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N J Leith

Publications and source records attributed to N J Leith.

18 recordsLinked to original sources
PubMed1987

Effects of amphetamine, methylphenidate, and apomorphine on regional brain serotonin and 5-hydroxyindole acetic acid.

Electrophysiological and cytofluorometric data suggest that doses of amphetamine which enhance locomotor activity and promote focused stereotypies produce pronounced effects on serotonin pathways in the CNS. However, the biochemical evidence regarding changes in serotonergic function produced by moderate doses of this drug is inconsistent. Therefore, the present study was designed to further examine the effects of amphetamine (1-5 mg/kg) on regional brain serotonin and its metabolite and to compare these effects to behaviorally comparable doses of methylphenidate and apomorphine. At doses which produce a multiphasic behavioral response pattern, including a stereotypy phase consisting primarily of repetitive head movements and occasional oral stereotypies, amphetamine (3 mg/kg) and methylphenidate (30 mg/kg) increased levels of 5HIAA in striatum and frontal cortex, two brain regions which receive serotonergic projections from the dorsal raphe nucleus. In contrast, these drugs decreased or had no effect on 5HIAA levels in hippocampus, a brain region which receives its serotonergic innervation from the median raphe nucleus. A moderate dose of apomorphine (0.5 mg/kg) produced a comparable pattern of neurochemical effects. These data are consistent with electrophysiological and cytofluorometric data suggesting enhanced dorsal raphe serotonergic function following amphetamine-like stimulants. Pretreatment of animals with alpha-methyltyrosine at a dose sufficient to prevent the locomotor stimulation and stereotypy promoted by amphetamine, or by haloperidol, failed to prevent the amphetamine-induced increase in 5HIAA, indicating that these serotonergic effects are not secondary to the amphetamine facilitation of dopaminergic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1983

Effects of apomorphine on self-stimulation responding: does the drug mimic the current?

The effects of apomorphine (APO) on self-stimulation responding were examined as a function of drug dose and stimulation current intensity. The lowest dose tested (0.02 mg/kg) significantly elevated the stimulation threshold, presumably reflecting the drug's preferential affinity for presynaptic dopamine (DA) receptors at this dose. At a dose which stimulates postsynaptic DA receptors (0.2 mg/kg), the rats responded with a pattern of behavior that resembled that obtained when non-drugged animals are given non-contingent current. However, during extinction, drugged animals were identical to non-drugged rats in their pattern of responding. These data indicate an interaction of APO with the stimulating current and suggest that APO may be mimicking only one component of the stimulation--perhaps the rewarding but not the motivating one.

Animals↗
PubMed1983

Striatal dopamine metabolism in response to apomorphine: the effects of repeated amphetamine pretreatment.

The dose-dependent decrease in striatal dopamine (DA) metabolites following apomorphine (APO) administration was utilized as an index of changes in DA receptor sensitivity following the repeated administration of amphetamine (AMPH). The results suggest that: (a) repeated AMPH pretreatment does not alter DA autoreceptor sensitivity; and (b) interpretations of the decline in striatal DA metabolites at high doses of APO (greater than 50 micrograms/kg), in terms of activation of postsynaptic DA receptors, may require re-evaluation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Two dissociable components of behavioral sensitization following repeated amphetamine administration.

The acute administration of moderate to high doses (greater than 2 mg/kg) of amphetamine (AMPH) to rats produces a multiphasic behavioral response consisting of an initial period of locomotor activity followed by episodes of intense stereotyped behavior, and a period of post-stereotype locomotion. Repeated administration of the drug results in a sensitization with two components: more rapid onset of stereotypy and enhancement of the post-stereotype locomotor activity. The studies presented below provide converging evidence that the two components of the sensitization are dissociable. 1. Rats from ten different strains or suppliers all exhibited more rapid onset of stereotypy following repeated AMPH pretreatment, whereas only five of these strains or supplier groups exhibited significantly enhanced poststereotypy locomotion. 2. The time course differed for the development of these two components of the sensitization. 3. The recovery from sensitization differed for these two components of the behavioral response. Following withdrawal of the drug, post-stereotypy motor activity diminished within 2 months while the more rapid onset of stereotypy persisted for at least 3 months. These observations have particular relevance to future studies directed at specifying the biochemical substrates of the sensitization.

Animals↗
PubMed1981

Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate.

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.

Amphetamine↗
PubMed1981

The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin.

The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the Bmax value of beta-adrenergic binding sites without appreciable changes in the Kd values, as assessed by specific 3H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of beta-adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of beta-adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).

Adenylyl Cyclases↗
PubMed1981

Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the drug.

Chronic administration of amphetamine (AMPH) has been reported to produce tolerance to the drug's behavioral effects in some paradigms (self-stimulation, discriminative stimulus, self-administration) and an enhanced effect or reverse tolerance when other behaviors are monitored (locomotor activity, stereotypy). The present study investigated whether the two phenomena are, in fact, related to the particular behavior monitored or reflect the marked differences in the injection regimens (1X vs. 3X daily injections) used to produce the phenomena. The effects of chronic AMPH administered once or three times daily on AMPH facilitation of self-stimulation responding and on the locomotor stimulant and stereotypy-producing effects of the drug were assessed. Regardless of the injection regimen used, chronic AMPH resulted in an enhancement of the locomotor stimulant effects of the drug as well as a more rapid onset and greater intensity of the stereotypy produced. In the self-stimulation paradigm, only the 3X daily regimen significantly reduced the effectiveness of a challenge dose of AMPH (tolerance), although the 1X regimen produced effects that were qualitatively similar but quantitatively less. Perhaps behavioral tasks in which tolerance develops reflect the mood-altering properties of the drug in humans whereas a process similar to reverse tolerance may underlie the increased susceptibility to psychoses elicited by the drug with repeated use.

Amphetamine↗
PubMed1981

Chronic amphetamine: is dopamine a link in or a mediator of the development of tolerance and reverse tolerance?

Rats were administered chronic multiple injections of amphetamine (AMPH) using dosage regimens which produce tolerance to the AMPH facilitation of self-stimulation responding, or reverse tolerance (sensitization) to the locomotor stimulant and stereotypy-producing effects of the drug. Subsequently rats were challenged with AMPH at behaviorally relevant doses and times and striatal and mesolimbic dopamine (DA) dynamics were assessed using the conversion of 3H-tyrosine to 3H-DA, and endogenous levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as indices of dopaminergic function. Acute administration of AMPH produced dose and time related changes in all indices of DA function in both the striatal and mesolimbic brain regions. Co-administration of haloperidol during chronic AMPH pretreatment prevented the appearance of most of the behavioral changes induced by chronic AMPH, suggesting an important role for DA systems. However, following chronic AMPH treatment, no additional biochemical changes in striatal or mesolimbic DA metabolism could be detected which would parallel the development of tolerance to AMPH facilitation of self-stimulation behavior or reverse tolerance to AMPH as reflected in enhanced post-stereotypy locomotor activity or a suggested increased intensity of stereotypy. Challenge with AMPH after chronic AMPH pretreatment did accelerate the changes in striatal but not mesolimbic DA metabolism, correlating with the more rapid onset of stereotypy induced by chronic AMPH. Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism.

Amphetamine↗
PubMed1980

Effects of chronic amphetamine or reserpine on self-stimulation responding: animal model of depression?

The mood-altering properties of amphetamine (AMPH) in humans (euphoria and depression) have been postulated to be related to the increases and decreases respectively which this drug produces in the sensitivity of the reward system of the brain. The present study further evaluated this relationship by testing the effects of chronic reserpine (RES), another treatment that produces depression in humans, on self-stimulation responding. Separate groups of animals implanted with stimulating electrodes in the medial forebrain bundle were administered daily injections of saline, d-AMPH (5 mg/kg X 7 days followed by 10 mg/kg X 7 days), or RES (0.05 mg/kg X 18 days). At treatment termination, both drug groups showed a significant elevation of the reinforcement threshold, with no recovery occurring during 18 subsequent days. Thus, drug-induced depression of self-stimulation responding may serve as an animal model for studying the underlying physiological basis for clinical depression, or at the very least, for drug-induced depression.

Animals↗
PubMed1978

Tolerance to amphetamine's facilitation of self-stimulation responding: anatomical specificity.

Further work on the phenomenon reported by Leith and Barrett, wherein tolerance was shown to develop to the well-known D-amphetamine-induced facilitation of self-stimulation, clearly indicates that the development of such tolerance is dependent on the location of the stimulating electrode. Thirty-seven Fisher or Harlan rats were trained to bar press for hypothalamic stimulation (60 Hz, AC). Following several sessions during which small doses of D-amphetamine were administered to demonstrate facilitation, the subjects were placed on a 4-day D-amphetamine regimen. During this time they were given three daily injections of continuously increasing doses of D-amphetamine (total 78 mg/kg). Subsequent tolerance was shown for electrodes stimulating dorsal or medial hypothalamic structures (H2 field of Forel, dorsal medial forebrain bundle, medial hypothalamic nuclei), but did not develop with ventral or lateral hypothalamic stimulation sites (fornix, ventral medial forebrain bundle).

Animals↗
PubMed1977

Effect of clonidine on the noradrenergic cyclic AMP generating system in the limbic forebrain and on medial forebrain bundle self-stimulation behavior.

The present results show that clonidine does not mimic the agonist action of norepinephrine (NE) on the noradrenergic cyclic AMP generating system of the limbic forebrain, but antagonizes the stimulatory effect of NE while not influencing the action of isoprenaline. In self-stimulation behavior, clonidine decreases responding and blocks the facilitation caused by d-amphetamine.

Adenosine Monophosphate↗
PubMed1976

Amphetamine and the reward system: evidence for tolerance and post-drug depression.

Existing reports of tolerance to the behavioral effects of d-amphetamine are most parsimoniously interpreted as reflecting behavioral adaptation to the disruptive effects of the drug rather than physiological tolerance. The present study shows that physiological tolerance does develop to the facilitation of self-stimulation behavior which the drug produces. Rats were trained to bar-press for electrical stimulation of the medial forebrain bundle and tested for facilitation of responding following the administration of 0.25 or 0.50 mg/kg d-amphetamine. Testing was terminated for 4 days during which increasing doses (1.0-12.0 mg/kg) of the drug were given. 16 h after the last injection, the test doses (0.25 or 0.50 mg/kg) no longer produced facilitation of self-stimulation. In addition, testing on the following day with no further drug administration showed a depression of responding indicating depression of the sensitivity of the reward system of the brain.

Animals↗