Opioid modulation of working memory: intraseptal, but not intraamygdaloid, infusions of beta-endorphin impair performance in spatial alternation.

The effect of beta-endorphin on spatial working memory was examined following microinfusions of beta-endorphin into the medial septal area and central amygdaloid nucleus in Long-Evans male rats. Working memory was assessed by spatial alternation in a T-maze. beta-Endorphin, 250 and 1000 ng/site, respectively, and muscimol, 20 ng/site, were infused into the medial septal area or central amygdaloid nucleus prior to behavioral testing. The hippocampal theta rhythm was examined following intraseptal infusions of beta-endorphin and muscimol. In the medial septal area, beta-endorphin and muscimol impaired choice accuracy and reduced the power of hippocampal theta rhythm. The degree of reduction in the power of hippocampal theta rhythm was correlated with the magnitude of behavioral impairment of choice accuracy in spatial alternation. In the central amygdaloid nucleus, beta-endorphin (1000 ng) and muscimol (20 ng) did not affect choice accuracy. The results suggest that septal, but not amygdaloid, opioid, and GABAergic activity modulate spatial working memory and hippocampal physiology.

Galanin in the medial septal area impairs working memory.

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1-16 and 21-29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1-16, and the complete peptide, 1-29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21-29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.

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.

Cholinergic and GABAergic modulation of medial septal area: effect on working memory.

The role of the septohippocampal pathway in working memory was investigated by direct microinfusion of compounds into the medial septal area (MSA). Behavior was measured by performance in a continuous spatial alteration task in a T maze, and hippocampal theta rhythm was also recorded. Intraseptal saline had no effect on choice accuracy or hippocampal theta rhythm. Tetracaine decreased choice accuracy and theta rhythm 10 min, but not 90 min, after infusion. Likewise, muscimol and scopolamine produced a transient, dose-dependent suppression of hippocampal theta rhythm and a simultaneous dose-dependent impairment in choice accuracy. A significant correlation (r = .78) emerged between a compound's influence on theta rhythm and its effect on choice accuracy. The data support a role for the septohippocampal projection in working memory and suggest that gamma-aminobutyric acid and acetylcholine may have opposing influences on neurons in the MSA.

Site-specific enhancement of gamma-aminobutyric acid-mediated inhibition of neural activity by ethanol in the rat medial septal area.

Because of uncertainty concerning the interaction of ethanol with gamma-aminobutyric acid (GABA) receptor-mediated events, the present work was designed to investigate the effect of ethanol on GABA transmission in the rat septal area using behavioral and electrophysiological techniques. Microinjection of the GABAA agonist muscimol into the medial septal area (MSA) enhanced, and bicuculline administration antagonized, ethanol-induced impairment of the aerial righting reflex. Microinjection of these drugs into the lateral septum (LSi) did not influence this measure of ethanol-induced sedation. Furthermore, intraseptal injections of muscimol or bicuculline in saline-treated rats had no effect on the aerial righting reflex. These data suggest that the MSA plays a critical modulatory role in the sedative actions of ethanol. To assess the effect of ethanol on muscimol responses in the MSA and LSi at the cellular level, GABA was applied by iontophoresis to rhythmically bursting neurons of the MSA and to cells in the LSi. The magnitude of the resultant inhibition by GABA on these cells was assessed before and after systemic administration of ethanol. Ethanol enhanced GABA-mediated inhibition of MSA neural activity, but did not alter GABA-mediated inhibition of cellular activity in the LSi. In contrast, the inhibition of cellular activity in the MSA, caused by a maximally effective concentration of the benzodiazepine flurazepam, was not altered by ethanol. Other work in the MSA demonstrated that electrical stimulation of the fimbria caused an inhibition of ongoing single unit activity that was reduced by concurrent application of bicuculline. The duration of this electrically elicited inhibition in the MSA was enhanced after ethanol injection and then recovered to base-line levels. In addition, ethanol (1.5 mg/kg) caused an enhancement of the inhibition induced by nipecotic acid, a GABA uptake inhibitor. These findings demonstrate that GABA-mediated neural inhibition is enhanced by ethanol in the MSA but not the LSi, indicating that the actions of ethanol on GABA-induced inhibition can be site specific. It is proposed that the cellular action of ethanol may depend upon a specific molecular composition of the GABA receptor complex which may vary at selected sites in the brain.

Electrophysiological evidence that ethanol alters function of medial septal area without affecting lateral septal function.

Evidence is provided in this manuscript that ethanol acts directly on neurons in the medial septal area (MSA). Initially, the electrophysiological characteristics of MSA neurons in freely moving rats were characterized and found similar to that observed in rats anesthetized with urethane, but not chloral hydrate. Therefore, urethane was used to evaluate the effects of ethanol in anesthetized rats. The conclusion that ethanol influences neural function in the MSA is based on electrophysiological data that ethanol (0.75-3.0 g/kg i.p.) suppresses neural firing of medial septal cells in urethane-anesthetized as well as in unanesthetized rats in a dose-related fashion. Concurrent with the suppression of firing rate, the rhythmic bursting pattern of activity of MSA neurons is disrupted by ethanol. The changes observed in the MSA could not be attributed to an indirect action of ethanol on afferents from the lateral septum to the MSA, because ethanol did not alter neural activity of cells in the lateral septum. These data indicate that ethanol does not have a common action on all neurons. Neural activity in the MSA recovered from the acute action of ethanol at a time when blood ethanol levels were near maximal, indicating an acute tolerance to this effect of ethanol. The time course of change in neural activity in the MSA was highly correlated with the time course of a measure of behavioral sedation, but not the hypothermia produced by ethanol. Thus, the work in this manuscript supports the view that ethanol has selective actions on MSA neurons in the rat septal area and that these actions may influence the behavioral sedation induced by ethanol.

Topography of basal glucose utilization in the hippocampus determined with [1-14C]glucose and [6-14C]glucose.

The activity of the pentose phosphate shunt was assessed under basal conditions in subregions of the hippocampus by measuring the uptake and retention of [1-14C]glucose and [6-14C]glucose and their 14C-labelled metabolites. The relative and absolute retention of carbon-14 from each of the two compounds was nearly identical in all regions examined. For each compound, the highest accumulation of 14C occurred in the granule cell layer of the dentate gyrus and in the pyramidal cell layer. Relatively high retention of radioactivity was also found in the molecular layer of dentate gyrus and in the stratum lacunosum-molecular. The stratum radiatum and stratum oriens contained the lowest levels of radioactivity among hippocampal regions. The equal retention of radioactivity from [1-14C]glucose and [6-14C]glucose implies that pentose phosphate shunt activity is very low throughout the hippocampus under the conditions of this study. The uptake and retention of radioactivity was evaluated in different hippocampal regions 10 or 30 min following intravenous injection of [1-14C]glucose. Although there was significantly more radioactivity at 30 min than at 10 min, the same topographic pattern of radioactivity within the hippocampus was observed in rats after both survival periods, indicating that an equal fraction of the [1-14C]glucose utilized in different hippocampal regions is oxidized to 14CO2 under these conditions. Most regions of high glucose utilization in the hippocampus determined with [1-14C]glucose and [6-14C]glucose correspond to regions of intense histochemical staining for cytochrome oxidase reported in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino acid influences on seizures elicited within the inferior colliculus.

Using a model in which seizure activity was elicited electrically from the inferior colliculus, the influence of both inhibitory and excitatory putative neurotransmitter amino acids on this seizure activity was assessed by manipulating neurotransmitter amino acid function. It was found that i.c.v. administration of the inhibitory amino acids taurine (2.5 micrograms) or glycine (30 micrograms), or the gamma-aminobutyric acidA agonist, muscimol (300 ng), significantly elevated the threshold current necessary to initiate seizure activity from the inferior collicular cortex. Similarly, the microinjection of muscimol (10 or 30 ng) or racemic baclofen (20 or 60 ng), a gamma-aminobutyric acidB agonist, into the inferior collicular cortex significantly elevated the seizure threshold current, but inferior collicular microinjections of taurine (1 microgram) or glycine (1 microgram) exerted no effect on the seizure threshold current. When excitatory amino acid influences were assessed on seizure production, neither ventricular administration of glutamate or aspartate (100 micrograms) nor inferior collicular administration of glutamate (1 or 10 micrograms) or aspartate (10 micrograms) changed the seizure initiation threshold. Although the site administration of 30 or 100 ng of N-methyl-D-aspartic acid did not alter the seizure initiation threshold, 300 ng of N-methyl-D-aspartic acid significantly lowered the amount of electrical stimulation necessary to elicit the seizure activity. Conversely, blockade of N-methyl-D-aspartic acid receptors in the inferior colliculus with L-3-amino-7-phosphonoheptanoic acid (100 ng) or gamma-glutamylglycine (200 ng) significantly elevated the threshold current for seizure production, whereas microinjection of DL-3-amino-phosphonobutyric acid (200 ng) or glutamic acid diethyl ester (1 microgram) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

SCH23390 effects on apomorphine-induced responses of nigral dopaminergic neurons.

SCH23390 is a dopamine antagonist which has a high affinity for D1-like dopaminergic receptors. Receptor binding studies demonstrated significant levels of specific SCH23390 binding within nigral tissue. Therefore, electrophysiological experiments were conducted to determine if this antagonist influenced apomorphine-induced suppressions of unit firing recorded from dopaminergic cells of the substantia nigra zona compacta. Results presented in this report indicate that the autoreceptors located on dendrites and cell bodies of dopamine-containing neurons are not directly acted upon by SCH23390. This conclusion is drawn because: doses of SCH23390 known to block behaviors caused by dopamine agonists were ineffective in blocking rate reductions produced by apomorphine and pretreatment with 0.1 mg/kg of SCH23390 did not change the apomorphine dose-response curve for inhibition of dopaminergic neurons. Consistent with this finding, microinjections of SCH23390 into the zona compacta did not alter apomorphine-induced behaviors which are known to be blocked by haloperidol (a D2-like antagonist) intranigral injections. However, when only the larger apomorphine doses (64 and 128 micrograms/kg i.v.) are considered, SCH23390 pretreatment did attenuate the maximum response to apomorphine in some nigral cells. Because larger apomorphine concentrations alter striatal activity, such results may be reflective of alterations in a subpopulation of nigral neurons which are postsynaptic to neurons containing D1-like receptors and located elsewhere in the brain (e.g., in striatum). Collectively, these results agree with previous studies which suggest that dopamine receptors located on dopamine-containing neurons of the substantia nigra zona compacta are likely not of the D1-type.