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Biomedical subjects

E L Gardner

Publications and source records attributed to E L Gardner.

At least 55 records · Page 3Linked to original sources
PubMed1985

Neurochemical and functional correlates of naltrexone-induced opiate receptor up-regulation.

The neurochemical and functional correlates of opioid receptor up-regulation after chronic antagonist administration in vivo and of down-regulation after withdrawal of antagonist were examined. Total brain opioid receptors increased 1.9-fold by day 8 of naltrexone administration, after which no further increase was observed; the newly synthesized or unmasked receptors exhibited an enhanced sensitivity to guanyl nucleotide modulation. Withdrawal from chronic naltrexone treatment resulted in a return to nearly control levels of receptor density and guanyl nucleotide sensitivity in a period of 6 days. These results suggest that up-regulation is accompanied by an increased coupling of the receptors to the inhibitory guanyl nucleotide binding protein (Ni) and that down-regulation involves the dissociation of the receptor/Ni complex. In experiments designed to target opiate receptor subtypes, long-term treatment with naltrexone was found to produce a coordinated up-regulation of brain mu and delta receptors, but did not cause a significant change in the density or affinity of kappa or sigma receptors. These findings indicate that the kappa and sigma opiate receptor classes may be subject to independent control mechanisms. Chronic naltrexone treatment also resulted in an enhanced morphine-induced analgesia. This result indicates that a functional supersensitivity occurs as a result of the selective up-regulation of mu and delta receptors. After withdrawal from naltrexone, supersensitivity to morphine-induced analgesia decreased monotonically and, in parallel to opioid receptor density, to prenaltrexone treatment levels within 6 days. Together, these results suggest a functional significance for antagonist-induced mu and delta opiate receptor up-regulation.

Animals↗
PubMed1984

Visualization of opiate receptor upregulation by light microscopy autoradiography.

Light microscopy autoradiography has been used to visualize neuroanatomical patterns of brain opiate receptor upregulation in response to chronic naltrexone administration. Slide-mounted brain sections of frozen rat brain were labeled in vitro with dihydro[3H]morphine, a relatively selective mu opioid ligand. The greatest relative increases in opiate receptor density were observed in the nucleus accumbens, the amygdala, striatal patches, nuclei of the thalamus and hypothalamus, layers I and III of neocortex, substantia nigra compacta, midbrain periaqueductal gray regions, and the parabrachial nuclei of the brainstem. The substantia nigra reticulata, surrounding areas of striatal patches, and the locus ceruleus, were not affected by this drug treatment. These findings demonstrate that chronically administered naltrexone differentially regulates opiate receptors throughout the brain. In particular, three brain systems appear to be target areas of receptor upregulation : (i) the dopamine A9/A10 systems, (ii) the limbic system, and (iii) structures that receive input from afferent sensory pathways. Two possible mechanisms to account for this finding are (i) that the drug does not have uniform effects throughout the brain or (ii) that the receptors themselves may be associated with different functional systems. Receptor density changes are paralleled by increases in methionine-enkephalin content in the striatum, nucleus accumbens, periaqueductal gray, and hypothalamic areas of chronic naltrexone-treated rats relative to control rats. Thus opiate receptors and opioid peptides appear to be subject to regulatory mechanisms similar to those that modulate other neurotransmitters and their receptors. These results document in a visual manner brain patterns of opiate receptor upregulation .

Animals↗
PubMed1984

In vivo electrochemical and behavioral evidence for specific neural substrates modulated differentially by enkephalin in rat stimulant stereotypy and locomotion.

The enkephalinamide, D-Ala2-D-Pro5-enkephalinamide monoacetate (WY 42, 186), when systemically administered to male Sprague-Dawley rats, significantly inhibited sniffing, repetitive head movements, and frequency of rearing, stereotyped behaviors which are often associated with nigrostriatal dopamine activation. On the other hand, the locomotor component of amphetamine-induced stereotyped behavior, which is associated with mesolimbic dopaminergic activation, was not inhibited. In vivo electrochemical analysis showed a significant decrease in striatal dopamine release from striatum after systemic administration of D-Ala2-D-Pro5-enkephalinamide monoacetate in chloral hydrate anesthetized rats, whereas the dopamine signal from the nucleus accumbens, a mesolimbic neuroanatomigic modulation of dopamine both behaviorally and biochemically. Also, the concept of separate neural systems for the stereotypic and locomotor components of amphetamine-induced stereotypy is reinforced.

Animals↗
PubMed1983

Evidence for a role of endogenous opioids in the nigrostriatal system: influence of naloxone and morphine on nigrostriatal dopaminergic supersensitivity.

The effects of morphine and naloxone on nigrostriatal function were evaluated by their influence on rotational behavior in rats with unilateral lesions of the substantial nigra. Two different rotational syndromes which result from different lesion placements, were examined. Rats with the contraversive syndrome, when given apomorphine, rotate away from the lesioned side, while rats with the ipsiversive syndrome rotate toward the lesioned side. In both syndromes, rats rotate toward the lesioned side when given amphetamine. Morphine or naloxone, alone, was without effect in either syndrome. Morphine antagonized rotation by either apomorphine or amphetamine in both syndromes. Naloxone stimulated apomorphine-induced rotation in contraversive rats and antagonized amphetamine-induced rotation in ipsiversive rats. These findings support a functional role of endogenous opioids in this dopaminergic system. The effects of morphine and naloxone on apomorphine-induced rotation indicate that opiates act at a postsynaptic site in this system. Finally, the different responses to naloxone and morphine in the two rotational syndromes suggest that an enkephalinergic asymmetry may underlie the differences in behavioral responses between these two syndromes.

Amphetamine↗
PubMed1983

Similar effects of an enkephalin analog on mesolimbic dopamine release and hyperactivity in rats.

The effect of the metabolically stable enkephalin pentapeptide analog, D-Ala2-D-Pro5-enkephalinamide monoacetate (DAP) (WY 42, 186) was studied on amphetamine-induced hyperactive behavior and on dopamine release from tuberculum olfactorium in male, Sprague-Dawley rats. The behavioral results showed that D-Ala2-D-Pro5-enkephalinamide monoacetate did not significantly alter hyperactivity, the mesolimbic component of amphetamine-induced stereotypy. In vivo electrochemical evidence, derived from catecholamine sensitive electrodes, showed that the D-Ala2-D-Pro5-enkephalinamide monoacetate did not significantly alter dopamine release from the tuberculum olfactorium, a mesolimbic terminal brain region. The similarity in the behavioral and biochemical responses of dopamine to the enkephalinamide analog suggests that the behavior and biochemistry may be subserved by similar underlying neural mechanisms.

Animals↗
PubMed1983

Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation.

The ability of chronic treatment with the atypical neuroleptic clozapine to induce functional dopaminergic hypersensitivity in laboratory rats was assessed. The intracranial electrical self-stimulation paradigm, known to be sensitive to changes in functional dopaminergic sensitivity, was used. Animals with electrodes in the ventral tegmental nucleus (mesolimbic dopamine cell body area) showed a marked increase in self-stimulation rate following 3 weeks of chronic clozapine. This increase was similar in magnitude and duration to that shown by animals given 3 weeks of chronic haloperidol. In contrast, animals with electrodes in the substantia nigra (nigrostriatal dopamine cell body area) showed no change in self-stimulation rate following 3 weeks of chronic clozapine. These data are interpreted in the light of previous suggestions that clozapine and other atypical neuroleptics may possess functional selectivity for the mesolimbic dopamine system.

Animals↗
PubMed1982

Naltrexone-induced opiate receptor supersensitivity.

Chronic administration of the long-lived narcotic antagonist naltrexone resulted in a marked increase in brain opiate receptors. Similar changes in receptor density were observed for binding of the putative mu agonist [3H]dihydromorphine, the mu antagonist [3H]naloxone, the putative delta ligand [3H]D-Ala2,D-Leu5-enkephalin and [3H]etorphine. In addition, the sensitivity of agonist binding to guanyl nucleotide inhibition increased significantly. In contrast, no such changes in opiate binding were observed following acute administration of naltrexone. The increase in opiate receptor number following chronic naltrexone was highest in the mesolimbic and frontal cortex areas, and lowest in the dorsal hippocampus and periaqueductal gray. These results indicate a degree of plasticity in the opiate receptor system that may correlate with specific functional pathways.

Animals↗
PubMed1982

Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: studies with chronic clozapine and haloperidol.

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and choline acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced 3H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tubercle) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on 3H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.

Acetylcholine↗
PubMed1981

Acetylmethadol metabolites influence opiate receptors and adenylate cyclase in amygdala.

The activity of acetylmethadol and two major metabolites of this drug, noracetylmethadol and dinoracetyl-methadol were studied in monkey brain amygdaloid tissue. This tissue contains opiate receptors which may be assessed by direct binding studies; also these receptors are coupled to and capable of modulating a dopamine-stimulated adenylate cyclase system. Etrophine and D-ALa2-Met-enkephalin exhibited similar potencies when assessed for inhibition of dopamine-stimulated adenylate cyclase or competition for [3H] D-Ala2-Met-enkephalin binding sites. While acetylmethadol displaced [3H] D-Ala2-Met-enkephalin binding sites with a Ki of 7.4 X 10(-7) M, it had no detectable activity in the opiate receptor coupled adenylate cyclase system. Noracetylmethadol and dinoracetylmethodol, however, were capable of both binding (Ki values, 5.6 and 1140 nM respectively) as well as inhibiting the dopamine stimulated adenylate cyclase system (IC50 values, 1.2 and 800 nM respectively). Thus, it appears that metabolism of acetylmethadol to its mono-demethylated form results in a compound more active in both assay systems. The further demethylation of noracetylmethadol results in a second, but less potent, active metabolite. This process of biological activation can be assumed to account for the slow onset and long duration of action of acetylmethadol.

Adenylyl Cyclases↗
PubMed1981

Increase in mesolimbic electrical self-stimulation after chronic haloperidol: reversal by L-DOPA or lithium.

After chronic neuroleptic drug treatment, an increase in electrical intracranial self-stimulation (ICSS) rate is seen from electrodes in the A10 dopaminergic nucleus. This increase, which persists for approximately 3 weeks following drug withdrawal, is believed to represent a behavioral manifestation of drug-induced dopaminergic synaptic supersensitivity. Chronic L-DOPA caused a partial reversal of haloperidol-induced ICSS increase. Lithium carbonate, given concurrently with the haloperidol, partially prevented the development of ICSS supersensitivity. It is concluded that dopaminergic synaptic sensitivity has a two-way modulatory capability.

Animals↗
PubMed1981

Morphine differentially affects ventral tegmental and substantia nigra brain reward thresholds.

In order to differentiate the roles of the nigrostriatal and mesolimbic-mesocortical dopamine systems in the action of opiates on dopaminergically mediated intracranial self-stimulation (ICSS), the effects of chronic morphine administration and acute naloxone administration on ICSS were tested in rats with electrode placements in the substantia nigra pars compacta (A-9) and the ventral tegmentum (A-10). Acute morphine (5.0 mg/kg SC) did not affect ICSS thresholds of rats with electrodes in the A-9 nucleus when tested 1, 3, 5, and 23 hours after administration. With repeated daily administration, though, these animals showed increases in thresholds which grew progressively larger with each day of morphine treatment. This threshold elevation was not reversed by naloxone given 0.5 hour after the final morphine treatment on the fifth day. In contrast, acute morphine significantly lowered self-stimulation thresholds in rats with A-10 placements. Tolerance to this facilitatory effect was evident with chronic administration. Naloxone attentuated the lowering of threshold caused by opiate administration in these A-10 animals. The present data suggest a specificity of action of opiates on different brain systems subserving reward and reinforcement. These findings also suggest that the mesolimbic-mesocortical system may play an important role in mediating the rewarding properties of morphine.

Animals↗
PubMed1980

Selective inhibition of mesolimbic behavioral supersensitivity by naloxone.

Rats trained on ventral tegmental intracranial self-stimulation (ICSS) were unaffected by acute injection of naloxone (2 mg/kg), while acute morphine (5 mg/kg) increased ICSS rate by 46%. Chronic haloperidol (1 mg/kg/day for 21 days) produced mesolimbic dopaminergic supersensitivity, as seen by 42% increase in ICSS. Acute naloxone partially blocked this supersensitivity (to 13% over basal), while acute morphine augmented it (66% over basal). These findings suggest that enkephalinergic systems may be involved in neuroleptic-induced dopaminergic behavioral supersensitivity.

Animals↗
PubMed1979

Enhancement of self-stimulation behavior in rats and monkeys after chronic neuroleptic treatment: evidence for mesolimbic supersensitivity.

The effect of chronic neuroleptic drug treatment on self-stimulation of the mesolimbic dopamine system was tested. Rats with electrodes implanted into the ventral tegmental nucleus (A10 cell body area) were treated with haloperidol for three weeks. Afterwards, the rats showed a 35% increase in self-stimulation rate, as compared to pre-drug control rates. This increase persisted for three weeks after drug withdrawal before returning to baseline rates. Rats treated for three weeks with the atypical neuroleptic, clozapine, also showed an increase, the duration and magnitude of which was similar to that seen in the haloperidol group. In addition, four rhesus monkeys with electrodes in the nucleus accumbens (one of the terminal projection areas of the A10 mesolimbic dopamine system) were given a three week treatment with haloperidol, after which all animals showed a significant, long-lasting decrease in self-stimulation threshold, as measured by a rate-independent reward paradigm. Taken together, these results suggest the induction of receptor supersensitivity in the mesolimbic dopamine system by long-term treatment with neuroleptic drugs.

Animals↗