Biomedical subjects

J Peris

Publications and source records attributed to J Peris.

At least 19 recordsLinked to original sources

PubMed1996

Repeated cocaine injections decrease the function of striatal gamma-aminobutyric acid(A) receptors.

Although behavioral sensitization to cocaine is commonly thought to involve increased dopamine (DA) neurotransmission in nigrostriatal and mesolimbic pathways, it is possible that alterations in the characteristics of other neurotransmitters, such as gamma-aminobutyric acid (GABA), contribute to cocaine-induced behavioral changes. The function of GABA(A) receptors to transport chloride was assessed in striatum and other brain regions of male rats that had received daily injections of cocaine (15 mg/kg i.p.) or saline for 5 to 14 days. GABA-stimulated 36Cl uptake in striatal microsacs was decreased significantly in animals receiving cocaine treatments sufficient to cause behavioral sensitization, and the magnitude of this decrease paralleled the magnitude of cocaine sensitization. There was no effect of cocaine treatment on GABA-stimulated uptake in cortex or substantia nigra nor was basal uptake affected by cocaine exposure in any of three regions. Muscimol-stimulated uptake was similarly decreased in striatal microsacs from female rats exposed to daily cocaine (10 mg/kg i.p.) injections for 14 days. This decrease in receptor function was not due to a direct effect of cocaine on GABA(A) receptors because neither in vitro nor in vivo acute cocaine exposure affected uptake in any way. Thus, GABA(A) receptor function in striatum may be selectively decreased by cocaine treatment which may contribute to changes in behavioral sensitization caused by cocaine.

Analysis of Variance↗

PubMed1994

Chronic ethanol exposure enhances [3H]GABA release and does not affect GABAA receptor mediated 36Cl uptake.

Chronic ethanol treatment (CET) produces a permanent reduction in hippocampal long-term potentiation (LTP). The CET produced reduction of LTP can be eliminated acutely by pharmacological blockade of gamma-aminobutyric acid (GABA)ergicA synaptic transmission with the specific antagonist, bicuculline methiodide. Since LTP induction is normally modulated by activation of GABAergic synaptic transmission, we hypothesized that CET reduced LTP by enhancing either postsynaptic GABAA channel function or GABA release from presynaptic terminals. In the present study, we examined the long term effects of CET on GABAA channel function by measuring the efficacy of GABA to stimulate and bicuculline to antagonize GABA-stimulated 36Cl- uptake in hippocampal and cortical membrane preparations. CET did not affect basal uptake of chloride or the efficacy of either GABA or bicuculline at the GABAA channel. We next measured the long term effects of CET on basal and stimulated GABA release. When basal and electrically-stimulated [3H]GABA release were measured in superfused hippocampal slices, stimulated release was increased by 30% in CET rats. Basal release was unaffected. Thus it appears that CET may be reducing LTP by enhancing plasticity-related GABA release from presynaptic terminals.

Animals↗

PubMed1993

Behavioral and neurochemical changes caused by repeated ethanol and cocaine administration.

Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behavioral and neurochemical interactions of these two substances is limited. Four groups of male rats received either daily cocaine (10 mg/kg, IP) or saline injections with either water (groups C and S) or only 15% ethanol to drink (groups CE and E). Initially, locomotor activity was increased equally by ethanol or cocaine and to the greatest extent by both. After 2 weeks of drug treatment, group C exhibited behavioral sensitization to cocaine, group E exhibited ethanol tolerance and group CE exhibited greater cocaine sensitization with no indication of ethanol tolerance. In support of enhanced sensitization to cocaine, amphetamine-stimulated 3H-dopamine (DA) release in striatum and D2 DA receptor binding in the nucleus accumbens (NAC) were increased in group CE compared to group C. In support of a loss of ethanol tolerance, increases in striatal D2 DA and 35S-TBPS binding seen in group E (which exhibited ethanol tolerance) were absent in group CE (which did not exhibit tolerance). Thus, the synergistic effect of ethanol and cocaine on behavior may be due to complex interactions of these two drugs both on DA and GABA transmission in mesolimbic and nigrostriatal areas.

Animals↗

PubMed1993

Antagonist inhibition of GABAA-mediated chloride uptake is atypical in nigrocollicular areas.

Marked regional differences in the mRNA levels for the different subunits of the GABAA receptor may result in functional differences throughout the brain. The effects of different GABAA agonists and antagonists on GABAA receptor function was measured using 36Cl- uptake in microsacs made from cerebellum (CB), superior colliculus (SC), substantia nigra (SN), inferior colliculus (IC) or cortex (CT) containing equal amounts of protein. GABA increased Cl- uptake in all regions in a dose-dependent and saturable manner but with markedly different efficacies across brain regions. Maximal GABA-stimulated uptake was 59 +/- 2 nmoles of Cl- per mg protein in CT, 25 +/- 5 in SC, 24 +/- 4 in CB, 16 +/- 1 in IC and 6.7 +/- 1.4 in SN. Muscimol increased Cl- uptake with greater potency than GABA but with similar efficacies in CT, CB, SC and SN; the efficacy of muscimol in IC was increased to 27.4 +/- 5. Picrotoxin inhibited maximal GABA-stimulated Cl- uptake in CB, SC and CT but did not decrease uptake in IC or SN. Bicuculline methiodide completely inhibited uptake in CB and CT, partially inhibited uptake in IC, and did not affect uptake in SC and SN. These data provide functional support for regional heterogeneity of the GABAA receptor/Cl- ionophore between nigrocollicular regions and CB and CT.

Animals↗

PubMed1993

FG7142 causes opposite changes in [3H]GABA release from nigrocollicular regions.

The activity of GABAergic neurons projecting from the striatum to the substantia nigra (SN) and from the SN to the superior colliculus (SC) may be involved in regulating seizure sensitivity such that striatonigral transmission is decreased and nigrocollicular transmission is increased in proconvulsant states. To test whether these changes occur in FG7142-treated rats, GABA transmission was assessed by measuring [3H]GABA release from superfused slices of the SN and SC and measuring [35S]TBPS binding to GABAA receptors throughout the brain. Nine daily injections of FG7142 (30 mg/kg IP) greatly increased myoclonic seizures in about one half of the animals. These animals exhibited a decrease in stimulated [3H]GABA release from the SN and an increase in both basal and stimulated release from the SC. Animals that were less sensitive to FG7142 treatment also had increased collicular release but not decreased nigral release. [35S]TBPS binding was unchanged by FG7142 treatment. Thus, decreased nigral GABA release may contribute to decreased striatonigral transmission after seizure occurrence whereas increased collicular GABA release may contribute to increased nigrocollicular transmission preceding multiple-seizure occurrence.

Animals↗

PubMed1992

Cocaine in utero enhances the behavioral response to cocaine in adult rats.

The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmission in the nigrostriatal and mesolimbic pathways were measured in adult rats. Pregnant rats received either saline or cocaine (1 or 3 mg/kg, IV) daily throughout gestation. When offspring were 3 months of age, locomotor and stereotypic behaviors were rated after an injection of either saline or cocaine (10 mg/kg, IP). Cocaine in utero increased the response to cocaine in adult offspring and increased basal locomotion in female offspring. Cocaine in utero increased amphetamine-stimulated release in female offspring but decreased release in males. On the other hand, male rats that had received cocaine in utero exhibited greater basal tritium release. One injection of cocaine increased amphetamine-stimulated [3H]DA release from striatal slices of male rats but not female rats. Neither cocaine in utero nor in vivo affected D2 DA receptor binding in striatum nor nucleus accumbens. Thus, cocaine in utero behaviorally sensitized animals to subsequent cocaine exposure and increased [3H]DA release from nigrostriatal endings, but the relationship of these two variables depended upon gender.

Animals↗

PubMed1992

Selective changes in GABAergic transmission in substantia nigra and superior colliculus caused by ethanol and ethanol withdrawal.

One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal from chronic ethanol exposure increases convulsant activity. An increase in neuronal transmission in the GABAergic pathways from striatum to the substantia nigra (SN) and a decrease in GABAergic transmission from SN to superior colliculus (SC) both appear to play a major role in inhibiting seizure propagation. If this is the case, then the changes in seizure sensitivity caused by ethanol may be expected to affect GABAergic transmission in opposite ways in SN and SC. We measured the effects of in vitro ethanol on pre- and postsynaptic indices of GABA transmission using SN and SC tissue from both ethanol-naive rats and rats given ethanol in their drinking water for 24 days and then withdrawn for 24 hr, a treatment that decreases seizure latency. While ethanol inhibited 3H-GABA release from slices of SC at low concentrations (20-100 nM), much higher concentrations were required to inhibit release from SN (100-500 mM). In fact, release from SN was increased by low concentrations of ethanol. Ethanol in vitro (20-1000 mM) also inhibited specific binding of 35S-TBPS to the GABAA receptor but this effect was similar in both potency and efficacy in SC and SN. Next, the in vitro effects of ethanol were measured in rats that had consumed an average of 9.8 g ethanol/kg body weight/day and were then withdrawn for 24 hr. Ethanol inhibition of 3H-GABA release from SC was significantly less in ethanol-treated rats compared to controls whereas the inhibitory effect of ethanol was increased in SN from ethanol-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Withdrawal Delirium↗

PubMed1991

Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release.

Locomotor activity and stereotypy induced by cocaine is increased or 'sensitized' after repeated cocaine administration. This behavioral sensitization may be mediated by a persistent increase in dopamine (DA) transmission in mesolimbic and nigrostriatal pathways. Since the female estrous cycle and ovarian steroid hormones appear to affect both cocaine sensitization and DA transmission, studies were undertaken to determine the effects of ovarian steroids on sensitization of the behavioral responses to repeated cocaine injections and any concomitant effects on striatal DA release. Young female adult rats were ovariectomized and 2 weeks later were implanted with chronic release forms of estradiol (E), progesterone (P), both (EP) or vehicle (V). Locomotor and stereotypic behavior were rated after an initial injection of either saline or cocaine (10 mg/kg, i.p.) and after the 8th daily injection of saline or cocaine. A significant increase in both locomotor and stereotypic behaviors was seen after the first cocaine injection relative to saline-injected animals and this response was not affected by steroid treatment. Repeated injections of cocaine caused sensitization of the initial behavioral response to cocaine (i.e. an increase in stereotypic and locomotor behavior) and the degree of cocaine sensitization was greatest in group E. Steroid treatment did not affect behavior in saline-treated rats. When striatal [3H]DA release was measured in vitro 1 or 7 days after the last injection, amphetamine-stimulated release was greater in vehicle-treated rats 7 days after cocaine injections but not 1 day after injections. In contrast, release was enhanced in group E both 1 and 7 days after cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed1991

Regulation of 35S-TBPS binding by bicuculline is region specific in rat brain.

The allosteric regulation of specific 35S-TBPS binding to the convulsant site on the GABAA receptor/chloride (Cl-) ionophore complex was studied in various brain regions in an attempt to characterize regional heterogeneity of the protein subunits forming the complex. Bicuculline methiodide (BIC), a GABAA antagonist, enhanced binding in cortex (CTX), substantia nigra (SN) and cerebellum (CBL), inhibited binding in inferior colliculus (IC) and did not affect binding in superior colliculus (SC). Similar results were found in CBL and IC using SR-95531, another GABAA antagonist. The levels of endogenous GABA in the different tissue samples could not account for the regional differences in binding. When the functional regulation of these receptors was measured using 36Cl- uptake in microsomes, muscimol-stimulated uptake was completely blocked by BIC in CBL and IC but was not affected by BIC in SC. Additionally, picrotoxin completely blocked muscimol-stimulated uptake in CBL but had no effect in IC or SC. These findings provide a functional basis for regional heterogeneity of GABAA receptor.

Animals↗

PubMed1990

Persistence of neurochemical changes in dopamine systems after repeated cocaine administration.

The purpose of this study was to test whether persistent changes consistent with behavioral sensitization occur in dopamine (DA) uptake, release or receptors following repeated cocaine administration. Our neurochemical experiments focused primarily on the striatum; however, quantitative autoradiography was used to measure D-1 and D-2 DA receptors in both cell body and terminal regions of the nigrostriatal and mesolimbic dopaminergic pathways. After receiving eight once-daily injections of cocaine (10 mg/kg, i.p.), rats remained behaviorally sensitized for 1 week. This repeated treatment with cocaine induced two changes consistent with increased dopaminergic transmission. Postsynaptic D-2 DA receptors were selectively increased in nucleus accumbens one day after termination of the repeated cocaine administration; however, these receptors returned to control levels one week after cocaine administration had been terminated. In contrast, amphetamine-stimulated [3H] DA release from striatal slices was increased in rats receiving repeated cocaine injections, but this increase was not apparent until 1 week after the drug administration had been terminated. While neither of these two changes is sufficient to explain cocaine-induced behavioral sensitization, both are consistent with increased dopaminergic responsiveness and may contribute to sensitization.

Amphetamine↗

PubMed1989

[35S]TBPS binding sites are decreased in the colliculi of mice with a genetic predisposition to bicuculline-induced seizures.

Several differences have been found in GABAergic function between the long sleep (LS) and short sleep (SS) mice which were genetically selected for different ethanol-induced sleeptimes, and it has been suggested that these differences may explain their differential ethanol sensitivity. However, these lines also differ in seizure susceptibility, a behavior which may also be mediated by GABAergic pathways. Thus, it is difficult to associate differences in GABA neurochemistry with either of these behaviors, particularly when only two selected lines are used. We measured differences in the density and affinity of the [35S]TBPS binding site on the GABAA receptor/Cl- ionophore complex in discrete brain areas; and in order to determine the relationship between receptor binding and behavioral differences, we included mice from 5 of the LS and SS recombinant inbred strains (LS x SS RI) in addition to mice from the LS and SS lines. [35S]TBPS binding in sagittal brain sections was analyzed by quantitative autoradiography, and the amount of binding differed depending on whether bicuculline was added to inhibit endogenous GABA binding. In the presence of bicuculline, the number of [35S]TBPS sites in SS mice was highest in the colliculi (4.5 +/- 0.5 pmol/mg protein), cerebellum (4.8 +/- 0.6 pmol/mg), hippocampus (3.2 +/- 0.7 pmol/mg) and cortex (2.9 +/- 0.3 pmol/mg). The Bmax was two-fold lower in both superior and inferior colliculi (IC) of LS mice. There were no differences between lines in Bmax in any other area and in Kd values in any area (58 +/- 4.0 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Chemical kindling decreases GABA-activated chloride channels of mouse brain.

The repeated administration of N-methyl-beta-carboline-3-carboxamide (FG 7142) to mice leads to 'chemical kindling', i.e. the development of seizures in response to doses which were initially insufficient to produce convulsive activity. To determine if chemical kindling produced changes in the GABAA receptor/chloride channel complex, we measured the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of the complex by quantitative autoradiography. As a measure of chloride channel function, we studied muscimol-stimulated uptake of 36Cl- by isolated brain synaptosomes. Kindling decreased the Bmax of [35S]TBPS binding in cortex but not in cerebellum or hippocampus. Kindling did not alter binding affinities in any of these brain regions. Some mice injected with FG 7142 did not kindle despite receiving the same treatment as kindled mice. These 'injected but not kindled' mice did not display decreased receptor binding in any of these brain areas. Muscimol-stimulated 36Cl- uptake into cortical synaptosomes was also diminished by chemical kindling. These findings suggest that a decrease in functioning GABA-regulated chloride channels may be responsible for chemical kindling with FG 7142.

Animals↗

PubMed1989

Persistent augmented dopamine release after acute cocaine requires dopamine receptor activation.

Pretreatment of rats with a single injection of cocaine produces a persistent augmentation of amphetamine-induced [3H]dopamine [( 3H]DA) release measured using the in vitro striatal slice preparation. Cocaine has several actions in the nigrostriatal DA system: it blocks DA uptake and thereby indirectly stimulates DA receptors and it also acts as a local anesthetic. We investigated which of these actions is responsible for the augmented amphetamine-stimulated [3H]DA release by determining whether pretreatment with drugs sharing one or more of these actions also augmented release. Release was increased in striatal slices one week after a single injection of either mazindol, a DA uptake blocker and indirect DA receptor agonist, or apomorphine, a direct-acting receptor agonist, whereas the local anesthetic lidocaine had no effect. The prerequisite of DA receptor stimulation was confirmed by pretreatment prior to the cocaine injection with either a nonselective, a D-1 selective or a D-2 selective DA receptor antagonist. Each of these blocked the long-lasting augmentation of release. From these experiments, we conclude that cocaine indirectly activates both D-1 and D-2 DA receptors to produce the persistent augmentation of striatal amphetamine-stimulated [3H]DA release.

Animals↗

PubMed1989

Diazepam sensitizes mice to FG 7142 and reduces muscimol-stimulated 36Cl- flux.

Chronic treatment with benzodiazepine receptor agonists increases sensitivity to the convulsant action of FG 7142, an inverse agonist. We investigated whether or not changes in the number and function of GABA-gated chloride channels accompanies this increased sensitivity. Diazepam, 5 mg.kg-1, was administered to mice daily for five days, and mice were then tested with a single injection of FG 7142, 40 mg.kg-1, at several intervals thereafter. At 24 hours after the last diazepam dose, 10 of 15 mice had clonic seizures following FG 7142 and four of the remaining five had myoclonic jerks. At 48 hours, only one of six mice developed a clonic seizure, and none were observed in mice tested at 96 or 144 hours. Muscimol-stimulated chloride flux was reduced in cortical synaptosomes from diazepam-treated mice at 24 hours but not at 48 or 96 hours. However, the binding of [35S]TBPS, a ligand closely associated with the chloride channel, was unchanged at 24 hours. These results suggest that a transient diminution in GABA-gated chloride channel function; unaccompanied by a reduction in channel number, may underlie the sensitization to the convulsant action of FG 7142 observed after withdrawal from chronic diazepam treatment.

Animals↗

PubMed1988

Biphasic modulation of evoked [3H]D-aspartate release by D-2 dopamine receptors in rat striatal slices.

It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D-2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D-2 receptor ligands on K+-stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [3H]D-aspartate ([3H]ASP was measured. The D-2 receptor antagonist S-sulpiride increased stimulated [3H]ASP release by 75% (EC50 value = 240 nM) and the biologically less-active isomer R-sulpiride, although equally effective, was tenfold less potent. The D-2 receptor agonists pergolide and (+)-4-propyl-9-hydroxynapthoxazine (+PHNO) inhibited [3H]ASP release at nM concentrations; however, this effect was small (20%). This low efficacy of the exogenous agonists was apparently due to competition by high concentrations of endogenous DA since the effect of pergolide was increased in rats whose striatal DA levels were decreased by 97%. These data support the hypothesis that D-2 DA receptors modulate [3H]ASP release in an inhibitory fashion. However, when the agonists were tested at lower concentrations, [3H]ASP release was increased significantly by 20% in control rats and 60% in DA-depleted rats. Both the facilitory and inhibitory effects of pergolide were blocked by 10 microM S-sulpiride, suggesting D-2 receptor mediation. In addition, the facilitory effect of pergolide was blocked by tetrodotoxin (TTX) and by the GABAA antagonist bicuculline, implying mediation of this D-2 effect by an inhibitory GABAergic interneuron. The inhibitory effect of pergolide was decreased by the muscarinic antagonist atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide.

Groups of rats administered cocaine-HC1 (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with [3H]DA, modulation of [3H]-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in [3H]spiperone binding assays.

Animals↗

PubMed1988

Sensitization to cocaine in the nigrostriatal dopamine system.

Behavioral sensitization involving the nigrostriatal dopaminergic tract is manifested after treatment with only a single dose of cocaine and is augmented following repeated treatment. One neurochemical change observed that is consistent with behavioral sensitization is the increase in amphetamine-induced 3H-DA release from striatal slices seen after one injection of cocaine. One day after repeated administration of cocaine, however, the increase is no longer evident. It is possible that transient compensatory changes, such as increased D-2 autoreceptor inhibition, may obscure this effect when it is measured at relatively short times after the repeated administration has been terminated. One day after cessation of repeated cocaine administration, D-2 autoreceptors in both striatum and substantia nigra compacta were upregulated consistent with a compensatory mechanism and the development of behavioral tolerance rather than sensitization. In contrast, DA content, neuronal DA uptake, and postsynaptic D-2 DA receptors in striatum were not regulated by this treatment. Likewise, D-1 DA receptors in striatum and substantia nigra were unaffected. In the mesolimbic system, both the pre- and postsynaptic receptor changes are consistent with sensitization. Amphetamine-stimulated release from nucleus accumbens has not yet been measured in cocaine-sensitized animals. It is possible that changes similar to those seen in striatum may occur in this area. It is interesting that, in general, presynaptic parameters associated with the DA neuron, with the notable exception of the uptake pump, appear to be more sensitive to regulation by cocaine administration than do postsynaptic parameters. The long-lasting effects of a single moderate dose of cocaine are also surprising. It will be important to determine the molecular mechanisms underlying this regulation and whether or not similar changes are induced in mesolimbic dopaminergic systems by single and repeated administration of cocaine.

Animals↗

PubMed1987

Modulation of gamma-[3H]aminobutyric acid release from rat cortical slices by alpha 2-adrenoceptors.

Modulation of gamma-aminobutyric acid (GABA) release by alpha 2-adrenoceptor agonists has not been consistently demonstrated. This could be due to high levels of norepinephrine (NE) concomitantly evoked by stimulation parameters needed for GABA release. In the present experiments, NE release was preferentially decreased by omission of calcium (Ca2+) and alpha 2-modulation of [3H]GABA release from cortical slices was measured. The antagonist rauwolscine increased only Ca2+-dependent [3H]GABA release, while the agonists guanabenz and clonidine inhibited only Ca2+-independent GABA release. These results suggest that release of endogenous NE diminished the effect of alpha 2-agonists but reveals the effect of antagonists and support the hypothesis that endogenous NE inhibits GABA release in cortex.

Animals↗