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Biomedical subjects

G E Hunt

Publications and source records attributed to G E Hunt.

At least 19 recordsLinked to original sources
PubMed1999

The distribution of 3,4-methylenedioxymethamphetamine "Ecstasy"-induced c-fos expression in rat brain.

Rats were injected with 3,4-methylenedioxymethamphetamine ("Ecstasy") and assessed for changes in locomotor activity and for the expression of the immediate early gene c-fos throughout the brain. A dose-dependent increase in locomotor activity was seen with 3,4-methylenedioxymethamphetamine (0, 5 and 20 mg/kg) that continued for at least 2 h following administration. Dose-dependent increases in c-fos expression were seen in much of the cortex, forebrain, brainstem and cerebellum in rats given 3,4-methylenedioxymethamphetamine. Expression was pronounced in 5-hydroxytryptamine terminal regions including the medial prefrontal cortex, caudate-putamen, nucleus accumbens, olfactory tubercle, islands of Calleja, lateral septum, paraventricular hypothalamus and paraventricular thalamus. High levels of c-fos expression were also seen in the supraoptic and median preoptic nuclei, regions involved in the control of fluid balance and body temperature, respectively. This is potentially important since deaths in 3,4-methylenedioxymethamphetamine users have been linked to hyperthermia and hyponatremia. In the brainstem, two regions of high c-fos expression were Barrington's nucleus, which is involved in micturition, and the pontine reticular nucleus oralis, a region involved in motor control of mastication. Activation of this latter structure may partly explain the bruxism (grinding of the jaw) reported by human 3,4-methylenedioxymethamphetamine users. Robust c-fos expression was seen in the cerebellum, particularly in the flocculus, and this may explain the reported deleterious effects of 3,4-methylenedioxymethamphetamine on balance and co-ordination. Significant c-fos expression was also seen in the ventral tegmental area, amidst the cell bodies of mesolimbic and mesocortical dopamine neurons, and in the median and dorsal raphe, where the serotonergic innervation of the forebrain originates. Double-labelling of fos-positive neurons with 5-hydroxytryptamine showed that only a small number of serotonergic neurons in the raphe expressed c-fos following 3,4-methylenedioxymethamphetamine. The widespread distribution of 3,4-methylenedioxymethamphetamine-induced c-fos expression seen in this study can be linked to the profound alterations in physiological function, mood and behaviour produced by this drug.

Animals↗
PubMed1999

Beer consumption in rats: the influence of ethanol content, food deprivation, and cocaine.

A series of experiments examined various aspects of beer consumption in male Wistar rats. In the first experiment, rats were given home cage access to either beer or ethanol solutions under free access conditions. It was found that rats consumed greater amounts of moderate strength beer (2.7% ethanol by volume) or regular strength beer (5.0% ethanol) than equivalent dilute ethanol solutions in water. Consumption of 2.7% beer was greater than 5.0% beer and access to either beer, but not dilute ethanol, solutions caused substantial increases in total fluid intake per day. In the second experiment, individual rats given daily 30-min drink sessions consumed more 2.7% beer than 3.85% beer and more 3.85% than 5.0% beer. A "hangover" effect was evident after the first day of consumption of 5.0% beer with subsequent intake of this beer suppressed after high intake on first exposure. Intake of the low-strength beer approached intake of isocaloric (8.6%) sucrose solution. In a third experiment, a lick-based progressive ratio paradigm was implemented where rats had to emit progressively greater number of licks for a fixed volume (0.1 ml) of 2.7% beer or 8.6% sucrose. Using this paradigm, it was shown that food deprivation increased the motivation to consume beer and sucrose as shown by elevated break points (the highest ratio reached). Food deprivation also increased locomotor activity in the drinking environment. In contrast, cocaine (20 but not 10 mg/kg) caused a decrease in the break point for sucrose and beer, an effect probably mediated by the anorexic properties of the drug. It is concluded that rats will avidly consume beer, particularly of moderate alcohol content, but that such consumption may be mediated more by the nutritive and palatable characteristics of the beer rather than by the psychoactive effects of the alcohol it contains.

Animals↗
PubMed1998

A comparison of delta 9-THC and anandamide induced c-fos expression in the rat forebrain.

Rats were injected with the cannabinoid receptor agonists delta 9-THC (5 mg/kg) or anandamide (20 mg/kg) and assessed for changes in body temperature and locomotor activity. Their brains were then examined for the expression of the immediate early gene c-fos. Similar reductions in body temperature and locomotor activity were seen with delta 9-THC and anandamide although there was evidence, in line with previous reports, to suggest a shorter duration of action of anandamide. delta 9-THC and anandamide caused equally high levels of c-fos expression in the paraventricular nucleus of the hypothalamus and the lateral septum. Both drugs also increased c-fos expression in the central nucleus of the amygdala although the effect was greater with delta 9-THC. Only delta 9-THC caused significant increases in c-fos expression in the nucleus accumbens and caudate-putamen. These differences may be linked to differential activation of cannabinoid receptor subtypes or to differences in efficacy in activating second messenger systems linked to cannabinoid receptors. These findings complement evidence of qualitative differences in the actions of anandamide and delta 9-THC emerging from tests of drug discrimination, cross-tolerance, conditioned place preference and anxiety.

Animals↗
PubMed1998

Possible neural substrates of beer-craving in rats.

Rats voluntarily consumed beer in a distinctive environment during 30 min daily sessions over 21 days, ingesting a daily average of 0.96 g/kg of ethanol. On a final test day, rats in a 'craving' condition were denied access to the beer in the drinking environment. The expression of c-fos in the brain of 'craving' rats was compared with that in rats given free access on the test day ('beer' condition), and to rats which had been repeatedly placed in the drinking environment without ever having access to beer ('control' condition). Rats in the 'craving' condition showed significantly higher c-fos counts than either the 'beer' or 'control' rats in a variety of corticolimbic and brainstem structures, indicating that activation of these regions occurs when a desirable alcoholic beverage is expected but not received.

Alcoholism↗
PubMed1998

Effects of pre-exposure and co-administration of the cannabinoid receptor agonist CP 55,940 on behavioral sensitization to cocaine.

Rats given cocaine (15 mg/kg, i.p.) every second day over a 2-week period displayed a progressively greater locomotor response to the drug over days indicating behavioral sensitization. When the cannabinoid receptor agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl)cyclohexanol) (10, 25 or 50 microg/kg) was administered under a similar regime, no such sensitization was observed. Rather, the two highest doses of CP 55,940 (25 and 50 microg/kg) caused locomotor suppression that lasted throughout administration. When rats pre-exposed 10 times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, the cannabinoid continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 microg/kg) was co-administered with cocaine, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioral sensitization. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioral effects of cocaine.

Analgesics↗
PubMed1998

Rewarding brain stimulation induces only sparse Fos-like immunoreactivity in dopaminergic neurons.

In this study, c-fos immunohistochemistry was used to identify the brain regions activated by rewarding brain stimulation in rats. Rats had monopolar electrodes implanted in the medial forebrain bundle and were allocated to either a self-stimulation (n = 4), yoked stimulation (n = 4) or no stimulation (n = 6) group. In a single 1 h test session, each rat in the self-stimulation group made 1000 nose poke responses with each response followed by a 0.5 s train of brain stimulation. Rats in the yoked-stimulation group were paired with a partner in the self-stimulation group and received brain stimulation whenever their partner did. However, their nose poke responses did not trigger stimulation. This yoked procedure was thus used to identify any Fos-like immunoreactivity due to operant responding. Rats in the no stimulation group were placed in the same apparatus as the other rats but received no brain stimulation and were thus used to assess baseline Fos-like immunoreactivity. Results showed that stimulation increased Fos-like immunoreactivity in many areas of the brain in both the self-stimulation and yoked groups. The areas with the highest Fos-like immunoreactivity were ipsilateral to the electrode site and included the medial prefrontal cortex, lateral septum, nucleus accumbens (shell), the medial and lateral preoptic areas, bed nucleus of the stria terminalis, central amygdala, lateral habenula, dorsomedial hypothalamus, lateral hypothalamus and the anterior ventral tegmental area. Bilateral Fos-like immunoreactivity was evident in the nucleus accumbens core, paraventricular nucleus of the hypothalamus, the retrorubral fields and the locus coeruleus. A double-labelling procedure identifying both Fos and tyrosine hydroxylase was used to show that very few (< 5%) of the A10 dopamine cell bodies in the ventral tegmental area expressed Fos following brain stimulation. In contrast, most of the noradrenergic neurons of the locus coeruleus (A6), rubrospinal tract (A5) and pontine tegmental area (A7) were Fos positive. Overall, the results show that rewarding, brain stimulation induces Fos-like immunoreactivity in many forebrain regions but only sparsely in mesolimbic and mesocortical dopamine neurons. The similar patterns of Fos-like immunoreactivity seen in the self-stimulation and yoked-stimulation groups suggests that the operant responding for brain stimulation causes minimal Fos expression in itself.

Animals↗
PubMed1998

Nitric oxide and cyclic GMP attenuate sensitivity of the blood-tumor barrier permeability to bradykinin.

Intracarotid infusion of bradykinin and its analogue, RMP-7, selectively increase the permeability of brain tumor capillaries though the nitrix oxide (NO) and cyclic GMP pathway. Maximum blood-tumor barrier (BTB) permeability induced by bradykinin is observed at 15 min after intracarotid infusion and this effect is decreased even if the infusion continues. The mechanism for this decreased effect with long term infusion has not been clearly defined. This study sought to determine the involvement of the NO-cyclic GMP pathway in this event. Regional permeability was investigated in 44 Wistar rats with implanted RG2 gliomas, using quantitative autoradiography to determine the unidirectional transfer constant (Ki) of radiolabeled 14C-dextran. Tumor bearing rats were treated by intracarotid infusion of bradykinin (10 micrograms kg-1 min-1) with or without pretreatment with bradykinin, the NO donor s-nitrosoglutathione (10 nmol kg-1 min-1), or the cyclic GMP analogue, 8Br-cyclic GMP (200 micrograms kg-1 min-1). At 30 min of bradykinin infusion, BTB permeability was significantly lower compared to 15 min of bradykinin infusion (3.79 +/- 0.99 vs. 16.20 +/- 3.43 microliters g-1 min-1, p < 0.001). Pretreatment with an NO donor significantly decreased BTB permeability in bradykinin infused rats (5.09 +/- 2.61 vs. 13.51 +/- 4.19 microliters g-1 min-1, p < 0.001), as did pretreatment with a cyclic GMP analogue (4.48 +/- 0.95 vs. 12.31 +/- 3.90 microliters g-1 min-1, p < 0.001). There was no increased permeability in nontumor brain areas. Increased tumor permeability by bradykinin appears to be regulated by NO and cyclic GMP which are second messengers involved in the bradykinin B2 receptor mediated cascade.

Animals↗
PubMed1997

Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects.

The pharmacokinetics of dexamethasone (DEX) were studied in 9 drug-free melancholically depressed patients and 10 healthy control subjects matched by sex and age. Each subject received 1 mg of DEX administered orally and by the (i.v.) route at 11:00 PM and serial blood samples were collected over the next 17 hours until 4:00 PM. There were no significant differences between the diagnostic groups and DEX bioavailability, peak plasma level, time to maximum concentration, or in elimination half-life after oral administration. Bioavailability estimates indicated that DEX absorption was incomplete and variable mean = 61%, SD = 14) in controls as well as depressed patients. In both groups there was a wide interindividual variability in plasma DEX levels following both oral and i.v. routes of administration. This variability could not be reliably predicted by differences in age, sex, or weight between subjects. The factors that accounted for most the variability in 4:00 PM plasma DEX levels after oral administration were clearance, bioavailability, and time to reach maximum concentration. Plasma DEX levels were lower in 3 depressed nonsuppressors compared to 3 matched controls who suppressed. No single pharmacokinetic factor was shown to be responsible for the lower DEX levels in the depressed nonsuppressors. These results indicate that plasma DEX levels need to be measured in each individual during the DST procedure so that this information may be taken into consideration when interpreting DST results.

Administration, Oral↗
PubMed1994

Reward summation and the effects of dopamine D1 and D2 agonists and antagonists on fixed-interval responding for brain stimulation.

The effects of dopamine D1 and D2 agonists and antagonists on fixed-interval (FI) self-stimulation were investigated using a reward-summation model, trading off frequency with train duration. The D1 antagonist SCH 23390 (0.005-0.02 mg/kg) decreased FI self-stimulation and the inhibition was reversed by increasing stimulation frequency. Moreover, amphetamine (0.5 mg/kg) reversed the inhibition by a low dose of SCH 23390 (0.005 mg/kg) but not after a higher dose inhibition could not be dissociated from a performance deficit. There was no significant interaction between low doses of spiperone and SCH 23390 when coadministered that could not be predicted from their effects when given individually. Self-stimulation was inhibited by the D1 agonist SKF 38393 (5 mg/kg). When coadministered with amphetamine, SKF 38393 partially blocked amphetamine's facilitation. The D2 agonist bromocriptine (10 mg/kg) produced an extraordinary enhancement of performance that was also evident after a lower dose (5 mg/kg) when it was combined with amphetamine. This enhancement of performance showed little extinction when stimulation was no longer available, suggesting it was a novel form of stereotypy. These results support the concept that D1 dopamine receptors play a critical role in modulating the reinforcing consequences of lateral hypothalamic stimulation. The involvement of D2 receptors on reinforcement processes remains contentious due to their effects on performance and insensitivity of responding to coincide with changes in reinforcement magnitude.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Parametric manipulations and fixed-interval self-stimulation.

Three experiments investigated hypothalamic self-stimulation under a fixed-interval (FI) reinforcement schedule. An FI 20-s schedule was chosen to reduce stimulation density in order to minimize the influence of priming effects or stimulation aftereffects that can affect responding under other schedules of reinforcement. The first experiment showed that the influence of train duration is greatest at levels up to 1 s and thereafter level off over a wide range of train durations (1-32 s). The second experiment showed that altering frequency, current, or pulse width produced almost identical changes in FI responding. These findings show that the neutral network subserving hypothalamic self-stimulation simply integrates the amount of charge over time. It is relatively insensitive to the combination of stimulation parameters that make up a given waveform. In the third experiment, the chronaxies from the strength-duration curves indicate the neural substrate supporting self-stimulation has a great current-integrating capacity. Together, these experiments show that varying the amount of brain stimulation produce large and consistent changes in a number of FI response measures. These measures effectively describe different attributes of FI performance and include response rate, the postreinforcement pause, interresponse times of short duration and the temporal distribution of responses within the interval.

Animals↗
PubMed1992

Reward summation and the effects of pimozide, clonidine, and amphetamine on fixed-interval responding for brain stimulation.

Two models of reward summation were examined in 16 rats lever pressing for intracranial stimulation under fixed-interval (FI) reinforcement. The first model examined rate-frequency functions and the second model traded off frequency and train duration. The second model was selected to assess the effects of three drugs on reward summation. Both clonidine and pimozide inhibited FI self-stimulation, but pimozide's effect could not be distinguished from a performance deficit. Two amphetamine isomers facilitated self-stimulation in a manner suggesting enhanced reinforcement. The dextro isomer was four times more effective than the levo isomer to facilitate self-stimulation. This study shows that the combination of the FI schedule with a reward-summation model is well suited for evaluating the effects of drugs on self-stimulation. The advantages of this model are that inter-reinforcement intervals are separated, which minimizes priming and stimulation aftereffects, and more responding does not increase stimulation availability, thus eliminating rate-dependency effects.

Amphetamine↗
PubMed1991

Effect of high plasma dexamethasone levels on DST sensitivity: dose-response study in depressed patients and controls.

The aim of this study was to examine cortisol dynamics over a range of plasma dexamethasone (DEX) levels using a two-dose dexamethasone suppression test (DST). Two doses of DEX (0.5 and 1.5 mg) were administered in a randomized crossover design to 29 inpatients with major depression and 26 controls to identify the upper range of plasma DEX levels that would allow reliable interpretation of DST results. It was hypothesized that due to inappropriately high plasma DEX levels following 1.5 mg, several depressed patients would switch from suppressors after the 1.5 mg dose to nonsuppressors after 0.5 mg. In contrast, the nondepressed controls with high DEX levels following 1.5 mg would remain suppressors after the lower dose. Fourteen patients were identified as having high 4 p.m. DEX levels (greater than 4 nmol/l) after the 1.5 mg DST. Cortisol was suppressed in all of the subjects with high DEX levels. After 0.5 mg, five of the eight depressed patients with high DEX levels switched to nonsuppressors. In contrast, all six controls with high DEX levels remained suppressors. These results indicate that patients with high DEX levels after a 1 mg DST should be retested with a lower dose. This strategy enhances the sensitivity of the DST without loss of specificity.

Depressive Disorder↗
PubMed1989

The plasma dexamethasone window: evidence supporting its usefulness to validate dexamethasone suppression test results.

Two doses of dexamethasone (DEX) (0.5 and 1.0 mg) were administered in a randomized crossover design to 31 patients with major depression, 9 healthy controls, and 14 nondepressed psychiatric patients. Using this modified Dexamethasone Suppression Test (DST), minimum DEX levels of 6 nmol/liter at 8:00 AM and 2.0 nmol/liter at 4:00 PM were required to achieve reliable suppression of cortisol in healthy controls and nondepressed psychiatric patients. Failure to achieve these minimum plasma DEX levels was associated with similar rates of nonsuppression in both depressed and nondepressed patients, thereby reducing the specificity of the DST. Conversely, high DEX levels greater than 13 nmol/liter at 8:00 AM or 4.0 nmol/liter at 4:00 PM were associated with abnormal "suppressibility" in depressed patients, thereby reducing the sensitivity of the test. Controlling for plasma DEX concentrations by selecting a test result that fell within a plasma DEX window at 8:00 AM and 4:00 PM increased the sensitivity and specificity of the DST. Significant differences in plasma DEX between suppressors and nonsuppressors were no longer evident when comparing patients with adequate DEX levels, thus ensuring that cortisol escape reflected HPA axis changes associated with depression and not peripheral mechanisms responsible for the availability of DEX. These results suggest that the clinical utility of the DST would be significantly enhanced by extending the standard 1.0-mg DST and retesting those patients with levels outside the DEX window with a higher or lower dose. The data also indicate that the measurement of plasma DEX is essential to validly interpret DST status and highlight the need to standardize DEX assays to compare DST results between research centers.

Adult↗
PubMed1986

Growth hormone and cortisol secretion after oral clonidine in healthy adults.

The purpose of this study was to evaluate oral clonidine for testing growth hormone (GH) responsiveness in healthy adults. Oral clonidine (0.15 mg) produced a satisfactory GH response (greater than 4 ng/ml from basal) in eight out of 10 subjects, which is similar to rates reported after an equivalent intravenous dose. Elevated GH levels at baseline occurred in four out of five female subjects; this did not affect the clonidine-induced GH release. There were no significant differences at any time point in plasma prolactin or cortisol levels following clonidine, compared to placebo controls. Adequate plasma clonidine levels (greater than 0.4 ng/ml) were achieved in all subjects, with corresponding reductions in mean arterial blood pressure, but with only minimal adverse effects. Results from this study indicate that oral clonidine is a reliable method for testing GH responsiveness in adult subjects.

Administration, Oral↗