Gamma-butyrolactone Research Articles

Potentiation by TRH of the effect of antidepressants in the forced‐swimming test, involvement of dopaminergic and opioid systems

1. It has been shown that thyrotropin releasing hormone (TRH) can potentiate the effects of the antidepressant, imipramine, as measured by the mouse forced-swimming test. This potentiation is not associated with an increase of effective levels of noradrenaline in the synaptic clefts, but depends upon the integrity of opioid systems. The present study was designed to investigate: (a) the potentiation by TRH of the effects of other antidepressants, using the same test; (b) the possible involvement of other neuronal systems, such as the 5-hydroxytryptaminergic and dopaminergic systems; (c) the contribution of the opioid and dopaminergic systems to the potentiation of the actions of other antidepressants by TRH. 2. The effects of nortriptyline, amineptine, maprotiline, nomifensine and mianserin, but not that of clomipramine, were potentiated by TRH (2 mg kg-1, i.p.). The inhibitor of 5-hydroxytryptamine synthesis, p-chlorophenylalanine (PCPA), did not prevent the effect induced by imipramine plus TRH. Blockade of dopaminergic systems by gamma-butyrolactone (GBL) (37.5 mg kg-1, i.p.), alpha-methyl-p-tyrosine (AMPT) (125 mg kg-1, i.p.) and apomorphine (0.025 mg kg-1, i.p.) antagonized the effects induced by various antidepressants alone (at high, effective doses) or at lower ineffective doses in association with TRH. The effect induced by imipramine plus TRH was also blocked by sulpiride (16 mg kg-1, i.p.). Pretreatment with the opioid antagonist, naloxone, inhibited the effects induced by nomifensine plus TRH or mianserin plus TRH but not those induced by nortriptyline plus TRH, maprotiline plus TRH or amineptine plus TRH. When high active doses of the antidepressants were used alone, only the clomipramine effect was blocked by naloxone. 3. These data indicate that TRH is able to potentiate the effect not only of imipramine but of other antidepressants in the mouse forced-swimming test, although these other antidepressants act in various ways on cerebral amines. The antagonism of the effects induced by the antidepressants alone or in association with TRH after blockade of dopaminergic systems may indicate a reversal of the effect of the antidepressants by blockade of dopaminergic systems. Hence, the same mechanisms would be involved in the effects induced by antidepressants alone or in association with TRH, with respect to dopaminergic systems. However, different mechanisms of action seem to be responsible for the potentiation of TRH of the effect of the various antidepressants, since the involvement of the opioid systems varies according to the antidepressant tested.

Dopamine receptor agonist activity of U‐66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties

AbstractInvestigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, and d‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be therapeutically useful.

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.

Effects of alterations in the activity of tuberohypophysial dopaminergic neurons on the secretion of alpha-melanocyte stimulating hormone.

Administration of gamma-butyrolactone (GBL), an anesthetic which reduces dopaminergic neuronal activity, decreased the concentration of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the intermediate lobe of the pituitary gland, and increased alpha-melanocyte stimulating hormone (alpha MSH) concentrations in the serum of male rats. Bilateral electrical stimulation of the rostral arcuate nucleus, which contains perikarya of tuberohypophysial DA neurons, increased DOPAC concentrations in the intermediate lobe and decreased alpha MSH concentrations in the serum of GBL-anesthetized rats. Administration of the DA antagonist haloperidol prevented the decline in serum alpha MSH levels following arcuate nucleus stimulation, but had no effect on serum alpha MSH concentrations in sham-stimulated GBL-treated rats. These results indicate that GBL-induced decreases or stimulation-induced increases in the activity of tuberohypophysial DA neurons are accompanied by corresponding changes in the metabolism of DA in the intermediate lobe of the rat pituitary gland, and by reciprocal changes in the secretion of alpha MSH.

6- and 8-hydroxy-3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans. Dopamine agonists with autoreceptor selectivity.

The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.

Presynaptic inhibition of nigrostriatal dopamine release in the mouse: Lack of cross tolerance between apomorphine, GBL and CGS 10746B

Acute parenteral injections of apomorphine, gamma-butyrolactone (GBL) and CGS 10746B decreased dopamine release in the mouse nigrostriatal pathway as evidenced by decreases in striatal 3-methoxytyramine levels. In a 7 day treatment paradigm, the effects of acute apomorphine, GBL and CGS 10746B were unaltered in animals treated b.i.d. with GBL (500 mg/kg, i.p.). In contrast, the actions of acute CGS 10746B expressed a complete tolerance in mice treated b.i.d. with CGS 10746B (20 mg/kg, i.p.), while the actions of acute apomorphine or GBL were similar in the chronic saline and chronic CGS 10746 groups. These data show that the inhibition of striatal dopamine release by CGS 10746B is susceptible to tolerance. In addition, the lack of cross tolerance between GBL, apomorphine and CGS 10746B suggests independent sites of action for these agents in inhibiting dopamine release.

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC- 4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392. 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.

Absence of synthesis-modulating nerve terminal autoreceptors on mesoamygdaloid and other mesolimbic dopamine neuronal populations

The present study sought to map the distribution of dopamine (DA) synthesis-modulating autoreceptors on DA nerve terminals innervating the amygdala and other limbic structures of the rat brain at a level of anatomic resolution (i.e., discrete component nuclei) commensurate with the functional organization of such structures. The biochemically estimated response of mesoamygdaloid and other limbic DA neuronal populations to conditions of minimal (gammabutyrolactone administration or surgical axotomy) and maximal (low-dose apomorphine administration) activation of nerve terminal DA autoreceptors was examined and compared to the response of mesostriatal and mesocortical DA neurons. In contrast to the caudate nucleus, nucleus accumbens, and olfactory tubercle, neither gammabutyrolactone (GBL) nor axotomy increased biochemically estimated DA synthesis (DOPA accumulation) in any of the amygdaloid nuclei, the anterior amygdaloid area, septal nuclei, or subdivisions of the interstitial (bed) nucleus of the stria terminalis. These results indicate that, similar to the medial prefrontal cortex and median eminence, DA synthesis in mesoamygdaloid and other subcortical limbic DA neuronal populations is not under the regulatory influence of tonically active, nerve terminal-localized autoreceptors. Both GBL and axotomy increased DOPA accumulation in the anterior cingulate cortex, but not in allocortical projection fields. In contrast to the differential distribution of DA synthesis-modulating terminal autoreceptors, the end-product inhibition of tyrosine hydroxylase activity appears to be a ubiquitously expressed regulatory property of DA neurons. The decrease in DA metabolism produced by the administration of a low, presumably auto-receptor-selective, dose of apomorphine exhibited a DA neuronal population distribution distinctly unlike that of the aforementioned effects of GBL or axotomy on DOPA accumulation. These results reinforce the DA neuronal population-selective distribution of synthesis-modulating autoreceptors and indicate that nerve terminal-localized autoreceptors are operative in regulating DA synthesis in only a minority of DA-innervated brain structures. Further, the demonstration of such autoreceptors is dependent upon the preparation, pharmacological tools, and functional endpoints chosen for study.

Neuroleptic-like effects of the ι-isomer of fenfluramine on striatal dopamine release in freely moving rats

ι-Fenfluramine (ι-F) was studied for its ability to release dopamine (DA) and its metabolites in freely moving rats through the trans-striatal dialysis technique. ι-F's effect on striatal DA release was also studied in animals made tolerant to the effect of haloperidol by chronic treatment (1 mg/kg i.p. twice daily for 11 days and 48 hr wash-out) with the neuroleptic or pretreated with 300 mg/kg i.p. gamma-butyrolactone (GBL). Five and 10 mg/kg ι-F dose-dependently increased the release of DA and its metabolites with a pattern of effects similar to that observed with neuroleptic drugs. The dose of 20 mg/kg ι-F had the same effect as 10 mg/kg. Repeated haloperidol treatment reduced the basal release of DA and its metabolites and a much smaller amount of DA and metabolites was released by ι-F (10 mg/kg i.p.) and haloperidol (0.1 mg/kg i.p.) in animals treated with haloperidol than in controls. GBL 300 mg/kg i.p. reduced basal DA release by about 50%. When 10 mg/kg ι-F, 0.1 mg/kg haloperidol and 0.25 mg/kg d-amphetamine were injected i.p. 40 min after GBL, ι-F and haloperidol did not significantly raise DA release in GBL-treated rats whereas a significant effect was observed at various times after d-amphetamine. The data show that ι-F resembles haloperidol in its ability to release DA and its metabolites from the corpus striatum of freely moving rats. The cross-tolerance between haloperidol and ι-F for their effect on DA release suggests that a common site is involved in the mechanism of these drugs.

Sexually differentiated actions of 3-PPP enantiomers on prolactin secretion

The ability of the enantiomers of the atypical dopamine receptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) to counteract gamma-butyrolactone-induced hyperprolactinemia was compared in male and female rats. Following gamma-butyrolactone (GBL) pretreatment serum prolactin concentrations were higher in female than in male rats. In males (−)-3-PPP tended to be somewhat less effective than (+)-3-PPP in decreasing serum prolactin concentrations (levels after (+)-3-PPP and (−)-3-PPP: 21 % and 33 %, respectively, of levels in GBL-pretreated controls). In females the (−)-form induced a much weaker response than did the (+)-form (levels after (+)-3-PPP and (−)-3-PPP: 8 % and 74 %, respectively, of levels in GBL pretreated controls). Parallel experiments replacing GBL by reserplne yielded similar results. Data are discussed in terms of sex differences in responsiveness of pituitary dopamine receptors.

Central dopaminergic properties of HW-165 and its enantiomers; trans-octahydrobenzo(f)quinoline congeners of 3-PPP.

In the further development of CNS dopamine autoreceptor active compounds related to 3-PPP, the transfused 7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline HW-165 and its enantiomers were synthesised. This paper describes the basic pharmacological properties of these latter, novel "atypical" dopaminergic agents, based on an extensive series of biochemical and behavioural experiments in rats. By and large, the pharmacological activities of HW-165 - essentially, if not exclusively, residing in its (4aS,10bS)-(-)-enantiomer - were similar to those displayed by (S)-(-)-3-PPP, indicating the simultaneous presence of central dopamine (autoreceptor) agonist and weak (postsynaptic) antagonist properties in the molecule. Thus, in non-pretreated animals HW-165 and its active species monotonically suppressed the spontaneous locomotion without causing catalepsy or other appreciable motor disabilities, and at the same time selectively reduced the dopamine synthesis, release/turnover and utilisation. Some differences in these biochemical responses to HW-165 [racemate or (-)-enantiomer] were, however, noted in the limbic vs. striatal brain areas (e.g. decrease of dopamine synthesis particularly in the limbic parts). On the other hand, while failing to reverse reserpine-induced akinesia or to elicit stereotyped behaviour, the agents markedly inhibited the dopamine synthesis in either of the dopamine-dominated cerebral regions in the reserpinised as well as in gamma-butyrolactone (GBL)-treated rats. As shown for racemic HW-165 after reserpine pretreatment, the inhibition of dopamine synthesis was completely and stereoselectively blocked by (+)-butaclamol, thereby supporting direct dopamine receptor interaction. Racemic HW-165 readily antagonised the d-amphetamine-induced locomotor hyperactivity. Apomorphine-induced hyperactivity was, however, distinctly more resistant to antagonism by HW-165 [racemate or (-)-enantiomer]. Moreover, the latter agents fully prevented the apomorphine-induced inhibition of striatal dopamine synthesis in otherwise non-pretreated rats, while only partly counteracting this effect of apomorphine in the limbic regions of such animals, and in either brain area of rats treated with gamma-butyro-lactone. The findings are interpreted within the context of the mixed dopamine agonist/antagonist properties (referred above) of HW-165 and its active (-)-species in relation to the adaptive state of central dopamine receptors and possible regional variations in feedback strength and organisation.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonin agonists reduce dopamine synthesis in the striatum only when the impulse flow of nigro-striatal neurons is intact.

The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and m-chlorophenylpiperazine (CPP), two 5-hydroxytryptamine (5-HT, serotonin) agonists, on the accumulation of 3,4-dihydroxyphenylalanine (DOPA] were studied in the striatum of rats treated with gamma-butyrolactone (GBL). Unlike 2 mg/kg i.p. apomorphine, neither 5 mg/kg i.p. 5-MeO-DMT nor 2.5 mg/kg i.p. CPP significantly reduced the GBL-induced increase in DOPA accumulation in the striatum. 5-MeO-DMT and CPP significantly reduced DOPA accumulation in animals that had received the aromatic amino acid decarboxylase inhibitor Ro 4-4602 but not GBL. 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum. The data indicate that 5-HT agonists can reduce 3,4-dihydroxyphenylethylamine (DA, dopamine) synthesis in the striatum of rats only when the impulse flow of DA neurons is intact. An indirect effect through mechanisms controlling DA synthesis in the striatum, for instance cholinergic and GABA-ergic neurons, is suggested.

Chronic haloperidol during development attenuates dopamine autoreceptor function in striatal and mesolimbic brain regions of young and older adult rats.

The effects of chronic haloperidol administration during the prenatal and preweanling periods on dopamine autoreceptor function were examined in striatum, olfactory tubercles, and nucleus accumbens of young (2-3 month) and older (12-13 month) adult rats. In striatum of young and older adult rats that had been chronically treated with haloperidol early in life, as well as in the nucleus accumbens of older adults receiving early chronic haloperidol, gamma-butyrolactone (GBL) did not induce significant increases in dopamine levels. In olfactory tubercles of young adults that had received early chronic treatment with haloperidol, apomorphine pretreatment failed to reverse the observed GBL-induced increase in dopamine levels. Thus, dopamine autoreceptor function appears to be attenuated in rats chronically treated with haloperidol during early development, in contrast to reports of autoreceptor supersensitivity following neuroleptic treatment in adulthood.

The effectiveness of yohimbine in blocking rat central dopamine autoreceptors in vivo

The influence of various alpha-adrenoceptor antagonists (10 mg/kg i.p.) upon the rate of turnover of dopamine (DA) in the rat brain was investigated. Taking the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as a measure of the rate of DA turnover, it was found that prazosin and phenoxybenzamine decreased, whereas piperoxane and yohimbine increased the turnover rate both in the corpus striatum and in the tuberculum olfactorium. Azapetine, phentolamine and tolazoline as well as the beta-adrenoceptor antagonist propranolol were without a significant effect, whereas the DA antagonist haloperidol increased DOPAC and HVA levels and decreased the levels of DA itself. The possibility that the yohimbine-induced increase in the DA turnover rate was produced by a direct blockade of DA autoreceptors, was investigated under conditions where influences other than those elicited via DA autoreceptors are thought to be eliminated, i.e. in rats treated with reserpine or gamma-butyrolactone (GBL). In rats that were pretreated with reserpine, yohimbine (10 mg/kg i.p.) was found to be ineffective in antagonizing the reduction of the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following decarboxylase inhibition, that was produced by the DA agonist apomorphine (2.0 mg/kg i.p.). In rats pretreated with reserpine, yohimbine (10 mg/kg i.p.) was also ineffective in antagonizing the reduction of the DOPAC and HVA levels produced by apomorphine (2.0 mg/kg i.p.), but it was effective in antagonizing the reduction of the HVA level that was produced by the selective DA autoreceptor agonist N,N-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT, 1.0 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for down-regulation of GABA receptors following long-term gamma-butyrolactone.

Long-term oral administration (12 weeks) of gamma-butyrolactone (GBL) to mice resulted in pharmacological and neurochemical changes which may be interpreted as a decrease in GABA-mediated synaptic activity. The depression in motor activity produced by the GABA-mimetic muscimol was reduced following long-term GBL. The binding of GABA to its putative receptor was reduced in the GBL group as evidenced by a decrease in the Bmax in the cerebral cortex, cerebellum, and striatum, but not in the hippocampus. No difference in the concentration of GABA was observed between the two groups. However, the reduction in GABA accumulation which normally results after an acute injection of GBL (560 mg/kg) was markedly attenuated in the mice receiving 12 weeks of GBL. Similarly, the muscimol-induced alteration in the concentration of DOPAC, a dopamine metabolite, was also reduced in the GBL group. These results, illustrating tolerance to the pharmacological effects of GBL and muscimol and in vitro evidence of a reduction in GABA binding sites, suggest that long-term exposure to GBL is accompanied by an alteration in GABA receptors and provides a possible mechanism for the tolerance to GBL-induced changes in dopamine.

Biochemical and behavioral evaluation of pergolide as a dopamine agonist in the rat brain

The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (O.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses. Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility. Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolideinduced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide. On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.

Evidence for dopamine autoreceptors in mesocortical dopamine neurons

The effect of different treatments which are thought to modify dopamine (DA) synthesis by an action on DA autoreceptors was compared in the caudate nucleus and two frontal cortical areas: the medial prefrontal cortex and dorsolateral frontal cortex, having the highest and lowest DA concentration, respectively, but having equal concentrations of norepinephrine (NE); the NE to DA ratio being 3:2 and 8:1, respectively. DA synthesis was measured by the rate of DOPA accumulation after inhibition of DOPA decar☐ylase. Gamma-butyrolactone (GBL) (750 mg/kg) increased DOPA accumulation by 200% in the caudate nucleus but only by 40% in the medial prefrontal cortex and was ineffective in the dorsalateral frontal cortex. Apomorphine (25–100 μg/kg) decreased DOPA accumulation by 7–30% in the medial prefrontal cortex and by 20–40% in the caudate nucleus in a dose-dependent manner. N- n-propylnorapomorphine (NPA) produced a similar effect within the dose range of 2.5–10 μg/kg. Both DA agonists were completely ineffective in the dorsolateral frontal cortical area. Haloperidol (0.5 mg/kg) increased DOPA accumulation by 80 and 220% in the medial prefrontal cortex and the caudate nucleus, respectively. It is concluded that DA autoreceptors regulate DA synthesis in the medial prefrontal cortex as in the caudate nucleus. Moreover, it was found that DOPA accumulation was approximately equal in the medial prefrontal cortex, with dense dopaminergic innervation, as in the dorsolateral area, devoid of dopaminergic terminals, suggesting that only a small fraction of cortical DA synthesis takes place in dopaminergic neurons, while the major part occurs in noradrenergic neurons. These results may explain why DA autoreceptor-mediated changes in DOPA accumulation are less evident in the medial prefrontal cortex than in the caudate nucleus.

Influence of gamma-butyrolactone on behavior due to dopaminergic drugs

Gamma-butyrolactone (GBL) is well known to reduce dopamine neuronal impulse flow, but the effects of the drug on dopamine-dependent behavioral states is not well studied. Qualitative and quantitative data are presented, detailing the influence of GBL on stereotypy when this drug is given after administration of the indirectly-acting dopamine mimetics amphetamine and methylphenidate, and the direct dopamine agonist apomorphine. GBL reversed the stereotypy produced by all three drugs, given at moderate doses producing comparable intensities of stereotypy. GBL unexpectedly proved effective in reversing stereotypy after higher-dose apomorphine while producing a rather weak influence on that of higher-dose amphetamine and methylphenidate. The results are discussed in terms of the dopamine impulse flow, and possible GABA-potentiating, effects of GBL, and the sedative effects of apomorphine.

Effect of low dose gamma-butyrolactone therapy on forebrain neuronal ischemia in the unrestrained, awake rat.

Low dose gamma-butyrolactone (GBL) therapy alters the natural history of experimental forebrain ischemia in the awake rat. After 30 minutes of four-vessel ischemia, repeated hydrogen cerebral blood flow determinations in awake rats over 72 hours revealed that low dose GBL therapy prevented the development of regional cerebral hyperemia and later the prolonged cerebral hypoperfusion that was experienced by the nontreated controls. Moreover, the low dose GBL-treated group had significantly less neuronal tissue loss than that in comparable brain regions of the nontreated controls. Before the stroke studies, GBL dose-response experiments performed on normal rats indicated that high dose GBL therapy produced seizures, systemic hypertension, metabolic acidosis, hyperthermia, and death.

Suppression of voluntary ethanol consumption in rats by gamma-butyrolactone

The effect of gamma-butyrolactone (GBL) on voluntary ethanol intake was studied in a group of Wistar rats in which a stable preference had been induced by exposure to increasing ethanol concentrations. These rats drank 60% of their daily fluid intake as 15% ethanol solution, corresponding to about 6 g ethanol/kg/day. GBL, injected intraperitoneally at the dose of 200 mg/kg, twice daily for 3 consecutive days, decreased ethanol intake by about 80% on the days of treatment, but did not reduce total fluid intake. Ethanol intake remained significantly reduced up to the 5th day following cessation of GBL administration. GBL, up to a concentration of 10 −3 M, inhibited neither alcohol-dehydrogenase nor aldehyde-dehydrogenase in rat liver homogenates, nor dopamine-β-hydroxylase in homogenates of adrenal medulla or hypothalamus of rats. It is suggested that inhibition of firing in dopaminergic neurons mediates the suppressant effect of GBL on ethanol preference.