Ana Hitri

GABA-active steroids : endogenous modulators of GABA-gated chloride ion conductance

Naturally occurring 3-alpha-hydroxy ring A-reduced metabolites of progesterone and deoxycorticosterone and their synthetic analogues bind to specific sites within the hydrophobic channel domain of the GABAA receptor complex. Acting at these sites, these ligands function as positive allosteric effectors of the complex; they potentiate GABA-stimulated membrane chloride ion conductance, enhance the binding of [3H]muscimol and [3H]flunitrazepam, and displace the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), a channel ligand that is a specific marker of the GABA-associated chloride ionophore. Moreover, steroid metabolites (namely pregnenolone sulfate and dehydroepiandrosterone sulfate) have been identified that display properties of GABA-negative allosteric effectors. The identification of this membrane-associated steroid binding should stimulate development of new classes of anxiolytic, sedative-hypnotic, anticonvulsant, anesthetic, and muscle-relaxant medications that may be devoid of many of the side effects associated with benzodiazepines and barbiturates. Also, elucidation of the physiologic role of this binding site should contribute both to our understanding of endogenous mechanisms for modulating inhibitory neurotransmission, and the pathophysiologic role of the GABAA receptor complex in a variety of neuropsychiatric disorders.

Regional differences in rat brain dopamine transporter binding: function of time after chronic cocaine.

Summary: Chronic administration of cocaine to rats has been shown to produce a persistent decrease in dopamine (DA) and its metabolites in the brain and periphery. To further explore the alterations in the DA system following repeated administration of cocaine, we studied the regional differences in DA transporter binding as a function of time after the last injection of cocaine. Two groups of rats were treated with cocaine (10 mg/kg twice a day) or saline for 7 days. Rats were sacrificed 1, 2, 3, 6, and 12 weeks after the last injection. The corpus striatum and the frontal cortex were dissected and assayed with [3H]GBR 12935 for DA transporter binding. Time-related differences were observed in the frontal cortex but not in the striatum of the saline-treated control rats. Cocaine treatment prevented the time-dependent increase in Bmax over the course of 6 weeks, but not over the course of 12 weeks following withdrawal. Although there was no difference between the cocaine- and saline-treated group in the striatum at any of the time points, cocaine in the frontal cortex produced a 33% reduction in Bmax during weeks 2 and 3 and a 57% reduction in Bmax at week 6 of withdrawal; the reduction persisted for ± 12 weeks. The KD was not affected by cocaine or time in either brain region. These findings may be functionally related to cocaine craving because the DA transporter has been identified as the neuronal structure and the medial pre-frontal cortex as the anatomical site mediating cocaine reinforcement.

Concurrent treatment with benztropine and haloperidol attenuates development of behavioral hypersensitivity but not dopamine receptor proliferation

Groups of male rats (n = 16 each) were treated with normal saline, haloperidol (0.75 mg/kg), benztropine (1.8 mg/kg) or haloperidol and benztropine once a day for 24 days. Following a 96 hour drug free interval, subsets of these animals were assessed for apomorphine-induced (0.75 mg/kg) stereotypic behavior, sacrificed and analyzed for striatal dopamine biochemistry or sacrificed and analyzed for spiroperidol binding sites. Benztropine cotreatment attenuated the development of behavioral hypersensitivity to haloperidol but did not alter either the dopamine receptor proliferation or the striatal dopamine biochemical changes induced by haloperidol. These results suggest that behavioral hypersensitivity is not an automatic manifestation of dopamine receptor proliferation but must depend, in part, on other factors.

Alterations in brain monoamines and GABAA receptors in transgenic mice overexpressing TGFα

This study investigated the possibility that overexpression of transforming growth factor alpha (TGF alpha) changes those neurotransmitter systems that have been associated with behaviors found to be altered in the transgenic TGF alpha CD-1 mice. The female TGF alpha mice showed elevated levels of norepinephrine (NE) in the hypothalamus and serotonin (5-HT) in the cortex and brain stem when compared with nontransgenic CD-1 females. The concentrations of monoamines were not altered in the male transgenic brain. The 5-hydroxyindoleacitic acid (5-HIAA)/5-HT ratio was significantly reduced in the brain stem of the male TGF alpha mice and frontal cortex in the female transgenics. The binding of the [3H]GBR 12935-labeled DA transporter was lower in the frontal cortex in the transgenic male TGF alpha mice than in the female TGF alpha mice. No gender difference in dopamine (DA) transporter binding was noted between the nontransgenic male and female mice. Serotonin and GABAA receptors were measured only in males. No differences in the number of 5-HT1A and 5-HT2 receptors were found in the cortex or hippocampus. Maximal GABA stimulation of [3H]flunitrazepam binding in the forebrain hemispheres and cerebellar binding of an imidazobenzodiazepine, [3H]Ro 15-4513, were not different between transgenic and nontransgenic male mice. However, forebrain [35S]TBPS binding in male TGF alpha mice was less affected by the blockade of the GABA agonist sites by the specific GABAA antagonists SR 95531 and bicuculline than the binding of the controls, suggesting either altered endogenous GABA concentrations or a change in receptor populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug levels and antiparkinsonian drugs in neuroleptic-treated schizophrenic patients

The limitations of antiparkinsonian treatment strategy when using anticholinergic drugs are determined by their side effects induced through excessive inhibition of parasympathetic functions. In the present study we have investigated the peripheral effects of antiparkinsonian agents on blood levels of concomitantly administered neuroleptic drugs. We have compared the anticholinergic and a dopamine mimetic antiparkinsonian agent in their effects on serum neuroleptic activity (SNA) and serum anticholinergic activity (SAA). Sixteen schizophrenic patients on chronic neuroleptic therapy with steady state neuroleptic levels were receiving either amantadine, 200 mg/day, or anticholinergic drugs (trihexyphenidyl, 10 mg/day, or benztropine, 6 mg/day) for the first 2 weeks, after which the amantadine group was crossed over to anticholinergic and the anticholinergic group to amantadine for the following 2 weeks. Blood samples were obtained once a week along with clinical testing. The results indicate that SAA was fivefold higher with benztropine than with trihexyphenidyl and that amantadine had no effect on SAA. Moreover, SNA was not altered either by anticholinergics or amantadine coadministration, indicating that the therapeutic blood neuroleptic levels are not compromised by antiparkinsonian administration.

THE TIME COURSE OF HALOPERIDOL-INDUCED DOPAMINE RECEPTOR SITE SUPERSENSITIVITY IN GUINEA PIGS

We have studied the time course of haloperidol-induced alterations in striatal DA receptor site characteristics in guinea pigs. After 3 weeks of haloperidol treatment, behavioral supersensitivity for apomorphine stereotypy developed, and striatal DA receptor site and concentration increased. Supersensitivity of DA receptors persisted at 3 weeks post-treatment, behavioral and binding assays reavealed a return to control values. These findings suggest that haloperidol-induced supersensitivity of DA receptor sites can be reversible.

Evidence for the Existence of Two Striatal Dopamine Receptors

Striatal dopaminergic mechanisms have been implicated in two separate human neurologic syndromes. The first of these is parkinsonism; a syndrome consisting of rigidity, akinesia, resting tremor and loss of postural reflexes which is felt to be related to decreased activity of dopamine (DA) at striatal DA receptors (Hornykiewicz, 1966; Klawans, 1973). The second is chorea which is felt to reflect increased dopaminergic activity at at least some striatal DA receptors (Klawans, 1971; Klawans, 1973).

NATURE OF DOPAMINE RECEPTORS IN THE STRIATUM AND NUCLEUS ACCUMBENS

Both clinical and preclinical studies have suggested that there nay be regional differences in the characteristics of DA receptors. Results obtained from binding studies of tritated dopamine (DA) to guinea pig striatal and nucleus accumbens (NA) membranes, indicate the existence of two types of DA receptors in the striatum and accumbens of mature animals but only a single receptor in younger animals. The high and low affinity striatal and nucleus accumben binding sites appear to have a different ontological order of appearance.