Mecamylamine blocks enhancement of reference memory but not working memory produced by post-training injection of nicotine in rats tested on the radial arm maze.

The focus of this study was to analyze whether the psychostimulant nicotine would enhance reference and working memory consolidation in rats tested on the 8-arm radial arm maze. Mecamylamine, a nicotine antagonist, was used to attempt to block the enhancement of memory consolidation. All rats were given one training trial/day for 12 consecutive days, and 4 arms were baited. Rats were separated into five groups: the saline-nicotine group received an intraperitoneal (i.p.) injection of saline immediately after each trial followed 15 min later by an subcutaneous (s.c.) injection of nicotine (0.6 mg/kg free base); the nicotine-delay group received an s.c. injection of nicotine 2 h after each training trial, two groups received an i. p. injection of one of two different doses of mecamylamine (2.5 and 6.0 mg/kg) immediately after each trial, which was followed 15 min later by an s.c. nicotine injection, and a control group received an i.p. injection of saline immediately and 15 min after each training trial. Results showed that the saline-nicotine group made fewer reference and working memory errors than the saline- or nicotine-delay groups, but only the effect of nicotine on reference memory was blocked by the higher dose of mecamylamine. It appears from these results that nicotine's effects on reference and working memory may be mediated through different mechanisms.

Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons.

Previously we found postnatal binge-like ethanol exposure using an artificial-rearing method in the rat delayed developmental up-regulation of GABA(A) receptors (GABA(A)Rs) in both medial septum/diagonal band (MS/DB) and cerebellar Purkinje neurons. In the present study, the impact of ethanol on developing GABA(A)Rs in MS/DB neurons was further tested under conditions not requiring anesthesia or maternal deprivation. Nursing rat pups received ethanol (4.5-5.25 g/kg/day) on postnatal days (PD) 4-9, which was administrated manually by oral intragastric intubation. This treatment caused dose-dependent blunting of peak GABA(A) receptor whole cell currents in acutely dissociated MS/DB cells on PD 12-15. The threshold with oral intubation was slightly higher than previously observed for artificial-rearing (4.9 vs. 4.5 g/kg/day). The previously observed reduced sensitivity of GABA(A)Rs to Zn(2+)-inhibition after ethanol was not found with the intubation model. In studies only carried out using the intubation method, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) caused an allosteric concentration-dependent potentiation of currents activated by non-saturated concentrations of GABA. A bicuculline sensitive direct activation of GABA(A)Rs also occurred with higher concentrations of 3alpha-OH-DHP alone. Ethanol intubation up-regulated allosteric neurosteroid potentiation with low concentrations of GABA, but did not change direct agonist actions of 3alpha-OH-DHP. Finally, 3alpha-OH-DHP did not prime ethanol insensitive GABA(A)Rs to become sensitivity to acute ethanol potentiation. These results indicate ethanol consistently blunts postnatal GABA(A) receptor up-regulation across early postnatal binge-type ethanol exposure models and may increase positive modulation of GABA(A) receptors by endogenous neurosteroids.

Sustained ethanol inhibition of native AMPA receptors on medial septum/diagonal band (MS/DB) neurons.

The direct impact of ethanol on native, non-NMDA glutamate receptors was examined in acutely isolated MS/DB neurons from rat. The impact of ethanol functional tolerance and physical dependence on non-NMDA receptor function was also determined. Non-NMDA receptors were defined pharmacologically as predominantly the AMPA subtype, because both AMPA- or kainate-activated currents were blocked by GYKI 52466, a selective AMPA receptor antagonist. The relative magnitude of potentiation of AMPA-activated currents by 10 or 100 microM cyclothiazide was consistent with recombinant AMPA flop-subtype receptors. Finally, the selective kainate receptor agonist, SYM 8021, induced little current in MS/DB neurons. AMPA receptor currents when activated by kainate were sensitive to ethanol, showing inhibition of approximately 5 - 50% when 10 - 300 mM ethanol and kainate were briefly co-applied (3 s). Ethanol (100 mM) also inhibited both the initial transient peak and sustained currents activated by AMPA. Inhibition was sustained during continuous ethanol superfusions of 5 min, suggesting a lack of acute tolerance to ethanol-induced AMPA receptor blockade. Rapid application of 3 - 3000 microM kainate activated concentration-dependent currents in MS/DB neurons from Control and Ethanol Dependent animals that were not significantly different. Also, direct ethanol inhibition (300 mM) of kainate-activated currents was not reduced by ethanol dependence, suggesting a lack of functional tolerance. These results suggest that native AMPA receptors on MS/DB neurons are inhibited by pharmacologically-relevant concentrations of ethanol. However, these receptors, unlike NMDA receptors, do not undergo adaptation with sustained ethanol exposure sufficient to induce physical dependence. British Journal of Pharmacology (2000) 129, 87 - 94

Postnatal ethanol exposure blunts upregulation of GABAA receptor currents in Purkinje neurons.

Recently, we found that early postnatal ethanol exposure inhibits the maturation of GABAA receptors (GABAARs) in developing medial septum/diagonal band (MS/DB) neurons, suggesting that these receptors may represent a target for ethanol related to fetal alcohol syndrome (FAS). To determine whether GABAARs on other neurons are also sensitive to a postnatal ethanol insult, postnatal day (PD) 4-9, rat pups were artificially reared and exposed to ethanol (4.5 g kg-1 day-1, 10.2% v/v). The pharmacological profile of acutely dissociated cerebellar Purkinje cell GABAARs from untreated, artificially reared controls and ethanol-treated animals was examined with conventional whole-cell patch clamp recordings during PD 12-16 (juveniles) and PD 25-35 (young adults). For untreated animals, GABA (0.3-100 microM) consistently induced inward Cl- currents in a concentration-dependent manner showing an age-related increase in maximum response without change in EC50 or slope value. Acute ethanol (100 mM) consistently inhibited 3 microM GABA currents (10-20%); positive modulators, pentobarbital (10 microM), midazolam (1 microM) and loreclezole (10 microM), consistently potentiated; the negative modulator, Zn2+ (30 microM), inhibited GABA currents across both juvenile and young adult groups. Loreclezole potentiation increased while Zn2+ inhibition decreased with age in untreated Purkinje neurons. Postnatal ethanol exposure (PD 4-9) decreased GABAAR maximum current density in young adult Purkinje cells but not in juvenile neurons. However, sensitivity to allosteric modulators did not change after ethanol. These data are consistent with the hypothesis that postnatal ethanol exposure during the brain growth spurt can disturb GABAAR development across the brain, although the mechanism(s) underlying this action remains to be determined.

Development of GABAA receptors on medial septum/diagonal band (MS/DB) neurons after postnatal ethanol exposure.

The impact of 'binge-like' ethanol exposure on postnatal days (PD) 4-9 was examined on development of gamma-aminobutyric acid type A receptors (GABAAR) during the first month of life in the rat. Whole-cell patch-clamp recordings in acutely isolated medial septum/diagonal band (MS/DB) neurons were used to define effects of rapidly applied ethanol and other allosteric modulators on bicuculline-sensitive GABA currents. Three age groups were examined including 'pups' (PD 4-10), 'juveniles' (PD 11-16) and 'young adults' (PD 25-35). In untreated neurons, maximum responses to GABA and the apparent GABA EC50 increased approximately 2-fold during the first month of life. Potentiation of GABA responses by pentobarbital, midazolam, and loreclezole all increased with age, while Zn2+ inhibition declined. Initial inhibition by ethanol switched to potentiation of GABA responses during this time. In vivo, binge-like ethanol treatment (4.5 g kg-1 day-1 divided into two doses, 2 h apart on PD 4-9) reduced both the GABA maximal response and GABA EC50 measured on PD 11-16. These measures returned to control levels by PD 25-35. After binge-like postnatal ethanol exposure, age-dependent loss of Zn2+ inhibition of GABA responses was increased, while potentiating actions of in vitro ethanol were blocked. GABAAR modulation by other drugs was unaffected. These data suggest that early postnatal ethanol exposure disrupts the expected developmental pattern of GABAAR function in MS/DB neurons, an action that could contribute to neurobehavioral deficits associated with the fetal alcohol syndrome. Whether these changes are due to cellular damage, delayed gene expression or post-translational modification needs to be determined.

Ethanol inhibition of NMDA currents in acutely dissociated medial septum/diagonal band neurons from ethanol dependent rats.

The effect of acutely applied ethanol and the impact of chronic ethanol treatment, sufficient to induce tolerance and physical dependence, on N-methyl-D-aspartate (NMDA) receptor function were studied in acutely isolated neurons from the medial septum/diagonal band (MS/DB) of adult rats using whole cell, patch-clamp electrophysiology. There was a small positive correlation for capacitance and current amplitude activated by 100 microM NMDA for all groups. Also, cell membrane capacitance was significantly smaller for Ethanol Dependent (approximately 80-84%) than either Naive or Control cells. Therefore NMDA-activated responses were normalized for capacitance (current density, pA/pF) across all three groups. NMDA-activated (30-1000 microM) responses were significantly larger in cells from Control and Ethanol Dependent rats relative to those from Naives. In addition, estimated maximal responses were significantly larger for Ethanol Dependent cells, compared to either Control or Naive, respectively, while EC50s and slopes were not significantly different. Acute 60 mM ethanol significantly inhibited responses to 100 microM NMDA in all three groups, however, mean ethanol inhibition was 12-25% smaller after ethanol dependence. There was no evidence of acute tolerance to ethanol inhibition for any group, but examination of patterns of inhibition for individual neurons showed a few cells were resistant to ethanol or exhibited progressive loss of ethanol inhibition. These results suggest that NMDA receptor function in acutely isolated MS/DB neurons is increased following in vivo chronic ethanol treatment, and shows resistance to acute ethanol inhibition suggesting NMDA receptor-mediated cellular tolerance.

Halogenated aromatic hydrocarbons suppress CA1 field excitatory postsynaptic potentials in rat hippocampal slices.

Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs) and dibenzo-p-dioxins (PCDDs), alter cognitive function and learning. The cellular basis of HAH-induced alteration of brain function is not well-understood. The hippocampus is a likely site of toxic action because of its well-known roles in learning and memory, as well as its propensity to accumulate environmental neurotoxicants. A hippocampal function that can be measured readily is evoked excitatory postsynaptic potentials (EPSPs), which are an index of excitatory synaptic function. In this study, effects of HAHs on EPSPs were characterized in hippocampal slices from adolescent to adult male Sprague-Dawley rats. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4-TCDD were used because these HAHs are prototypical potent and weak aryl hydrocarbon (Ah) receptor agonists, respectively. 2,2',5,5'-Tetrachlorobiphenyl (TCB) was used as a prototypical ortho-substituted PCB, which acts through Ah receptor-independent pathways. For each hippocampal slice, peak amplitudes of EPSPs during a 15-min recording period (1 recording/min) were averaged and used as baseline (100%). Subsequent EPSPs were expressed as percentage of baseline. TCDD and 1,2,3,4-TCDD did not alter EPSPs in slices from the middle third of the hippocampus. However, in ventral slices, TCDD significantly decreased EPSPs, whereas 1,2,3,4-TCDD was inactive. TCB decreased EPSPs in both middle and ventral slices at half-maximal stimulation. An unexpected reversal of inhibition was observed within 30 min of continuous application of TCDD or TCB. In ventral slices, L-type calcium channel blocker nifedipine blocked inhibition of EPSPs induced by TCDD but not EPSPs inhibited by TCB. These results suggest that, while TCB-induced inhibition of EPSPs occurs through an unknown mechanism, TCDD-induced inhibition of EPSPs was mediated by L-type calcium channel activity in a congener-specific manner.

Ethanol inhibition of reduced frequency-dependent rundown of calcium currents in acutely dissociated MS/nDB neurons from chronic in vivo lead-exposed adult rats.

Although it is well known that lead (Pb2+0 acutely blocks voltage-gated calcium currents (VGCCs) in mammalian neurons, little is known about the long-term effects of continuous exposure to this metal on VGCCs. In the present study, the effects of chronic lead exposure on VGCCs (with barium ions as the charge carrier) were studied using whole-cell patch-clamp electrophysiological techniques in acutely dissociated medial septum (MS)/nucleus diagonal band (nDB) neurons. Neither peak, end current amplitudes, nor the current-voltage relationship were affected by chronic lead exposure. However, VGCCs repetitively evoked at frequent 6 s intervals displayed diminished whole-cell current rundown after 2 min of stimulation in cells from chronic Pb-exposed rats compared to cells from control Na-exposed rats. Because rundown after repetitive stimulation at a slower rate (20 s intervals) was not different between Pb-exposed and Na-exposed, reduced rundown at 6 s intervals was probably due to decreased slow inactivation of voltage-gated calcium channels. Interestingly, acute application of 60 mM ethanol reversed the reduced rundown in cells from Pb-exposed rats while having no effect on cells from Na-exposed rats. Clearly, acute ethanol treatment antagonized the effect of chronic lead exposure, unlike the additive interaction we observed previously with synaptic plasticity (Grover and Frye, 1996). Acute application of 1 microM Pb2+ completely blocked VGCCs similarly in neurons from Na-exposed and Pb-exposed rats. These findings do not suggest that major adaptive changes in VGCCs have occurred during chronic in vivo exposure to lead. But, subtle changes in channel efficiency only revealed under conditions of repetitive stimulation may exist, and are reversed by ethanol. These subtle changes may be sufficient to influence neuroplasticity such as LTP.

Sensitivity of postsynaptic GABAB receptors on hippocampal CA1 and CA3 pyramidal neurons to ethanol.

Baclofen-induced hyperpolarization of hippocampal CA1 and CA3 pyramidal neurons was examined to assess the impact of ethanol on postsynaptic GABAB receptors. These receptors activate outward K+ currents via a pertussis toxin-sensitive G protein cascade to reduce membrane potential during the slow inhibitory postsynaptic potential. This inhibitory action may play a role in ethanol intoxication and withdrawal excitability. In both types of pyramidal neurons, baclofen applied consecutively in increasing concentrations caused concentration dependent hyperpolarization. There were no significant differences in resting membrane potential, input resistance, maximum baclofen-induced hyperpolarization or EC50 between CA1 and CA3 neurons, although slope values were significantly smaller in the former neurons. These parameters were not significantly changed in the presence of ethanol 10-100 mM. Chronic ethanol treatment (12 days) sufficient to induce physical dependence also did not shift sensitivity or maximum response to baclofen in CA1 neurons. These results suggest that GABAB receptors in this model are essentially insensitive to ethanol and do not confirm our earlier preliminary observation of a possible down-regulation of postsynaptic GABAB receptor function by chronic ethanol treatment.

Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats.

The interaction of chronic in vivo lead exposure and acute in vitro ethanol treatment on synaptic neurotransmission and plasticity were studied using extracellular electrophysiological techniques in CA1 region of hippocampal brain slices from adult rats. Neither chronic lead exposure nor acute ethanol treatment had any significant effect on field excitatory postsynaptic potentials (EPSPs). In vivo lead exposure enhanced short-term potentiation (STP, potentiation that decays within 30 min) by 21% shortly after 'weak' tetanus, but had no effect on long-term potentiation (LTP, sustained at least 1 h). In vitro bath application of 60 mM ethanol inhibited STP by 35% and blocked LTP induced by 'weak' tetanus in slices from Pb exposed rats (500 ppm lead acetate, 56-70 days), while having no effect on STP or LTP in slices from control counterpart Na-exposed rats (pair-fed 216 ppm sodium acetate). In contrast, 'strong'-tetanus-induced LTP was abolished in Pb-exposed slices, and 60 mM ethanol slightly inhibited STP and blocked LTP in slices from Na-exposed rats. These differences could not be explained by differences in ethanol inhibition of NMDA-mediated field EPSPs because they were similarly reduced in slices from Na-exposed (30%) and Pb-exposed (25%) rats. These findings suggest that the strength of the tetanus used determines whether or not synaptic plasticity is blocked by either chronic lead exposure or acute ethanol treatment, and that even in adult rats, hippocampal synaptic LTP can be compromised by combined exposure to ethanol and lead. More importantly, these findings suggest the consequences of combined lead exposure and alcohol abuse in the adult human population may not be fully recognized yet.

Acute and chronic actions of ethanol on CA1 hippocampal responses to serotonin.

The effects of acute or chronic ethanol on serotonin (5-HT)-induced membrane hyperpolarization and inhibition of the slow Ca2(+)-dependent after hyperpolarization (sAHP) were recorded in rat CA1 pyramidal neurons in hippocampal slices using sharp intracellular electrodes. 5-HT (1-100 microM) caused concentration-dependent hyperpolarization of the membrane that was not altered by simultaneous 30 mM ethanol treatment, but blunted by 10 microM buspirone, a weak 5-HT1A agonist. 5-HT (1-30 microM) also partially inhibited (approximately 40%) the sAHP following a burst of five or more action potentials. Initially ethanol (30 mM) alone did not alter the sAHP, but over a period of 38 min, a slow increase in amplitude (approximately 40%) was observed. 5-HT-mediated inhibition of the sAHP was significantly greater with ethanol present, regardless of the length of exposure. Pyramidal neurons in hippocampal slices prepared from ethanol-dependent animals showed no obvious signs of withdrawal related hyperexcitability and neither concentration-dependent membrane hyperpolarization nor sAHP inhibition caused by 5-HT were significantly changed from responses in controls. These results suggest that hyperpolarizing responses to 5-HT in hippocampal CA1 pyramidal neurons are functionally resistant to acute or chronic ethanol treatment. 5-HT-mediated inhibition of the sAHP is enhanced by ethanol acutely, but does not show an adaptive change as a result of ethanol dependence.

Lanthanum and zinc sensitivity of GABAA-activated currents in adult medial septum/diagonal band neurons from ethanol dependent rats.

The impact of chronic ethanol treatment, sufficient to induce tolerance and physical dependence, on GABAA receptor function was studied in acutely isolated neurons from the medial septum/nucleus diagonal band (MS/nDB) of adult rats using whole cell, patch-clamp recordings. In ethanol-naive Controls, GABA (0.3-300 microM) induced concentration-dependent increases in Cl- current with a threshold of 0.3-1 microM, a mean maximal current of 7645 +/- 2148 pA at 100-300 microM, an EC50 of 11.3 +/- 1.3 microM and a slope of 1.53 +/- 0.07. GABA-activated currents in neurons from animals receiving two weeks of ethanol liquid diet treatment did not differ significantly on any of these measures. The rate of GABAA receptor desensitization (t1/2 = 6.49 +/- 1.19 s) estimated as the time required for loss of 50% of peak current during sustained application of 10 microM GABA, as well as the residual steady state current remaining following complete desensitization for controls was unchanged by chronic ethanol. The impact of chronic ethanol treatment on the GABAA receptor modulation by lanthanum and zinc which act as positive and negative allosteric modulators, respectively, was also evaluated. Test pulses of 3 microM GABA in control neurons showed maximal potentiation by 141 +/- 30% at approximately 1000 microM lanthanum with an EC50 of 107 +/- 34 microM and a slope of approximately 1. Lanthanum potentiation remained the same following chronic ethanol treatment. Initial estimates based on fitted concentration response curves suggested that maximal inhibition of 3 microM GABA responses by zinc at the level of 70.2 +/- 8.5% in control cells was significantly increased by chronic ethanol treatment to 95.3 +/- 2.5%, although the IC50 of 60.2 +/- 25 microM was not changed. However, this difference was not supported by direct tests of maximal 3-10 mM zinc concentrations. These results suggest that chronic ethanol treatment, sufficient to induce tolerance and physical dependence, probably does not lead to readily detectible changes in GABAA receptor function in MS/nDB neurons.

Acute ethanol dependence or long-term ethanol treatment and abstinence do not reduce hippocampal responses to carbachol.

In the hippocampus of human alcoholics, prolonged ethanol treatment reduces the number of muscarinic ligand binding sites present at autopsy suggesting a decrease in functional muscarinic receptors. Whether these changes are due to alcohol-induced brain damage or ethanol dependence and represent a reduced level of cholinergic function is unknown. The present studies tested the impact of ethanol dependence or long-term ethanol treatment and subsequent withdrawal on the function of pre- and postsynaptic muscarinic receptors in the CA1 region of the rat hippocampus. Field excitatory postsynaptic potentials (EPSPs) were inhibited in a concentration-dependent manner by 0.1-100 microM carbachol. This presynaptic inhibitory action of carbachol involving muscarinic receptors was not significantly reduced either by ethanol treatment (12 days), causing physical dependence, or by long-term ethanol treatment (97-120 days) and abstinence (3-6 months). Postspike after hyperpolarizations (AHPs) were inhibited in a concentration-dependent manner by carbachol (6-2000 nM). This postsynaptic excitatory action of muscarinic receptors also was not significantly reduced either by 12-day ethanol treatment or by long-term ethanol treatment. Taken together, these results suggest that neither pre- nor postsynaptic muscarinic receptor function measured electrophysiologically is reduced by either ethanol dependence or long-term ethanol consumption and abstinence in the rat as suggested by reduced muscarinic ligand binding in the hippocampus of human alcoholics.

Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus.

The time course of ethanol-induced inhibition of NMDA-mediated synaptic activity was studied in brain slices using extracellular electrophysiological techniques in the CA1 region of the hippocampus. Bath application of 60 mM ethanol inhibited NMDA-mediated field excitatory postsynaptic potentials (EPSPs) by at least 45% in 7/11 of the slices tested, with the remaining 4 slices inhibited by 8.7-35%. Most slices inhibited by at least 45% showed a significant reduction in ethanol inhibition over a 15 min ethanol exposure period, suggesting the development of acute tolerance. In a second set of experiments, tolerance to ethanol-induced inhibition of NMDA-mediated EPSPs that developed over time during the first ethanol exposure persisted during a second ethanol exposure. In contrast to ethanol, inhibition of EPSPs by the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (APV) remained stable during a comparable application of the drug. These results suggest that acute tolerance can develop to ethanol inhibition of NMDA mediated synaptic activity in the hippocampus.

Interaction of ethanol and allosteric modulators with GABAA-activated currents in adult medial septum/diagonal band neurons.

Behavioral and electrophysiological studies suggest that neurons in the medial septum may express ethanol sensitive GABAA receptors. In the present study, patch-clamp recordings of whole-cell currents were used to directly characterize the ethanol sensitivity of GABAA receptors on acutely dissociated neurons, isolated from the medial septum/nucleus of the diagonal band (MS/nDB) of the adult rat brains. MS/nDB neurons displayed inward currents in response to GABA applied rapidly with a large-bore dual pipette system. The currents were mediated by the activation of GABAA receptors, since they reversed near the calculated reversal potential for chloride and were completely blocked by bicuculline. GABA responses were concentration dependent with an EC50 of 8.7 microM GABA and a slope of 1.35 suggesting cooperativity. Pharmacologically relevant concentrations of ethanol (3-300 mM) neither significantly increased nor decreased mean responses to GABA in neurons from Sprague Dawley or High Alcohol Sensitivity (HAS) rats. Mean GABA currents were significantly increased by 300 mM ethanol in neurons from 'ethanol sensitive' Fischer 344, ACI and Wistar Kyoto inbred rats. In subsets of neurons, 12.5 to 57.1% of those tested from these 5 rats strains, ethanol (30-300 mM) significantly increased GABA currents by > or = 20%. An additional, 10 percent of cells from Sprague Dawley rats showed ethanol-induced inhibition of GABA-activated current by < or = 20%. Allosteric modulators pentobarbital (10 microM), midazolam (1 microM) and lanthanum (300 microM), enhanced, while zinc (30 microM) decreased GABA-activated currents in all neurons, consistent with the well-known actions of these agents. These results suggest that GABAA receptors on MS/dDB neurons are pharmacologically similar to those on other neurons with respect to regulation by allosteric modulators. On the other hand, ethanol sensitivity of GABAA receptors varies considerably from cell to cell ranging from significant enhancement to inhibition of GABA-activated current.

Dynamic stereotactic radiosurgery using a linear accelerator.

We describe a system for stereotactic radiosurgery with a linear accelerator. This technique allows treatment of small (less than 40 mm diameter) intracranial lesions, including vascular malformations, and primary and metastatic tumors that are deep within the brain or in areas not amenable to open surgery. A beam of ionizing radiation (1800 to 2500 cGy) is focused on the center of the lesion, which is determined by stereotactic localization. "Dynamic rotation" of the linac gantry and table continuously about this predetermined point ensures that only the lesion receives the full radiation dose, while the normal structures in the head receive minimal amounts of radiation. The system combines, for the first time in one place, elements of radiosurgical technique developed at various centers. Testing for accuracy compares favorably with results at other centers using linac-based systems as well as comparing favorably with the gamma knife.

Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake.

The functional state of GABAA receptors during physical dependence on ethanol was evaluated in two ways. First, the ability of ethanol dependence to change the convulsant potency of GABAA antagonists microinjected into the inferior colliculus was examined. A second approach evaluated the effects of ethanol dependence on the ability of muscimol or pentobarbital to stimulate chloride uptake in rat brain vesicles. In the studies examining changes in convulsant potency, bilateral microinfusions of GABAA antagonists, bicuculline methiodide and picrotoxinin, as well as the excitatory amino acid agonist, kainic acid (used as a positive control) induced similar dose-related increases in the frequency of wild-running seizures. Ethanol dependence did not significantly change susceptibility to wild-running seizure induction by an of the convulsants, although susceptibility to the more severe, clonic seizures was significantly increased for each convulsant. This suggested that the receptor-blocking effects of GABAA antagonists responsible for inducing wild-running seizures were not selectively increased by ethanol dependence, but that spread of seizure activity responsible for clonic seizures following the initiation of wild running was generally increased. Finally, in studies examining changes in GABAA receptor-mediated chloride uptake, both muscimol and pentobarbital were found to induce concentration-dependent increases in chloride uptake in rat brain vesicles. However, responses to these drugs were not reduced by ethanol dependence suggesting that a generalized adaptive decrease in GABAA receptor function was unlikely. Together these results do not provide support for the hypothesis that the GABAA receptor-chloride channel complex is down-regulated during the development of physical dependence on ethanol.

Effects of acute and chronic ethanol treatment on pre- and postsynaptic responses to baclofen in rat hippocampus.

Interactions between the GABAB receptor and acute or chronic ethanol treatment were studied using extracellular and intracellular electrophysiological recording techniques. Bath application of the GABAB receptor agonist, (-)-baclofen (0.1-100 microM) induced concentration-dependent inhibition of extracellularly recorded dendritic excitatory postsynaptic potentials (EPSPs) in the CA1 region of hippocampal slices. Responses to baclofen were unchanged relative to control either by simultaneous application of ethanol (10-60 mM) or by previous chronic ethanol exposure. The membrane potential of CA1 pyramidal neurons was reversibly hyperpolarized an average of 5 mV by pressure ejection of baclofen (1 mM). Bath application of ethanol (30 mM) alone occasionally caused a small depolarization of resting membrane potentials in CA1 neurons but failed to increase hyperpolarizing responses to pressure-ejected baclofen. However, in slices from chronic ethanol-treated animals hyperpolarizing responses to bath-applied baclofen (10 microM) were reduced by approximately 30% relative to controls. These results suggest that GABAB-mediated responses in CA1 hippocampal pyramidal neurons are relatively resistant to the acute effects of ethanol, but that continuous exposure to ethanol sufficient to induce physical dependence may evoke an adaptive reduction in some GABAB receptor mediated responses.