Gonadal regulation of GABAA receptors in the different brain areas of the male Japanese quail

Summary Quantitative autoradiography was used to investigate the distribution and effects of gonadal hormones on [³H] muscimol (specific GABA_A receptor ligand) binding in the male Japanese quail brain. In gonadally intact Japanese quail brains, [³H] muscimol revealed a heterogeneous distribution with high GABA_A receptor levels in the cerebellum pars granularis (656 fmol/mg wet weight of tissue) and in the pars molecularis (405 fmol/mg wet weight of tissue). Low receptor levels were found in the nucleus preopticus anterior and the nucleus lateralis of the hypothalamic regions (<220 fmol/mg wet weight of tissue) as well as thalamic nuclei such as rotundus and pretectalis (220–261 fmol/ mg wet weight of tissue). Castration resulted in [³H] muscimol binding changes in both brain areas that contain steroid receptors and brain areas devoid of steroid receptors. In fact, castration led to high binding levels in the preopticus anterior nucleus and in the anterior neostriatum area, brain areas that are known to contain gonadal steroid receptors. Castration also elevated [³H] muscimol binding in the hyperstriatum ventrale and reduced binding levels in the paleostriatum augmentatum and the stratum griseum centrale area; all of these areas are known to be devoid of gonadal steroid receptors. At this point it was also important to know whether the gonadal steroid effect is due to alterations in the number of binding sites (B_max) and/or the affinity binding state (K_D). The saturation binding study, dealing with some of the areas described above in brains of male quails castrated or castrated and treated with testosterone or estradiol, demonstrated that the steroid replacement therapy was responsible for the changes of the B_max. Diminishing B_max values were displayed in the hypothalamic preoptic area and the hyperstriatum ventrale of the male quail treated with testosterone and estradiol while a reduced B_max was obtained in the anterior neostriatum of the quail treated with the former steroid. Our findings suggest that these steroids might control some centrally mediated behavior activities through effects on the maximum number of GABA_A binding sites in the male Japanese quail.     

GABA[A] receptor level changes in female hamster forebrain following in vivo estrogen progesterone and benzodiazepine treatment: a quantitative autoradiography analysis

Summary The levels of gamma amino butyric acid (GABA_A) receptors (i.e. ³H-Muscimol binding sites) were determined by quantitative neurotransmitter receptors autoradiography in ovariectomized (OVX), OVX-estradiolo (E), OVX-progesterone (P), OVX-E+P, diazepam (DZ) and DZ + Ro15-1788 treated female hamsters.The various hormonal treatments altered ³H muscimol binding in many brain areas, whereas DZ and DZ + Ro15-1788 had little influence on GABA_A receptor levels at the onset of the blocked aggressive behavioral activity. For example, E, P and E+P all significantly increased ³H muscimol binding in medial preoptic area, ventromedial hypothalamic nuclei, and vertical diagonal bandmedial septal nucleus, whereas P treatment increased binding in the caudate-putamen and decreased it in reuniens nucleus of the thalamus. E and E+P treatments increased ³H muscimol binding in the corticomedial amygdala nucleus and hippocampus. Diazepam treatment decreased the GABA_A receptor binding in the caudate-putamen and basolateral amygdala, while having no effect in the other brain regions where hormone treatment was effective. In vitro incubation of brain sections with micromolar concentrations of E or P did not change muscimol binding. These results suggest that ovarian steroids, and benzodiazepines to a lesser extent, modulate ³H muscimol binding but do so in different brain regions. The hormone effects on ³H muscimol binding in the critical reproductive centres at a time period that coincides with the onset of its behavioral effect is consistent with a genomic controlled activity.     

Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia

The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In a previous study we reported a decrease in the density of M1 and M2/M4 muscarinic receptors in the STG in schizophrenia. In this study, we investigated the density of GABA_A receptors in the left STG of schizophrenia patients compared to control subjects. We used quantitative autoradiography to investigate the binding of the agonist [³H] muscimol to GABA_A receptors in the STG. A significantly higher density of [³H] muscimol binding was observed in the upper three quarters of the STG grey matter (corresponding to layers I–IV) than in the lower one-quarter (layers V–VI) in both groups. A significant increase (about 30%, P<0.05) in binding of [³H] muscimol was clearly observed in schizophrenia patients compared to control subjects. There were no significant correlations between [³H] muscimol binding density and age, post-mortem interval, brain pH or final recorded antipsychotic drug use. These results suggest an increase of GABA_A receptor densities in the STG of schizophrenia patients.     

Reduction of GABAA receptor binding of [3H]muscimol in the barrel field of mice after peripheral denervation: transient and long-lasting effects

The effect of peripheral sensory deprivation upon GABA_A receptor binding of [³H]muscimol was investigated in the barrel cortex — cortical representation of mystacial vibrissae of mice — by means of in vitro quantitative autoradiography. Unilateral lesions of all vibrissae or selected rows of whiskers were performed neonatally or in adulthood. [³H]muscimol binding was examined after various survival times up to 60 days. Both types of lesions performed in adult mice resulted in a transient decrease (10–25%) of binding values in the deafferented areas of the barrel field as compared with the unoperated control side. Sixty days after denervation [³H]muscimol binding returned to control values. Similar results were found after neonatal removal of all vibrissae. Neonatal lesion of selected rows of vibrissae, however, resulted in a decrease of [³H]muscimol binding (by about 26%) lasting up to 60 days in corresponding rows of barrels. This last result was accompanied by severe cytoarchitectonic malformation of the barrel field. The results support the hypothesis that a decrease of inhibition plays a facilitatory role in the plastic reorganization of cortical circuitry.     

Sex differences in GABAA receptor binding in rat brain measured by an improved in vitro binding assay

Summary The distribution of GABA_A receptor sites was studied in female and male rat brain by an improved in vitro binding assay using ³H-muscimol and carefully washed membrane fractions. The binding studies revealed a single class of binding sites exhibiting the properties of GABA_A receptors. The specific binding of ³H-muscimol was measured in four brain areas: the preoptic brain area, mediobasal hypothalamus, corticomedial amygdala and cerebral cortex. The equilibrium dissociation constants (K _D) ranged from 11.2 to 23.3 nM in diestrous females and from 13.1 to 50.4 nM in males, the maximal number of binding sites (B _max) from 3290 to 10240 fmol/mg protein in females and from 5495 to 17449 fmol/mg protein in males. In the preoptic area and mediobasal hypothalamus both, K _D and B _max, were significantly higher in males than in females. The sex differences in the binding of muscimol observed in vitro indicated sexually dimorphic GABAergic neurotransmission that is probably related to the control of gonadotropin secretion and/or sexual behavior.Supported by the Deutsche Forschungsgemeinschaft grant Hi 399/1.     

Synaptic activity-induced Ca(2+) signaling in avian cochlear nucleus magnocellularis neurons

Neurons of the avian cochlear nucleus magnocellularis (NM) receive glutamatergic inputs from the spiral ganglion cells via the auditory nerve and feedback GABAergic inputs primarily from the superior olivary nucleus. We investigated regulation of Ca²⁺ signaling in NM neurons with ratiometric Ca²⁺ imaging in chicken brain slices. Application of exogenous glutamate or GABA increased the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in NM neurons. Interestingly, GABA-induced Ca²⁺ responses persisted into neuronal maturation, in both standard and energy substrate enriched artificial cerebrospinal fluid. More importantly, we found that electrical stimulation applied to the glutamatergic and GABAergic afferent fibers innervating the NM was able to elicit transient [Ca²⁺]_i increases in NM neurons, and the amplitude of the Ca²⁺ responses increased with increasing frequency and duration of the electrical stimulation. Antagonists for ionotropic glutamate receptors significantly blocked these [Ca²⁺]_i increases, whereas blocking GABA_A receptors did not affect the Ca²⁺ responses, suggesting that synaptically released glutamate but not GABA induced the Ca²⁺ signaling in vitro. Furthermore, activation of GABA_A receptors with exogenous agonists inhibited synaptic activity-induced [Ca²⁺]_i increases in NM neurons, suggesting a role of GABA_A receptors in the regulation of Ca²⁺ homeostasis in the avian cochlear nucleus neurons.     

γ-Hydroxybutyrate (GHB) induces GABAB receptor independent intracellular Ca transients in astrocytes,but has no effect on GHB or GABAB receptors of medium spiny neurons in the nucleus accumbens

We report on cellular actions of the illicit recreational drug γ-hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA_B receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA_B receptors, and the presence of GHB insensitive presynaptic GABA_B receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca²⁺ transients, preserved in slices from GABA_B receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca²⁺ with/without intracellular Ca²⁺ store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca²⁺ transients depend on external Ca²⁺ and intracellular Ca²⁺ stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca²⁺ transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA_B receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity.     

Direct and indirect effects of muscimol on medial vestibular nucleus neurones in guinea-pig brainstem slices

Inhibitory amino acids are considered as major transmitters in the vestibular system. Using intracellular recordings in slices, we applied gamma-aminobutyric acid (GABA) and muscimol (a specific agonist of the GABA_A receptor) to the two main types of medial vestibular nucleus neurones (A and B MVNn). In either a high Mg²⁺/low Ca²⁺ solution, or a solution containing tetrodotoxin, all MVNn were hyperpolarized by GABA and muscimol. This indicates that both types of MVNn are endowed with postsynaptic, hyperpolarising GABA_A receptors. In a normal medium, about half of A and B MVNn were, in contrast, depolarised by GABA and muscimol, whereas the remaining cells were hyperpolarised. These results could be due to a modulation by GABA and muscimol of a tonic GABA release in the slice. Such a release was, indeed, suggested by results showing the depolarising effect of either tetrodotoxin (TTX) or bicuculline, when applied alone. The cells that were depolarised by GABA or muscimol in control conditions were always hyperpolarised in the presence of TTX. Our data therefore suggest that GABA acting at GABA_A receptors in the medial vestibular nucleus can play a role either through a postsynaptic hyperpolarising action or indirectly by inhibiting a tonic GABA release, probably resulting from the spontaneous activity of local inhibitory interneurones. A GABAergic regulation of these interneurones could be important in processes of vestibular habituation and/or adaptation.     

Pharmacological and autoradiographic studies on the pathophysiological role of GABAB receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections

The GABA_B receptor (GABA_BR) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt^sz hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA_A receptor (GABA_AR) binding in several brain regions. In order to clarify the pathophysiological role of central GABA_BRs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA_BR agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt^sz hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 μg/0.5 μl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA_BR antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 μg/0.5 μl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt^sz hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt^sz hamsters. In view of the absence of striatal changes in GABA_B binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.     

Role for GABA agonists in the nucleus accumbens in regulating morphine self-administration

In the present study, functional roles of GABA receptors in the nucleus accumbens on morphine self-administration behavior were investigated. Male Sprague–Dawley rats were trained to press lever for morphine (0.1 mg/kg per infusion) during daily 1-h self-administration session. After establishing stable baseline responses, rats were given microinjections of the GABA_A receptor agonist muscimol (0, 250 and 500 ng/μl, bilateral) or the GABA_B receptor agonist baclofen (0, 100 and 250 ng/μl, bilateral) into the nucleus accumbens immediately before the morphine self-administration. Microinjection of muscimol (250 and 500 ng/μl) into the nucleus accumbens, but not baclofen, decreased morphine self-administration responses. These results suggest that activation of GABA_A receptors, but not GABA_B receptors, in the nucleus accumbens plays a critical role in modulating the reinforcing effects of morphine.     

Neurogenesis in the basal forebrain of the Chinese hamster (Cricetulus griseus). I. Time of neuron origin.

Summary The time of neuron origin has been determined in the basal ganglia and related basal forebrain structures of the Chinese hamster with the aid of ³H-thymidine autoradiography. Large-celled structures like the globus pallidus, nucleus of the horizontal limb of the diagonal band of Broca as well as large cells in the rostral part of the substantia innominata, in the caudate-putamen-complex and in the olfactory tubercle arise early (E₁₂–E₁₆), whereas medium-sized and small cells in the basal forebrain have a persistent origin over a much longer period. Neuron formation in the basal forebrain persists decrementally until P₄. A clear caudorostral spatiotemporal gradient as well as a distinct outside-in gradient have been observed in the caudate-putamen-complex. Medium-sized neurons in the neostriatum and in the nucleus accumbens, generated simultaneously, are usually arranged in scattered clusters. The present data on time of neuron origin strongly support other evidence which points to the conclusion that the nucleus accumbens can be considered as a ventromedial extension of the caudate-putamen-complex.     

Biochemical Parameters of Dopaminergic and GABAergic Neurotransmission in the CNS of Roman High-Avoidance and Roman Low-Avoidance Rats

The dopaminergic (DAergic) and GABAergic pathways in the central nervous system (CNS) are involved in the control of emotions, in the reactivity to stressful stimuli, and in the positive and negative reinforcing properties of psychotropic drugs. In the present review, we summarize the differences in a range of neurochemical markers of GABA- and DA-mediated neurotransmission in the CNS of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats, two psychogenetically selected lines that differ in what may be considered to be level of emotionality. The stimulatory effect of GABA on ³⁶Cl^– uptake was less pronounced in the cerebral cortex of RLA/Verh rats compared to RHA/Verh rats. In addition, the binding affinity of [³⁵S]TBPS, a selective ligand of the convulsant site located in the chloride channel of GABA_A receptors, was significantly lower in the hippocampus of RLA/Verh rats than in their high-avoidance counterparts. On the other hand, the density of D₁ DA receptors labeled with [³H]SCH 23390 was lower in the nucleus accumbens of RLA/Verh rats compared to RHA/Verh rats. Brain microdialysis studies demonstrated that tail-pinch stress and subconvulsant doses of the anxiogenic compound pentylenetetrazol increased the extracellular concentrations of DA in the prefrontal cortex of hypoemotive RHA/Verh rats but not in their hyperemotive RLA/Verh counterparts. These line-dependent differences in GABAergic and DAergic neurotransmission may contribute to the distinct emotionality and responsiveness to centrally active drugs of RHA/Verh and RLA/Verh rats.     

GABAA receptors in the mediodorsal thalamus play a crucial role in rat shell-specific acetylcholine-mediated,but not dopamine-mediated,turning behaviour

The role of GABA_A receptors in the mediodorsal thalamus (mdT) in turning behaviour of rats was studied. Neither the GABA_A receptor agonist muscimol (50 ng) nor the antagonist bicuculline (200 ng) unilaterally injected into the mdT elicited any behavioural change. Unilateral injection of the acetylcholine receptor agonist (carbachol, 5 μg) into the nucleus accumbens shell has been found to elicit contraversive circling while unilateral injection of a mixture of dopamine D₁ ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 μg) and D₂ (quinpirole, 10 μg) receptor agonists into the same site is known to elicit contraversive pivoting. The contraversive circling induced by unilateral injection of carbachol (5 μg) into the nucleus accumbens shell was dose-dependently inhibited by muscimol (25 and 50 ng) injected into the mdT. This inhibitory effect of muscimol (50 ng) was antagonised by co-administration of bicuculline (200 ng), which alone did not modify the contraversive circling induced by carbachol (5 μg). The contraversive pivoting induced by unilateral injection of a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) into the nucleus accumbens shell was inhibited by muscimol (25 and 50 ng) injected into the mdT, whereas bicuculline (200 ng) injected into the mdT did not significantly modify the pivoting. The inhibitory effect of muscimol (50 ng) on the pivoting induced by a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) was not dose-dependent and not antagonised by bicuculline (200 ng). The present study suggests that GABA_A receptors in the mdT play a limited role in spontaneously occurring locomotor activity. Secondly, this study demonstrates that GABA_A receptors in the mdT transmit accumbens-dependent cholinergic circling, but not accumbens-dependent dopaminergic pivoting, to other brain structures. Finally, the present study shows that muscimol-sensitive, non-GABA_A receptors in the mdT influence the accumbens-dependent dopaminergic pivoting. To what extent GABA_B receptors in the mdT mediate the muscimol-induced effects upon the dopaminergic pivoting behaviour requires additional research.     

Characterization of subtypes of gamma-aminobutyric acid receptors in an Ascaris muscle preparation by binding assay and binding of PF1022A,a new anthelmintic,on the receptors

 We examined the effect of PF1022A, one of the gabergic anthelmintics newly developed in Japan, on gamma-aminobutyric acid (GABA) receptors using a radioligand binding technique in isolated membrane preparations of the nematode Ascaris suum. Membrane protein was prepared from the homogenate of somatic muscle cells after ultracentrifugation. In addition to the basic binding of [2,3-³H-(N)]-GABA, the radioligand [methyl-³H]-bicuculline is used to identify the GABA_A receptor, whereas [butyl-4-³H]-baclofen is employed for GABA_B receptor sites. The dissociation constants (K _d values) and the maximal numbers of binding sites (B_max values) from Scatchard plotting for GABA receptors are close to those obtained in mammalian brain. PF1022A displaced in a concentration-dependent way the binding of [2,3-³H(N)]-GABA and [methyl-³H]-bicuculline as did other specific gabergic agents. In addition, PF1022A decreased the binding of [butyl-4-³H]-baclofen at a higher concentration, although this binding did not represent GABA_B sites. In a comparison of the inhibition constants (K_i values) of PF1022A with those of other agents, it is conclusive that PF1022A bound with GABA receptors. A direct effect of PF1022A on GABA receptors can thus be postulated. Received: 10 March 1995 / Accepted: 27 June 1995     

Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat

The central actions of oxytocin on reproduction-related functions and behaviors are strongly steroid-dependent and gender specific. This study characterizes sexual differences in the oxytocin binding site expression in forebrain and spinal cord of the rat. Using film autoradiography, we quantified the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, the medial and central nuclei of the amygdala, the medial bed nucleus of the stria terminalis and the spinal cord dorsal horns both in adult male and female rats, and during development. In addition, neonatal castrated males and intact neonatal females treated with a single injection of testosterone (1 mg) were examined. Data showed a sexual dimorphism in the expression of oxytocin binding sites in the spinal cord dorsal horns and in restricted areas of the forebrain that are sensitive to gonadal steroids such as the ventromedial hypothalamic nucleus, but not in gonadal steroid insensitive sites such as the central nucleus of the amygdala. Adult males had higher oxytocin binding site densities in the ventromedial hypothalamic nucleus and dorsal horns than females. In the forebrain, but not in the dorsal horn, this sexual difference required a perinatal exposure to testosterone. Neonatal castration only abolished the sexual difference in the ventromedial hypothalamic nucleus of adults, but not in the dorsal horn. Furthermore, females that received a single injection of testosterone 1 day after birth showed significant increases in the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, medial nucleus of the amygdala and medial bed nucleus of the stria terminalis. In addition, the findings suggest that the sexual difference in the ventromedial hypothalamic nucleus also requires gonadal hormones in adulthood. Our data support the hypothesis that sexually dimorphic oxytocin binding sites may contribute to the regulatory central actions of oxytocin in gender specific functions and behaviors such as nociception and reproduction.     

Human locus coeruleus neurons express the GABAA receptor γ2 subunit gene and produce benzodiazepine binding

Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for γ-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA_A receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The γ2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABA_A receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the γ2 subunit's expression and participation in the functional GABA_A receptors in the mammalian locus coeruleus. We report here that the γ2 subunit is transcribed and participates in the assembly of functional GABA_A receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific γ2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [³H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the α1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the α1 and γ2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects.     

Sequential changes of [3H]forskolin, [3H]cyclohexyladenosine and [3H]PN200‐110 binding sites in the brain of 6‐hydroxydopamine‐lesioned rats

Receptor autoradiographic technique was studied to investigate sequential changes in adenylyl cyclase, adenosine A₁ receptors and L ‐type calcium channels in the striatum and substantia nigra 1–8 weeks after unilateral 6‐hydroxydopamine injection of the medial forebrain bundle in rats. [³H]Forskolin, [³H]cyclohexyladenosine (CHA) and [³H]PN200‐110 were used to label adenylyl cyclase, adenosine A₁ receptors and L ‐type calcium channels, respectively. The degeneration of the nigrostriatal pathway caused a significant increase in [³H]forskolin binding in the striatum of both the ipsilateral and contralateral sides from 2 to 4 weeks post‐lesion. The ipsilateral substantia nigra showed a transient increase in [³H]forskolin binding 4 weeks post‐lesion. In contrast, [³H]CHA binding showed no significant change in most brain areas after lesioning. On the other hand, a conspicuous decrease in [³H]PN200‐110 binding was observed in the dorsolateral striatum of ipsilateral side 4 weeks post‐lesion. Thereafter, the striatum of both the ipsilateral and contralateral sides showed a significant decrease in [³H]PN200‐110 binding 8 weeks post‐lesion. These results demonstrate that unilateral 6‐hydroxydopamine into the medial forebrain bundle of rats can experimentally cause a significant increase in adenylyl cyclase binding sites in the striatum and substantia nigra, whereas no conspicuous change in adenosine A₁ receptors is observed in these areas during post‐lesion. In contrast, L ‐type calcium channels were progressively damaged in the striatum after unilateral 6‐hydroxydopamine treatment. These findings suggest that adenylyl cyclase and calcium system may contribute to the degeneration processes of the dopaminergic neurones.     

Age-related GABAA receptor changes in rat auditory cortex

Auditory cortex (AI) shows age-related decreases in pre-synaptic markers for gamma-aminobutyric acid (GABA) and degraded AI neuronal response properties. Previous studies find age-related increases in spontaneous and driven activity, decreased spectral and directional sensitivity, and impaired novelty detection. The present study examined expression of GABA_A receptor (GABA_AR) subunit message, protein, and quantitative GABA_AR binding in young, middle-aged, and aged rat AI, with comparisons with adjoining parietal cortex. Significant loss of GABA_AR α₁ subunit message across AI layers was observed in middle-aged and aged rats and α₁ subunit protein levels declined in layers II and III. Age-related increases in GABA_AR α₃ subunit message and protein levels were observed in certain AI layers. GABA_AR subunits, including β₁, β₂, γ₁, γ_2s, and γ_2L, primarily, but not exclusively, showed age-related declines at the message and protein levels. The ability of GABA to modulate [³H]t-butylbicycloorthobenzoate binding in the chloride channel showed age-related decreases in peak binding and changes in desensitization kinetics. Collectively, age-related changes in GABA_AR subunit composition would alter the magnitude and temporal properties of inhibitory synaptic transmission and could underpin observed age-related functional changes seen in the elderly.     

Effects of age and visual experience on [3H] MK801 binding to NMDA receptors in the kitten visual cortex

Summary We have investigated the postnatal development of N-methyl-D-aspartate (NMDA) receptors in kitten neocortex by measuring the density of [³H] MK801 binding sites. NMDA receptor density in area 17 markedly increases between postnatal day 7 and 35, and then remains at a high level into adulthood. Similar temporal changes were observed in area 6. A brief period of binocular deprivation did not alter the density of [³H] MK801 binding sites in either brain region. However, dark rearing kittens from birth resulted in a significant decrease after 35 and 120 days in both area 17 and area 6. These results demonstrate that the density of NMDA receptors does not effectively predict the capacity for visual cortical plasticity in kitten neocortex. In addition, these results show that dark rearing produces significant effects in areas of the kitten neocortex not normally associated with visual function.     

Effect of bilateral destruction of the subretrofacial area on receptor mechanisms of neuroprotective effect of GABAergic agents

Both GBA_A (muscimol, gaboxadol, and isonipecotate) and GABA_B (baclofen) receptor agonists produce marked neuroprotective effect during total brain ischemia. The antagonists of GABA_A receptors bicuculline and picrotoxin attenuate the effect of muscimol, and the GABA_B receptor antagonists hydroxysaclofen and aminovaleriate decrease the effect of baclofen. The GABAergic substances protect the brain via GABA receptors of both types. The effect of the GABA agonists is central in nature. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 2, pp. 162–164, February, 1998.