Jeffery J. Feigenbaum

GAMMA HYDROXYBUTYRATE IS NOT A GABA AGONIST

Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAA or GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity.

Effect of γ-hydroxybutyrate on central dopamine release in vivo: A microdialysis study in awake and anesthetized animals☆

gamma-Hydroxybutyrate (GHB) is generally considered to be an inhibitor of striatal dopamine (DA) release. However, a number of recent reports and at least one major review suggest that GHB enhances rather than inhibits striatal DA release. To examine this discrepancy, the effect of GHB on striatal DA release was monitored for 2 hr by microdialysis in awake and urethane-anesthetized rats. GHB (500 mg/kg, i.p.) significantly inhibited striatal DA release in conscious animals. However, anesthetic pretreatment completely abolished the inhibitory effect of GHB on DA release. In urethane-anesthetized animals, intraperitoneal injections of GHB resulted in a dialysis DA output that was the same as basal and saline control levels for all but the last three intervals where DA release was elevated slightly. In contrast to the intraperitoneal route, subcutaneous injections of GHB in anesthetized animals produced significant elevations of DA release above baseline levels. The increases ranged from 125 to 133% of basal levels. These results indicate that while GHB enhances striatal DA release in anesthetized animals, it inhibits rather than enhances this release in awake animals. This would explain why GHB induces an inhibition of DA-release-dependent behaviors rather than an enhancement. The results also indicate that the route of GHB administration influences its effects on striatal DA release, at least in anesthetized animals.

Normal and abnormal determinants of dopamine receptor ontogeny in the central nervous system.

Introduction 193 PART I--Ontogeny of Dopaminergic Structures and Presynaptic Mechanisms 193 1. Development ofthe striatum: Anoverview 193 2. Ontogeny of presynaptic dopaminergic mechanisms 194 2.1. Ontogeny of DA synthesis in the CNS of the rat 194 2.1.1. DA levels and DA synthetic enzymes 194 2.1.2. Regional maturation of synthetic enzymes 194 2.1.3. Ontogeny of striatal tyrosine hydroxylase and neonatal drug studies altering DA levels, synthesis or release to assess neuronal functionality 194 2.2. Ontogeny of DA axonal projections and prenatal drug studies altering DA levels, synthesis or release to assess neuronal functionality 195 2.2.1. Ontogeny of DA axons 195 2.2.2. Prenatal studies of drugs altering presynaptic DA mechanisms to determine neuronal functionality 195 2.2.2.1. Reserpine 195 2.2.2.2. Amphetamine 195 2.2.2.3. AMPT 196 2.3. Central DA levels as a function of development 196 2.3.1. Prenatal 196 2.3.1.1. First appearance 196 2.3.1.2. Period of accumulation and increase 196 2.3.1.3. Regional development 196 2.3.2. Postnatal 196 2.3.2.1. Early postnatal period 196 2.3.2.2. Later postnatal development 197 2.3.2.3. Regional distribution 197

Does γ-Hydroxybutyrate Inhibit or Stimulate Central da Release?

Gamma-hydroxybutyrate (GHB), a four-carbon fatty acid and anaesthetic, is widely considered to be a relatively specific inhibitor of central dopamine (DA) release. The inhibitory effect of GHB on the latter is thought to occur as a consequence of its diminution of impulse flow in central dopaminergic neurons. However, a number of studies have recently reported that GHB primarily stimulates rather than inhibits central DA release, with any inhibitory effect produced of a modest and transitory nature. GHB has been and continues to be widely used as an important research tool largely because it is one of only a few drugs available that acts primarily on DA release. Consequently, it is important to determine whether GHB inhibits DA release as previously thought, or stimulates DA release, as more recently suggested. Following a critical review of the literature, the present report suggests that GHB does inhibit rather than stimulate presynaptic DA release in consonance with its behavioral and pharmacological a...

Effects of naloxone on amphetamine induced striatal dopamine release in vivo: A microdialysis study

The opiate antagonist naloxone (NX) alters amphetamine (AMPH) induced behaviors including locomotor activity, rearing and stereotypy. However, the exact nature of the NX induced alteration of AMPH induced behaviors is controversial, with some studies using high (5-40 mg/kg) doses of NX reporting an inhibition, and others using low (< or = 1-2 mg/kg) doses observing a potentiation. As these behaviors are mediated by AMPH induced dopamine (DA) release, the effect of NX on the latter was examined by microdialysis in an effort to resolve the controversy. Saline and NX pretreated groups subsequently administered AMPH were compared in vivo across nine separate 10 min intervals as well as by grouped intervals. NX alone (0.8 mg/kg) and saline exerted statistically equivalent effects on striatal DA release with the exception of the fifth interval, where a small but significant increase was seen after NX. On the other hand, the same dose of NX significantly enhanced AMPH induced striatal DA release relative to saline pretreated animals during each of four separate intervals, from 30 to 70 minutes following AMPH (1.5 mg/kg), and across all nine intervals combined. NX pretreatment (0.8 mg/kg) followed by a higher dose of AMPH (3.0 mg/kg) produced a significantly greater cumulative effect on DA release than saline pretreatment over the last six combined intervals (30-90 min) and over two grouped intervals (30-50 min and 40-60 min inclusive). However, a comparison of single rather than paired or grouped intervals revealed no significant differences. Previous studies have also examined the effect of NX on AMPH induced striatal DA release using in vivo microdialysis. However, the doses used were invariably high (5 mg/kg) and the results on striatal DA release always inhibitory. The present results suggest that NX potentiates AMPH induced striatal DA release when lower doses of NX are used. These results combined with those of previous studies also suggest that NX exerts a biphasic effect on AMPH induced DA release, with lower doses potentiating release and higher doses inhibiting release. This is close agreement with behavioral observations and may be due to the effect of low versus high doses of NX on intraterminal calcium influx.

Effect of naloxone and morphine on dopamine agonist-induced stereotypy in rats and guinea pigs

Naloxone (0.80 mg/kg) and morphine (7.5 mg/kg) were given to rats or guinea pigs with increasing doses of amphetamine (0.5-6.0 mg/kg) to determine their respective effects on amphetamine-induced stereotypy. In contrast to the inhibiting and potentiating effect of these agents on apomorphine-induced stereotyped behavior, naloxone enhanced and morphine markedly attenuated amphetamine-induced stereotypy. Since other investigators have reported that drugs inhibiting release of dopamine block amphetamine-induced stereotypy and enhance apomorphine-induced stereotypy, whilst compounds stimulating the release of dopamine potentiate amphetamine-induced stereotypy and inhibit apomorphine-elicited stereotyped behavior, it is likely that naloxone stimulates and morphine inhibits the release of DA following their acute administration.

The effect of drugs altering striatal dopamine levels on apomorphine induced stereotypy.

Drugs that increase or decrease striatal dopamine levels appear to affect apomorphine induced stereotypy. This finding was unexpected, as it has previously been maintained that drugs which exert any action on striatal DA terminals exclusively would affect only indirect dopaminergic agonists, as opposed to apomorphine which induces stereotypy by acting directly on postsynaptic dopamine receptors. Specifically, inhibiting intrastriatal dopamine levels inhibits this behavior. This effect is explained in terms of apomorphine having a greater intrinsic activity and agonist affinity for striatal dopamine receptors than dopamine itself. Thus, dopamine and drugs which promote its release, may diminish the central behavioral effects induced by apomorphine relative to drugs which inhibit dopamine release centrally.

The role of dopaminergic mechanisms in mediating the central behavioral effects of morphine in rodents

Morphine has been universally assumed to act solely on opiate receptors, and predominantly on mu receptors. In consonance with this, several studies have demonstrated that opiate mu agonists and dopaminergic agonists and antagonists are incapable of binding each others receptors, except at extremely high concentrations (nor, for that matter, are acetylcholine, serotonin, gamma-hydroxybutyrate, norepinephrine or histamine able to bind opiate receptors). Yet, while other neurotransmitter antagonists (e.g. alpha- and beta-adrenoceptor-blocking agents) are for the most part limited in their effect on opiate-induced responses, many of the central effects elicited by morphine and other opioids have been found to be markedly potentiated by dopamine (DA) antagonists and reversed by direct and indirect DA agonists. Even more significantly, DA antagonists (especially those appreciably inhibiting DA release selectively) can also mimic many of these effects in low to moderate doses. Since DA antagonists do not act by binding opiate receptors, it is quite likely that morphine and other opiate mu receptor agonists may at least partially induce many of their acute central effects by means of an inhibition of postsynaptic DA receptor arousal. This appears to be a consequence of morphine binding its own (mu) receptors localized on central DA nerve terminals, resulting in an alteration of presynaptic DA release. This review does not exclude the important role of other neurotransmitter substances in the action of morphine, but rather emphasizes, and limits itself to considering, the importance of the role of dopamine in morphine-induced behaviors.

The Comparative Roles of Dopaminergic and Serotonergic Mechanisms in Mediating Quipazine Induced Increases in Locomotor Acitivity

The effect of dopaminergic and serotonergic agonists and antagonists on quipazine induced locomotor activity was investigated in rats. Though quipazine is generally considered to be a relatively pure serotonergic agonist, its effects on locomotor activity were inhibited by small doses of a centrally acting DA receptor blocking agent (haloperidol), while three different serotonergic (5-HT) antagonists were without effect on this behavior. Moreover, quipazine induced locomotor activity was markedly inhibited by the 5-HT substrate 5-hydroxytryptophan. The data suggest that quipazine induced locomotor activity primarily involves dopaminergic mechanisms, with 5-HT playing either no role in stimulating this behavior, or a subsidiary one, requiring intact central dopaminergic receptors for its expression.

Implications of dopamine agonist-induced hypothermia following increased density of dopamine receptors in the mouse.

An investigation was made of hypothermia induced by dopamine (DA) agonists as a model of the effect of various treatments or conditions on the sensitivity of central postsynaptic DA receptors. Selective supersensitivity of these receptors (defined as an increase in Bmax) was induced by means of intraventricular injections of 6-hydroxydopamine (6-OHDA) in animals pretreated with desmethylimipramine (DMI). Supersensitivity was also produced by the chronic administration of haloperidol. The supersensitivity of DA receptors induced by 6-OHDA was found to be associated with a reduced hypothermic response to apomorphine. Supersensitivity elicited by the chronic administration of haloperidol, which very probably did not produce a specific effect on the density of DA receptors but also affected serotonergic receptors, did not elicit any change in hypothermia induced by apomorphine. The results of the present study are not consistent with the view that DA receptors mediate hypothermia per se, but rather suggest that hypothermia induced by DA agonists is more complex, probably involving serotonergic receptors primarily, though other factors may also be contributory. Furthermore, the results of the present study suggest that the functional significance of supersensitivity of DA receptors induced by 6-OHDA versus chronic treatment with haloperidol may be quite different, depending upon the effector system examined.