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E L Gardner

Publications and source records attributed to E L Gardner.

At least 37 records · Page 2Linked to original sources
PubMed1994

Clozapine produces potent antidopaminergic effects anatomically specific to the mesolimbic system.

Although weak as an antagonist at brain dopamine receptors, clozapine is very strongly antidopaminergic when measured by in vivo single-neuron electrophysiologic recording, in vivo brain microdialysis, in vivo brain voltammetric electrochemistry, in vivo electrical brain stimulation, or in vivo neurobehavioral techniques. Three aspects of clozapine's strong antidopaminergic actions are remarkable. First, clozapine's antidopaminergic potency is stronger than can be explained by its comparatively weak interaction with dopamine receptors, implying that a significant portion of its antidopaminergic action may be transsynaptic and secondary to actions on nondopamine neurotransmitter systems. Second, clozapine's strong antidopaminergic action is seen more reliably with chronic rather than acute administration, implying that some cumulative neurochemical process underlies the gradual recruitment of dopamine blockade. Third, and most remarkably, clozapine's strong antidopaminergic action is anatomically specific--present in the mesolimbic dopamine system but absent in the nigrostriatal dopamine system. This mesolimbic-specific dopamine blockade may underlie at least a portion of clozapine's atypical clinical profile.

Animals↗
PubMed1993

Ventral tegmental microinjection of delta 9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: evidence for local neural action by marijuana's psychoactive ingredient.

Basal extracellular levels of dopamine (DA) and its metabolites in both ventral tegmental area (VTA) and nucleus accumbens (Acb) were simultaneously monitored by in vivo brain microdialysis in laboratory rats. Microinjection of 12 micrograms or 24 micrograms delta 9-tetrahydrocannabinol (delta 9-THC), the psychoactive ingredient in marijuana and hashish, into the VTA produced a dose-dependent increase in somatodendritic DA levels in VTA but failed to produce any simultaneous change in extracellular DA in Acb. Direct delta 9-THC perfusion (5 x 10(-5) and 2 x 10(-4) M) into Acb via the microdialysis probes caused a significant increase in extracellular DA levels in Acb. These findings suggest that (1) delta 9-THC has a facilitating effect on somatodendritic DA efflux, and (2) the elevation of Acb DA levels seen in our previous studies with systemic administration of delta 9-THC may result from local actions of delta 9-THC at or near the DA terminal projections in Acb.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Clozapine's functional mesolimbic selectivity is not duplicated by the addition of anticholinergic action to haloperidol: a brain stimulation study in the rat.

This study examined whether the anticholinergic potency of the clinically superior antipsychotic drug clozapine contributes to clozapine's anatomically-selective functional inhibition of the mesolimbic dopamine (DA) system, using an electrical brain-stimulation reward (BSR) paradigm in rats that has been previously shown to be highly sensitive to clozapine's mesolimbic functional selectivity. Rats were chronically administered saline, clozapine, haloperidol, or haloperidol plus the anticholinergic compound trihexyphenidyl, and threshold sensitivity of the mesolimbic and nigrostriatal DA systems was assessed using the BSR paradigm, to infer degree of functional DA blockade produced by the chronic drug regimens. Chronic saline produced no change in either DA system. Congruent with previous findings, chronic clozapine powerfully inhibited the mesolimbic DA system but spared the nigrostriatal DA system. Also congruent with previous findings, chronic haloperidol powerfully inhibited both DA systems. Compared to chronic haloperidol alone, chronic haloperidol plus chronic trihexyphenidyl exerted diminished anti-DA action in both the mesolimbic and nigrostriatal DA systems. These results suggest that clozapine's anticholinergic potency is not an adequate explanation for its functional mesolimbic selectivity.

Animals↗
PubMed1993

Overview of chemical sampling techniques.

Although many of the ideas for sampling the chemical microenvironment of the brain were present, at least in nascent form, three decades ago or more, the last 10 years have witnessed a particularly spectacular surge of development, refinement, and use. We are now able to measure virtually any endogenous brain chemical in vivo at commendable levels of sensitivity, selectivity, and speed. The long-dreamt-of goal of being able to correlate neurochemical events with ongoing behavior and/or presentation of salient environmental cues and stimuli has already been largely achieved. Further refinements of existing techniques may well lead to levels of analysis inconceivable even a few years ago. The implications for theory-building and hypothesis-testing are enormous, particularly within such essentially virgin domains as behavioral neuroscience and biological psychiatry. These are truly exciting times.

Animals↗
PubMed1992

Serotonin denervation enhances responsiveness of presynaptic dopamine efflux to acute clozapine in nucleus accumbens but not in caudate-putamen.

Clozapine alters mesolimbic dopamine (DA) function but spares nigrostriatal DA function in laboratory animals, but the underlying mechanism is unknown. In the present study, acute intraperitoneal injection of clozapine (5-40 mg/kg) increased extracellular DA levels in nucleus accumbens (Acb) and caudate-putamen (CPu) of awake, freely moving rats as measured by in vivo brain microdialysis, without anatomic selectivity. However, in serotonin (5HT)-denervated rats acute clozapine preferentially enhanced DA levels in Acb as compared to CPu. Since (i) up-regulation of 5HT receptors on DA neurons may result from 5HT denervation, (ii) clozapine has potent anti-5HT action, and (iii) 5HT receptors are more dense in Acb than CPu, these data appear to add additional weight to previous suggestions that a serotonergic mechanism may partly underlie clozapine's mesolimbic selectivity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effects of acute and chronic clozapine on dopaminergic function in medial prefrontal cortex of awake, freely moving rats.

We previously showed that chronic administration of the clinically atypical and clinically superior antipsychotic drug clozapine selectively reduces dopamine (DA) release in the nucleus accumbens but not neostriatum, and that this effect appears mediated by anatomically selective mesolimbic DA depolarization blockade. The present study extends that research to another mesocorticolimbic DA locus, the medial prefrontal cortex. Acute clozapine challenge (5-40 mg/kg i.p.) produced dose-dependent increased extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the medial prefrontal cortex of awake, free-moving rats as measured by in vivo brain microdialysis. Chronic clozapine treatment (20 mg/kg/day for 21 days) did not significantly change basal extracellular levels of DA, DOPAC or HVA. Acute clozapine challenge on day 22 in the chronic clozapine-treated animals produced no significant differences in medial prefrontal cortex DA, DOPAC or HVA as compared to chronic vehicle-treated animals, indicating that tolerance to clozapine does not develop in the mesocortical DA system, in contrast to the mesolimbic system. The DA agonist apomorphine (100 micrograms/kg) produced decreased basal extracellular levels of DA, DOPAC and HVA in medial prefrontal cortex of both chronic clozapine-treated and chronic vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Strain-specific facilitation of dopamine efflux by delta 9-tetrahydrocannabinol in the nucleus accumbens of rat: an in vivo microdialysis study.

This study tests the hypothesis that delta 9-tetrahydrocannabinol (delta 9-THC) has a strain-specific facilitatory effect on dopamine (DA) efflux in rat nucleus accumbens, a crucial forebrain convergence of reward-relevant DA neural fibers that has been implicated as a focal brain locus mediating the euphorigenic properties of drugs of abuse. The dependent variable is presynaptic DA efflux measured by in vivo microdialysis in the nucleus accumbens. The independent variables are: (1) intraperitoneal injections of delta 9-THC at 0.0 (vehicle), 0.5 and 1.0 mg/kg; (2) Sprague-Dawley vs Lewis strain rat. Results show that delta 9-THC produces a dose-dependent, strain-specific enhancement of basal DA efflux in Lewis strain rats. These results suggest that genetic variation influences drug abuse vulnerability.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens.

The serotonin-3 (5-HT3) agonist 1-phenylbiguanide (0.1-1.0 mM in perfusate) caused a robust, dose-dependent enhancement of extracellular dopamine content in nucleus accumbens as measured by in vivo microdialysis. This action was antagonized by co-perfusion of the 5-HT3 antagonists zacopride and GR38032F (1 mM in perfusate). Similar effects were observed in 5-HT-denervated rats. These findings suggest that there is a potent modulation of dopamine (DA) release in the nucleus accumbens mediated via 5-HT3 receptors, which appear to be located presynaptically on DA terminals of the mesolimbic DA pathway.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured by in vivo brain microdialysis: further evidence for depolarization block.

As measured using in vivo brain microdialysis in conscious freely-moving rats, chronic treatment (20 mg/kg/day i.p. for 21 days) with the clinically atypical neuroleptic clozapine selectively reduced basal dopamine (DA) release in the nucleus accumbens (Acb) but not in caudate-putamen (CPu). Apomorphine (100 micrograms/kg s.c.) enhanced presynaptic Acb DA release in clozapine-treated rats, but reduced Acb DA release in vehicle-treated rats. These findings provide further evidence that depolarization block of mesolimbic DA neurons projecting to Acb but not of nigrostriatal DA neurons projecting to CPu may underlie clozapine's unusual clinical efficacy and its lack of production of extrapyramidal motoric effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Marijuana's interaction with brain reward systems: update 1991.

The most pervasive commonality amongst noncannabinoid drugs of abuse is that they enhance electrical brain stimulation reward and act as direct or indirect dopamine agonists in the reward relevant dopaminergic projections of the medial forebrain bundle (MFB). These dopaminergic projections constitute a crucial drug sensitive link in the brain's reward circuitry, and abused drugs derive significant abuse liability from enhancing these circuits. Marijuana and other cannabinoids were long considered "anomalous" drugs of abuse, lacking pharmacological interaction with these brain reward substrates. It is now clear, however, that delta 9-tetrahydrocannabinol (delta 9-THC), marijuana's principal psychoactive constituent, acts on these brain reward substrates in strikingly similar fashion to noncannabinoid drugs of abuse. Specifically, delta 9-THC enhances MFB electrical brain stimulation reward, and enhances both basal and stimulated dopamine release in reward relevant MFB projection loci. Furthermore, delta 9-THC's actions on these mechanisms is naloxone blockable, and delta 9-THC modulates brain mu and delta opioid receptors. This paper reviews these data, suggests that marijuana's interaction with brain reward systems is fundamentally similar to that of other abused drugs, and proposes a specific neural model of that interaction.

Animals↗
PubMed1990

Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex.

Acute administration of 1.0-2.0 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) increased presynaptic dopamine (DA) efflux in the medial prefrontal cortex of rats, as measured by intracerebral microdialysis in awake, behaving rats. These data are congruent with suggestions that (1) marijuana's euphorigenic effects and abuse potential may be related to augmentation of presynaptic DA mechanisms, and (2) the medial prefrontal cortex may be an important site of action for drugs of abuse in general and for delta 9-THC in particular.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis.

This study examined the effects of acute administration of delta-9-tetrahydrocannabinol (delta 9-THC), the psychoactive ingredient in marijuana, on extracellular efflux of dopamine (DA) and its metabolites as measured by in vivo microdialysis in nucleus accumbens of conscious, freely-moving rats. delta 9-THC, at low doses (0.5-1.0 mg/kg), which significantly enhance brain stimulation reward (intracranial self-stimulation), significantly increased DA efflux in nucleus accumbens. Augmentation of DA efflux by delta 9-THC was abolished by removal of calcium (Ca++) ions from the perfusion fluid, indicating a Ca(++)-dependence of delta 9-THC's action. Augmentation of DA efflux by delta 9-THC was either totally blocked or significantly attenuated by doses of naloxone as low as 0.1 mg/kg. Given the postulated role of mesocorticolimbic DA circuits in mediating and/or modulating brain stimulation reward, the present data raise the possibility that marijuana's rewarding effects, and hence its euphorigenic effects and abuse potential, may be related to pharmacological augmentation of presynaptic DA mechanisms. Additionally, the DA mechanisms enhanced by marijuana appear to be modulated by an endogenous opioid peptide system.

Animals↗
PubMed1988

The effects of delta 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study.

The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.

Caudate Nucleus↗
PubMed1988

Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol.

The present experiment explored whether delta 9-tetrahydrocannabinol (delta 9-THC), the psychoactive ingredient in marijuana, shares with other drugs of abuse the ability to facilitate brain stimulation reward acutely, as measured by electrical intracranial self-stimulation (ICSS). Laboratory rats were implanted with stimulation electrodes in the medial forebrain bundle, and trained to stable performance on a self-titrating threshold ICSS paradigm. delta 9-THC, at a dose believed pharmacologically relevant to moderate human use of marijuana, acutely lowered ICSS thresholds, suggesting that marijuana acts on similar CNS hedonic systems to most other drugs of abuse.

Animals↗
PubMed1987

Visualization of multiple opioid-receptor types in rat striatum after specific mesencephalic lesions.

In order to gain insight into a possible modulatory role for mu, delta, and kappa opioid receptors of the nigrostriatal dopaminergic pathway, we investigated the topographical organization of the receptors with respect to pre- and postsynaptic membranes. Dopaminergic terminals projecting from the substantia nigra to the corpus striatum were destroyed by unilateral injection of 6-hydroxydopamine into the substantia nigra. Quantitative receptor assays using highly specific radioligands were used to measure the density of striatal mu, delta, and kappa receptors before and after denervation. Denervation caused a 34 +/- 2% loss of striatal mu receptors and a 32 +/- 1% loss of striatal delta receptors on the lesioned side of the brain; in contrast, kappa receptors did not change significantly in density. Quantitative in vitro autoradiography was used to visualize the neuroanatomical pattern of receptors on lesioned and nonlesioned sides of the brain under the light microscope. Loss of mu receptors in striatal patches was striking in the ventrolateral areas of the striatum, whereas the most notable loss of delta receptors was found in the central striatum. Other brain areas did not differ significantly in mu receptor density between the lesioned and nonlesioned sides, as determined by autoradiography. These findings suggest that a high percentage of mu and delta receptors in the striatum are located on the nigrostriatal dopaminergic terminals and support the concept of a modulatory role for mu and delta opioid peptides in the nigrostriatal dopaminergic pathway.

Animals↗
PubMed1987

Modulation of rat brain opioid receptors by cannabinoids.

The interaction of delta 9-tetrahydrocannabinol (delta 9-THC) and related cannabinoids with opioid receptors of neuronal membranes has been investigated. Treatment of membranes with delta 9-THC consistently decreased specific in vitro binding of [3H]dihydromorphine (mu opioid) in a dose-dependent fashion. Similar dose-dependent changes were elicited by cannabidiol and (+/-)-hexahydrocannabinol. Equilibrium binding studies in which brain membranes were titrated with [3H]dihydromorphine in the presence of delta 9-THC demonstrated that the decrease in [3H]dihydromorphine binding is due to a reduction in the number of binding sites, with no significant alteration in receptor affinity. This result suggests that the interaction of delta 9-THC with opioid receptors is a noncompetitive one. Delta 9-THC also inhibited the binding of the delta opioid [3H]D-Pen2, D-Pen5-enkephalin and the opioid antagonist [3H]naloxone (Ki = 16 and 19 microM, respectively) but failed to inhibit the binding of the kappa opioid [3H]ethylketocyclazocine (after suppression of mu and delta receptor binding), the phencyclidine analog [3H]N-(1-[2-theinyl]cyclohexyl)piperidine, the dopamine antagonist [3H]spiroperidol or the muscarinic antagonist [3H]quinuclidinyl benzilate. Moreover, delta 9-THC inhibited the binding of [3H]etorphine (potent opioid agonist) to solubilized, partially purified opioid receptors with a Ki value similar to that observed for the membrane-bound receptors. This finding indicates that the allosteric modulation of the opioid receptor by delta 9-THC is the result of a direct interaction with the receptor protein or with a specific protein-lipid complex and not merely the result of a perturbation of the lipid bilayer of the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Interaction of [3H](-)-SKF-10,047 with brain sigma receptors: characterization and autoradiographic visualization.

The sigma opiates differ from other opiates in their stimulatory and psychotomimetic actions. The sigma opiate [3H](-)-SKF-10,047 has been used to characterize sigma receptors in rat nervous tissue. Binding of [3H](-)-SKF-10,047 to rat brain membranes was of high affinity, saturable, and reversible. Scatchard analysis revealed the apparent interaction of this drug with two distinct binding sites characterized by affinities of 0.03 and 75 nM (5 mM Tris-HCl buffer, pH 7.4, at 4 degrees C). Competition analyses involving rank order determinations for a series of opiates and other drugs indicate that the high-affinity binding site is the mu opiate receptor. The lower-affinity site (revealed after suppression of mu and delta receptor binding) has been identified as the sigma opiate/phencyclidine receptor. In vitro autoradiography has been used to visualize neuroanatomical patterns of receptors labeled using [3H](-)-SKF-10,047 in the presence of normorphine and [D-Ala2,D-Leu5]enkephalin to block mu and delta interactions, respectively. Labeling patterns differ markedly from those for mu, delta, or kappa receptors. The highest densities (determined by quantitative autoradiography) are found in the medial portion of the nucleus accumbens, amygdaloid nucleus, hippocampal formation, central gray, locus coeruleus, and the parabrachial nuclei. Receptors in these structures could account for the stimulatory, mood-altering, and analgesic properties of the sigma opiates. Although not the most selective sigma opiate ligand, [3H](-)-SKF-10,047 binds to sigma opiate receptors in brain, and this interaction can be readily distinguished from its interactions with other classes of brain opiate receptors.

Animals↗