in sensitivity to SKF-38393 between control and lesioned rats. Although autoradiographic determination of D1-DA receptor binding throughout the striatum and nucleus accumbens revealed no differences between unlesioned and lesioned rats, tyrosine hydroxylase-like immunoreactivity was reduced with a regional distribution inversely related to c-fos-like immunohistochemical expression. These findings demonstrate that regionally enhanced electrophysiological sensitivity of striatal neurons to D1-DA receptor agonists after neonatal 6-OHDA-induced lesions is associated with regional changes in c-fos-like immunoreactivity and tyrosine hydroxylase-like immunohistochemistry, but not with changes in D1-DA receptor autoradiography or D1-DA-stimulated adenylyl cyclase activity. Such regional consequences of 6-OHDA-induced lesions in neonates may contribute to the unique behavioral patterns observed when these rats are challenged with L-dopa or D1-DA agonists as adults.

Comparison of the D1-dopamine agonists SKF-38393 and A-68930 in neonatal 6-hydroxydopamine-lesioned rats: behavioral effects and induction of c-fos-like immunoreactivity.

Administration of the selective D1-dopamine receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) to neonatal 6-hydroxydopamine-lesioned rats results in profound behavioral manifestations and induction of striatal c-fos-like immunoreactivity. The full D1-dopamine agonist I,[R,S]1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl-1H-2-benzopyran hydrochloride (A-68930), like SKF-38393, produced a dose-dependent, D1-selective increase in locomotor activity and striatal c-fos-like immunoreactivity. These responses were antagonized by a D1-dopamine antagonist, but not by a D2-dopamine antagonist. A-68930 produced locomotor activation at a lower dose than SKF-38393, but no dose of A-68930 was able to produce the magnitude of locomotor activation seen with SKF-38393. Both A-68930 and SKF-38393 induced similar stereotyped behaviors and possessed similar propensities to induce self-injurious behavior in neonatally lesioned rats; however, A-68930 was significantly more potent than SKF-38393 in inducing these behaviors. When either SKF-38393 or A-68930 were administered repeatedly at 2-week intervals, behavioral sensitization (priming) occurred. However, unlike SKF-38393, a high dose of A-68930 produced seizure activity and markedly desensitized D1-dopamine receptor activation for up to 3 days after administration. These results with A-68930 provide additional evidence that the specific behavioral and biochemical responses observed in neonatally lesioned rats after SKF-38393 administration are due to actions on D1-dopamine receptors, and indicate that A-68930 provides a new tool for investigating D1-dopamine receptor function.

Ethanol potentiates gamma-aminobutyric acid-mediated inhibition in the inferior colliculus: evidence for local ethanol/gamma-aminobutyric acid interactions.

The effect of ethanol on gamma-aminobutyric acid (GABA)-mediated inhibition of neurons of the inferior collicular cortex (IC) was investigated. Systemic administration of 0.5 g/kg ethanol, but not 0.25 g/kg ethanol, potentiated the inhibitory effect of GABA on IC neuronal activity. As with systemic administration of ethanol, local application of two concentrations of ethanol potentiated, in a dose-dependent and concentration-dependent manner, GABA-mediated inhibition of IC activity. When utilizing the lower ethanol concentration (270 mM), increasing ethanol ejection currents produced a correspondingly greater amount of augmentation of GABA inhibition without concomitant changes in spontaneous neural activity. At the highest ejection current tested (90 nA), ethanol doubled the inhibitory effects of GABA on IC neuronal activity. Local application of a higher concentration of ethanol (2.7 M) also potentiated GABA-mediated inhibition, with greater ejection currents producing greater potentiation of GABA-inhibition. Compared to the lower ethanol concentration, the higher ethanol concentration required lower ejection currents to produce comparable amounts of potentiation of GABA inhibition. These findings demonstrate that ethanol potentiates GABA inhibition of IC activity via a local action. In contrast to the effects of ethanol on GABA inhibition, locally applied ethanol failed to potentiate the inhibition by glycine of IC activity, indicating that ethanol does not indiscriminately potentiate all types of inhibition of IC neural activity. Additionally, locally applied ethanol failed to potentiate inhibition by GABA in the lateral septum, indicating that ethanol/GABA interactions are site specific. These findings indicate that ethanol specifically potentiates GABA-mediated inhibition of neural activity, and that this action occurs via a local action at specific sites in brain.

Dopamine electrophysiology of ventral pallidal/substantia innominata neurons: comparison with the dorsal globus pallidus.

The ventral pallidum/substantia innominata (VP/SI) is an infracommissural extension of the dorsal globus pallidus (GP). Functional studies suggest that the VP/SI is indirectly influenced by dopamine (DA) via inputs from dopaminoceptive regions. However, recent anatomical evidence indicates a direct dopaminergic projection to the VP/SI, but the physiologic and pharmacologic consequences of this input have not been evaluated. Thus, the present study was designed to electrophysiologically characterize VP/SI neuronal responses to i.v. administered apomorphine (APO) and microiontophoretically applied DA. Because of similarities in circuitry and morphology, VP/SI responses were compared to those obtained from the GP. Single neurons recorded in vivo from rat VP/SI and GP exhibited similar electrophysiologic characteristics. The majority of the 50 neurons tested with APO demonstrated a dose-related increase in firing rate, with equivalent maximum responses and equivalent doses that produced half-maximal responding (ED50) for the two brain areas. APO generally was antagonized by haloperidol, indicating that the agonist was acting at dopaminergic receptors to produce the observed rate changes. From 212 neurons tested, it was determined that microiontophoretically applied DA altered neuronal firing throughout both regions. However, more DA-sensitive neurons were encountered in the GP than the VP/SI (75% vs. 42%, respectively). DA-induced rate increases and decreases were observed, with rate suppression occurring most frequently. The maximum response and the current that produced half-maximal responding were comparable for the two regions for both response directions. Systemic administration of antagonists revealed that pallidal responses to dopamine likely involve both the D1 and D2 receptor subtypes. These studies 1) demonstrate that the VP/SI is a functionally important dopaminoceptive brain region, and (2) confirm previous work regarding dopaminergic regulation of the GP. The similarities in pharmacologic profiles of responses by GP and VP/SI neurons to dopaminergic agents likely reflect comparable circuitries for the two regions. The differential responding to systemically administered DA agonists and locally applied DA implies that a combination of direct and indirect influences ultimately determines the impact that an activated dopaminergic system has on pallidal brain regions.

Ethanol inhibits NMDA-evoked electrophysiological activity in vivo.

Recent studies have demonstrated that ethanol blocks N-methyl-D-aspartate (NMDA) responses in vitro. In the present study, evidence is provided that ethanol, when administered by the systemic route to rats, also inhibits NMDA-evoked electrophysiological activity in vivo at behaviorally relevant doses. Ethanol, at doses in rats ranging from those producing minimal changes in spontaneous behavioral activity (0.75 g/kg) to those producing marked suppression of behavioral activity (2.5 g/kg), produced a dose-dependent inhibition of the ability of NMDA, when iontophoresed onto neurons of the medial septum (MS), to activate MS neurons. However, at all doses of ethanol tested, a proportion of MS neurons responded to ethanol with essentially complete inhibition of NMDA-evoked activity, whereas other MS neurons responded to ethanol with little or no inhibition of NMDA-evoked activity. By way of comparison, MK-801, a non-competitive NMDA antagonist, antagonized NMDA-evoked activity in all MS neurons tested. In contrast to the actions of ethanol, MK-801 increased, rather than decreased, behavioral activity even at doses that completely inhibited NMDA-evoked activity in all MS neurons tested. These latter findings provide evidence that inhibition of NMDA-evoked activity cannot account for all of the behavioral effects of ethanol. In conclusion, while the present results demonstrate for the first time that ethanol can inhibit NMDA-evoked neuronal activity in vivo, they also indicate that additional neural actions must contribute to ethanol's pharmacological profile.