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Biomedical subjects

D L Cameron

Publications and source records attributed to D L Cameron.

At least 19 recordsLinked to original sources
PubMed1997

A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids.

Neurons originating in the ventral tegmental area are thought to play a key role in the formation of addictive behaviors, particularly in response to drugs such as cocaine and opioids. In this study we identified different populations of ventral tegmental area neurons by the pharmacology of their evoked synaptic potentials and their response to dopamine, 5-hydroxytryptamine and opioids. Intracellular recordings were made from ventral tegmental area neurons in horizontal slices of guinea-pig brain and electrical stimulation was used to evoke synaptic potentials. The majority of cells (61.3%) hyperpolarized in response to dopamine, depolarized to 5-hydroxytryptamine, failed to respond to [Met]5enkephalin and exhibited a slow GABAB-mediated inhibitory postsynaptic potential. A smaller proportion of cells (11.3%) hyperpolarized in response to [Met]5enkephalin, depolarized to 5-hydroxytryptamine, failed to respond to dopamine and did not exhibit a slow inhibitory postsynaptic potential. These two groups of cells corresponded to previously described "principal" and "secondary" cells, respectively. A further group of cells (27.4%) was identified that like the principal cells, hyperpolarized to dopamine. However, these "tertiary cells" also hyperpolarized to both 5-hydroxytryptamine and [Met]5enkephalin and exhibited a slow, cocaine-sensitive 5-hydroxytryptamine(1A)-mediated inhibitory postsynaptic potential. When principal and tertiary cells were investigated immunohistochemically, 82% of the principal cells were positive for tyrosine hydroxylase compared with only 29% of the tertiary cells. The 5-hydroxytryptamine innervation of both these cell types was investigated and a similar density of putative contacts was observed near the somata and dendrites in both groups. This latter finding suggests that the existence of a 5-hydroxytryptamine-mediated inhibitory postsynaptic potential in the tertiary cells may be determined by the selective expression of 5-hydroxytryptamine receptors, rather than the distribution or density of the 5-hydroxytryptamine innervation. We conclude that tertiary cells are a distinct subset of ventral tegmental area neurons where cocaine and mu-opioids both mediate inhibition.

Animals↗
PubMed1995

Opposing roles for dopamine and serotonin at presynaptic receptors in the ventral tegmental area.

1. Dopamine D1 and 5HT1D receptors are found on the terminals of afferent GABA neurons that synapse on the ventral tegmental area (VTA) dopamine neurons. The role of these receptors in the actions of cocaine was investigated using intracellular recordings in a brain slice preparation. Synaptic potentials were generated in the slice and GABA-mediated inhibitory post-synaptic potentials (IPSP) were identified. 2. Stimulation of dopamine D1 receptors selectively enhanced the GABAB IPSP, and their effect was blocked by D1 antagonists. The magnitude of the IPSP was decreased when D1 antagonists were applied in isolation, suggesting tonic D1 receptor stimulation via dendritically released dopamine. 3. Cocaine had an opposite effect and selectively decreased the magnitude of GABAB IPSP. This action was mimicked by 5HT and the 5HT1D agonist sumatriptan, and attenuated by the 5HT1D/2C antagonist, metergoline. The action of cocaine was also mimicked by the 5HT-releasing agent, fenfluramine, and blocked by pre-incubation of the slice with the 5HT-depleting agent, para-chloroamphetamine. 4. The results of this study suggest that dopamine and 5HT have opposing roles in modulating GABA input into VTA dopamine neurons. The actions of cocaine on this interplay may have implications for understanding its addictive properties.

Animals↗
PubMed1995

Deterioration of the high-mounted brake light.

An unusually high failure rate in the high-mounted, center brake light was observed in a survey of normal local traffic. Such failure increases the potential for delay or error in perception of the rear lights by following drivers.

Accidents, Traffic↗
PubMed1995

Color-specificity to enhance identification of rear lights.

30 male and 13 female licensed drivers were given a static reaction-time test for Donders Type B reactions to the onset of automotive rear lights. The lights were displayed as by conventional systems and by a new color-specific method referred to as the "Red Light Means Stop approach." When subjects were instructed to regard all red colored light as brake-signal light, both incidence of identification error and reaction time decreased. Results support the hypothesis that addition of color specificity to rear lighting might prevent some rear-end collisions which occur under adverse driving circumstances.

Adolescent↗
PubMed1994

Cocaine inhibits GABA release in the VTA through endogenous 5-HT.

The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons.

Animals↗
PubMed1993

Dopamine D1 receptors facilitate transmitter release.

A physiological role for the dopamine D1 receptor has been difficult to define, particularly because of its complex pre- and postsynaptic localization in brain areas such as the striatum. In the midbrain, however, D1 receptors are selectively localized to the terminals of GABA (gamma-aminobutyric acid)-containing afferents. We have studied the actions of these D1 receptors on evoked GABA synaptic potentials recorded intracellularly from dopamine neurons in the ventral tegmental area (VTA). We report here that dopamine augmented GABAB inhibitory postsynaptic potentials (i.p.s.ps) in the presence of D2 receptor antagonists. This effect was mimicked by the D1 agonists SKF38393 and SKF82958 and blocked by the D1 antagonists SCH23390 and cis-flupenthixol. No modulation of the GABAA synaptic potential was observed. The postsynaptic actions of the GABAB agonist, baclofen, were unaffected by SKF38393, SCH23390 or cis-flupenthixol, confirming a presynaptic locus of D1 action. Additionally, D1 antagonists reduced the amplitude of the GABAB i.p.s.p. in the absence of D1 agonists. We conclude that dopamine acts tonically at presynaptic D1 receptors on the terminals of afferent GABA neurons to facilitate selectively GABAB-mediated neurotransmission in the midbrain.

Animals↗
PubMed1992

Localisation of striatal muscarinic receptors involved in dopamine receptor-mediated behavioural responses.

Stereotyped sniffing responses to the direct dopamine agonist, apomorphine, were assessed following intrastriatal injection of the alkylating derivative of oxotremorine, BR 401. Subsequently, the localisation and extent of muscarinic receptor alkylation after injection into various striatal sites were assessed by quantitative autoradiography. The results of these experiments provide evidence that a regional subset of striatal muscarinic receptors is involved in apomorphine-induced stereotyped sniffing. In addition, these receptors are localised in a similar area to that previously shown to contain the dopamine D2 receptors responsible for mediating apomorphine-induced sniffing. Thus, striatal muscarinic receptors involved in dopamine-agonist induced behaviours share a close anatomical association with the dopamine receptors at which the agonist acts.

Animals↗
PubMed1992

An innovative solution to continuing misuse of red light on automobiles.

A novel approach [referred to as the RLMS (Red Light Means Stop) approach] to automotive rear lighting has recently been suggested as a means to enhance perceptibility of the rear lights. In the RLMS approach, only red colored light is displayed during braking, and only amber colored light is displayed at other times. Color per se then provides, for most drivers, an immediately perceptible visual stimulus by which brake lights are distinguished from tail lights. In earlier testing, simultaneous display of nonred tail lights and red brake lights confronted test subjects with antagonistic visual stimuli, thereby compromising, and underutilizing, the value of color. It is suggested that the potential safety value of the RLMS approach is significant, and that comprehensive testing should be conducted in a timely manner.

Accidents, Traffic↗
PubMed1990

The hypothyroid rat as a model of increased sensitivity to dopamine receptor agonists.

Control and hypothyroid rats were challenged with a range of doses (0.5-4 mumol/kg) of either the nonselective dopamine agonist, apomorphine, or the selective D2 receptor agonist. LY 171555, and their stereotyped head-down sniffing (SHDS) responses measured. The dose-response curves for both agonists were shifted to the left in the hypothyroid rats compared to water-treated controls. Increasing doses of the selective D2 antagonist, raclopride, caused a parallel shift to the right in the LY 171555-induced SHDS dose-response curve. Schild analysis revealed a decreased sensitivity to raclopride in the hypothyroid animals. The selective D1 antagonist SCH 23390 was observed to decrease the maximal response elicited by LY 171555 in a dose-dependent manner and the hypothyroid rats were more sensitive to this effect. It was concluded that hypothyroid rats showed an apparent increased sensitivity to D2 receptor agonists and a decreased sensitivity to D2 antagonists. In addition, the facilitation effect of the D1 receptor on the D2 receptor appeared less tightly coupled in the hypothyroid rats.

Animals↗
PubMed1989

Localization of striatal dopamine receptor function by central injection of an irreversible receptor antagonist.

The stereotypic head-down sniffing response to systemically administered apomorphine (0.65 mumol/kg) was assessed in rats 48 h after the bilateral injection of 0.2-0.5 microliters of the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (60 micrograms/microliters) into the caudate-putamen and nucleus accumbens. This response was significantly attenuated in animals that had received injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into the anterior/ventral part of the caudate-putamen but not in those that received injections into regions more dorsal/posterior. Animals were killed after apomorphine challenge and the region of dopamine D1 or D2 receptor reduction due to N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline mapped and quantified. This analysis revealed that the dopamine receptors involved in the apomorphine-induced stereotyped head-down sniffing response were located in a discrete region of the ventrolateral caudate-putamen and the dorsolateral nucleus accumbens. Animals that were pretreated with the selective dopamine D2 receptor antagonist raclopride (0 20 mumol/kg, i.p.) 20 min prior to central injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into this area showed a dose-dependent protection of the stereotyped sniffing response to systemic apomorphine 48 h later. This combination of techniques constitutes a novel way to investigate striatal function and the results obtained support the concept of a functional subdivision of both the caudate-putamen and the nucleus accumbens.

Animals↗
PubMed1989

Receptor alkylating agents: novel tools for the study of receptor function in the central nervous system of the rat.

1. The use of alkylating agents to investigate receptor function in the central nervous system is discussed. 2. Examples of strategies which can be used are illustrated by studies with the irreversible dopamine receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). 3. Recent work, in which EEDQ was injected into selected sites of the striatum and receptor loss assessed by quantitative autoradiography, is described to show how this approach can be used to elucidate dopamine receptor function in the striatum.

Alkylating Agents↗
PubMed1988

Alkylation of striatal dopamine receptors abolishes stereotyped behavior but has no effect on dopamine stimulated adenylate cyclase activity.

The role of dopamine stimulated adenylate cyclase (AC) activity in behaviours elicited by apomorphine stimulation of striatal dopamine receptors was investigated. Rats were treated with the irreversible dopamine receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) alone or after pretreatment with either a D1 or D2 receptor antagonist and subsequently challenged with apomorphine. Animals that received no antagonist pretreatment showed significantly decreased striatal concentrations of D1 and D2 receptors and an abolition of apomorphine induced sniffing behaviour despite showing no change in striatal AC activity. In the groups which received antagonist pretreatment the reduction in the sniffing response paralleled the reduction in D2 receptor concentration whereas the incidence of vacuous oral movements was inversely related. In no case were the behavioural responses associated with changes in AC activity. We conclude that these behavioural effects observed in response to dopamine stimulation by apomorphine may be mediated through another second messenger system.

Adenylyl Cyclases↗
PubMed1988

Stimulation of D-1 dopamine receptors facilitates D-2 dopamine receptor recovery after irreversible receptor blockade.

The hypothesis that stimulation of the D-1 dopamine receptor subtype affects the recovery of the D-2 subtype after alkylation by EEDQ was investigated. Animals were pretreated with either SCH23390, to protect D-1 receptors, or saline, before administration of EEDQ. After EEDQ one group of saline pretreated animals received 12 hourly injections of the D-1 agonist SKF38393. Animals were sacrificed at 6, 24 and 48 hours after EEDQ and Kd and Bmax of striatal D-1 and D-2 receptors measured. The concentration of D-2 receptors in the groups in which D-1 receptors had been protected by SCH23390 or stimulated by SKF38393 were significantly greater than that of the EEDQ alone group.

Adrenergic alpha-Antagonists↗
PubMed1988

A fixed interval momentary sampling method for assessing on-going behaviours induced by dopamine receptor agonists.

1. An observational recording procedure for the objective measurement of unconditioned behaviour is described. 2. During an observation period an auditory cue (e.g. the click of a metronome) spaced at regular intervals (e.g. every 10 seconds) signals the observer to rate the presence or absence of target behaviours at the precise instant of the cue. 3. Practical and methodological considerations of the use of this technique are discussed. 4. This method has been used to compare behaviours elicited by the dopamine agonists apomorphine, LY-171555 and SK&F-38393. 5. These behaviours were also assessed using a stereotypy rating scale and these results are contrasted with those obtained using the time-sample method.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Evidence for post-synaptic changes mediating increased behavioural sensitivity to dopamine receptor agonists in hypothyroid rats.

1. Hypothyroidism was maintained for four weeks in male rats by administration of PTU daily. 2. Hypothyroid rats showed increased behavioural responses to apomorphine, a mixed D1/D2 dopamine receptor agonist, LY 171555, a selective D2 agonist and to SKF 38393, a selective D1 agonist, compared with euthyroid controls. 3. Responses to the selective D1 antagonist, SCH 23390, were decreased, but were increased to the D2 antagonist, haloperidol, in hypothyroid rats. 4. Ligand binding studies showed no significant differences in the affinity and concentration of D1 or D2 receptor sub-types in the striatum of hypothyroid compared with euthyroid rats. 5. However, hypothyroid rats had a greater increase in dopamine stimulated cyclic AMP in the striatum than euthyroid controls. 6. It is concluded that the changes in behavioural sensitivity observed in hypothyroid rats may be associated with these alterations in post-synaptic events.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Post-synaptic changes and increased dopamine receptor sensitivity in hypothyroid rats.

Hypothyroid rats showed increased behavioral sensitivity to both selective and non-selective dopamine agonists. Ligand binding analysis revealed no differences in concentration or affinity of striatal dopamine receptor subtypes in hypothyroid rats. Measurement of striatal cAMP levels however, indicated that hypothyroid rats showed a greater increase in cAMP production in response to stimulation by dopamine. It is concluded that the changes in behavioural sensitivity observed may be associated with alterations in post-synaptic mechanisms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1978

Chemical and functional homology of myotoxin a from prairie rattlesnake venom and crotamine from South American rattlesnake venom.

Myonecrosis is a serious result of rattlesnake bite and constitutes a persistent clinical problem. In the current study we have isolated crotamine from the venom of Crotalus durissus terrificus to test its ability to cause structural damage to skeletal muscle, and to make direct chemical comparisons with Myotoxin a, a myotoxic polypeptide we recently isolated from prairie rattlesnake (Crotalus viridis viridis) venom. Disc gel electrophoresis, isoelectric focusing, circular dichroic spectroscopy, and amino acid analysis, all indicated a high degree of chemical similarity. Light microscope histology revealed that crotamine caused vacuolizationof skeletal muscle fibers, qualitatively the same as the vacuolization caused by Myotoxin a. The ability of these two basic snake venom polypeptides to cause structural damage to skeletal muscle fibers has significant implications toward more complete understanding of the cause of snake venom-induced myonecrosis.

Amino Acids↗