Biomedical subjects

K B Franklin

Publications and source records attributed to K B Franklin.

At least 19 recordsLinked to original sources

PubMed2001

GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits.

We have examined the effects of muscimol and bicuculline microinjected in the rostral ventromedial medulla (RVM) on motor function and on nociception in three pain tests. In Exp. 1 microinjection of muscimol (6.25-400 ng in 1 microl) in the RVM dose-dependently decreased pain threshold of rats and the ED(50) for muscimol was the same in both the hot plate and tail immersion pain tests. In the hot plate test, but not in the tail immersion test, paw withdrawal latencies increased again with high doses of muscimol (75-400 ng). High doses also produced catalepsy. Exp. 2 examined the effects of muscimol (50 ng) and bicuculline (50 ng) over a range of formalin concentrations (0.25-4%) in the formalin test. Muscimol increased responsiveness to formalin and reduced the slope of the formalin dose-response relation. Bicuculline decreased responses to formalin and reduced the slope of the formalin dose-response relation. It is suggested that RVM cells with inhibitory projections to the dorsal horn are not subject to strong GABAergic influence under mild noxious stimulation. RVM cells are thus active, and spinal dorsal horn relay neurons are inhibited. On the other hand, intense noxious peripheral stimulation may stimulate the release of GABA onto RVM cells, which in turn shuts off descending inhibitory fibers to allow transmission of nociceptor input through the dorsal horn.

Animals↗

PubMed2001

Pentobarbital-induced place preference in rats is blocked by GABA, dopamine, and opioid antagonists.

RATIONALE: Drugs that are self-administered usually produce a conditioned place preference (CPP) but pentobarbital is self-administered by both animals and humans and is reported to be aversive in the CPP test. OBJECTIVES: We tested whether pentobarbital (5, 15, and 25 mg/kg; IP) could produce a place preference and examined the role of GABA, dopamine (DA) and opioid receptors in the pentobarbital CPP. METHODS: Place conditioning was carried out in an apparatus consisting of two compartments connected by an alley at the rear. During the pre-exposure and test phase, the rats were free to wander in the apparatus for 20 min, and were drug-free. During the 6-day conditioning phase, rats were injected with drug (or vehicle), and confined to one compartment for 30 min and on alternate days were injected with vehicle (or drug) and confined to the other compartment. Upon obtaining a CPP, we examined whether pretreatment of the GABAA antagonists picrotoxin or bicuculline (0.5, 1.0, and 2.0 mg/kg; IP), the DA antagonist eticlopride (0.01, 0.05, and 0.25 mg/kg; SC), or the opioid antagonist naloxone (0.02, 0.20, and 2.0 mg/kg; IP) would block the CPP. RESULTS: 15 mg/kg pentobarbital produced a CPP. The pentobarbital CPP was blocked by pretreatment of 1.0 and 2.0 mg/kg bicuculline, but not by 0.5, 1.0, or 2.0 mg/kg picrotoxin. The pentobarbital CPP was also blocked by 0.05 and 0.25 mg/kg eticlopride and by all of the doses of naloxone tested. CONCLUSIONS: Pretreatment with the antagonists bicuculline, eticlopride, and naloxone blocked a 15 mg/kg pentobarbital CPP. This indicates that GABAergic, dopaminergic, and opioid systems play a role in the reinforcing properties of pentobarbital.

Animals↗

PubMed2001

Characterization of the analgesic properties of nomifensine in rats.

The analgesic properties of the catecholamine uptake inhibitor nomifensine were investigated in the tail immersion, hot plate and formalin tests. Systemic administration of nomifensine produced analgesia only in the formalin test. The analgesia was dose-dependent (0.625-5 mg/kg), and the highest dose completely abolished nociceptive behaviors induced by 2% formalin. The analgesia was not affected by the opioid antagonist naltrexone (2.5-40 microg s.c.) but was dose-dependently reversed by the D2 antagonist eticlopride (181.3-270 microg/kg i.p.). Neither naltrexone nor eticlopride affected formalin pain scores. Nomifensine analgesia appears to be dopamine-mediated but independent of opioid mechanisms.

Analgesics↗

PubMed2000

Diazepam modifies the effect of pedunculopontine lesions on morphine but not on amphetamine conditioned place preference.

We have previously shown that T-maze learning impairments caused by lesions to the pedunculopontine tegmental nucleus (PPTg) can be reversed by the anxiolytic diazepam. We now report that diazepam also reverses the effect of PPTg lesions on conditioned place preference (CPP) to morphine but not to amphetamine. Rats with bilateral sham or N-methyl-D-aspartate lesions (0.1 or 0.05 M) to the PPTg were trained in a unbiased CPP paradigm with 2 mg/kg morphine or 2 mg/kg D-amphetamine associated with one compartment of the apparatus and vehicle injections in the alternative compartment. After three drug/saline-compartment pairings, the preference of the animals was assessed by allowing them to explore the entire apparatus for 20 min. In contrast to sham-lesioned subjects, the rats with PPTg lesions did not show a preference for the compartment paired with morphine or amphetamine. In two experiments the expression of a morphine CPP was restored by injecting the lesioned animals with 1 mg/kg of diazepam 30 min before the test session. Diazepam pre-treatment did not restore the expression of amphetamine CPP.

Amphetamine↗

PubMed2000

Diazepam in the ventral striatum dissociates dopamine-dependent and dopamine-independent place conditioning.

We have previously shown that diazepam blocks both the formation and the expression of amphetamine-induced conditioned place preference (CPP), but has no effect on the CPP induced by morphine. Because diazepam reduces dopamine activity in the nucleus accumbens, three experiments were conducted in order to investigate whether diazepam selectively blocks the expression of place conditioning dependent on mesolimbic dopamine. The first experiment found that systemic diazepam blocked the expression of conditioned place aversion induced by the kappa-receptor agonist U50-488. The second and third experiments demonstrated that intra-cranial injections of diazepam in the nucleus accumbens blocked the expression of amphetamine CPP but not of morphine CPP. It is concluded that diazepam interferes with mesolimbic dopamine-dependent motivational effects of drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2000

Effects of diazepam on conditioned place preference induced by morphine or amphetamine in the rat.

RATIONALE: The drug-abuse literature suggests that benzodiazepines may be preferentially abused in conjunction with opioids rather than stimulants. OBJECTIVE: To investigate possible effects of diazepam on the reinforcing effects of morphine and amphetamine. METHODS: The effects of diazepam (0.5, 1 or 2 mg/kg) on the formation and expression of conditioned place preferences (CPP) induced by morphine sulphate (0.3, 0.8, 2 and 8 mg/kg) or D-amphetamine (0.4, 0.8, 2 or 2.5 mg/kg) were studied in an unbiased CPP paradigm. The action of diazepam (1 mg/kg) on conditioned and unconditioned locomotion induced by morphine (2 mg/kg) or amphetamine (2 mg/kg) was assessed. RESULTS: Rats that received conditioning injections of morphine in one environment displayed a preference for this environment. Pre-testing injections of diazepam did not alter the magnitude of this CPP. When diazepam was given with morphine during training, rats displayed a CPP for the environment paired with the two drugs. Injections of amphetamine in one environment also induced a preference for this environment. However, pre-testing injections of diazepam blocked the expression of amphetamine-induced CPP, and co-injections of diazepam blocked the formation of amphetamine CPP. Diazepam itself did not produce a CPP nor did it alter spontaneous place preferences. Diazepam equally blocked both morphine and amphetamine unconditioned and conditioned locomotor hyperactivity. This indicates that its effects on morphine and amphetamine CPP were not due to a differential effect on locomotion. CONCLUSIONS: Diazepam interferes with the reinforcing properties of amphetamines but not of morphine. The reinforcing effects of morphine and amphetamine are pharmacologically dissociable.

Amphetamine↗

PubMed2000

Pontine tegmentum lesions increase anxiety-like behavior in rats: a comparison with anxiety produced by beta-CCE.

Electrolytic lesions of the pedunculopontine tegmental nucleus (PPTg) have been previously reported to increase anxiety-like behavior in rats. The aim of the present study was to compare these behavioral changes with those produced by an anxiogenic compound, the partial inverse agonist at benzodiazepine receptors, beta-CCE. Three groups of rats, sham-lesioned treated with vehicle, sham-lesioned treated with 10 mg/kg of beta-CCE, and PPTg-lesioned rats treated with vehicle, were tested in the elevated plus-maze, the social-interaction test, and for spontaneous locomotion. Histology showed that lesions were concentrated on the caudal half of the PPTg. Measures of both the PPTg-lesioned and beta-CCE-treated rats indicated increased anxiety-like behavior in the elevated plus-maze and in the social-interaction test. Spontaneous locomotion, measured in the open- field arena, did not differ between sham controls and PPTg-lesioned rats, but was decreased in rats treated with beta-CCE. Our results confirmed that electrolytic lesions of the caudal PPTg produce increased anxiety-like behavior. This behavior is quantitatively and qualitatively similar to that produced by 10 mg/kg of beta-CCE.

Animals↗

PubMed1999

Estrogen modulates spontaneous alternation and the cholinergic phenotype in the basal forebrain.

We report that a small population of neurons expresses both choline acetyltransferase and classical estrogen receptor immunoreactivity and they are found primarily in the bed nucleus of the stria terminalis. In short-term ovariectomized ageing mice (24 months, n = 5) there were 41.0 +/- 4.1% fewer of these double-labeled cells than in young (five months, n = 5) short-term ovariectomized C57BL/6J mice. To study cholinergic neuron estrogen responsiveness, young mice (n = 8) were ovariectomized at puberty (five weeks). After three months half of the mice (n = 4) were given physiological levels of 17beta estradiol for 10 days. Bed nucleus double-labeled neurons increased by 32.9% (P < or = 0.003) in the young mice given estrogen. In a gel shift assay, double-stranded oligonucleotides with putative estrogen response elements from the choline acetyltransferase gene were used as competitors against estrogen receptor binding to consensus estrogen response elements. A sequence with 60% homology to the vitellogenin estrogen response element was found to compete at 500- and 1000-fold excess. Young mice (five months) with ovaries demonstrated significantly (P < or = 0.04) better performance in the spontaneous alternation T-maze test than did old (19 month) mice with ovaries (young = 66.3 +/- 3.3% correct choices; vs old = 55.0 +/- 4.0% in old mice with ovaries). Young mice (five months old), ovariectomized for one month and treated with estrogen, showed significantly more spontaneous alternation than ovariectomized controls (69.1 +/- 2.8% vs 58.3 +/- 3.9%; P < or = 0.04). Estrogen also increased spontaneous alternation in old, short-term ovariectomized mice (61.5 +/- 2.7% vs 48 +/- 3.3%; P < or = 0.005). In either young or old ovariectomized mice, estrogen increased spontaneous alternation to levels seen in young animals with ovaries. Estrogen increases the number of choline acetyltransferase-immunoreactive and choline acetyltransferase/estrogen receptor-immunoreactive cells in old or young mice lacking estrogen, and enhances working memory in old or young mice lacking estrogen. Our data suggest that estrogen may act at the level of the choline acetyltransferase gene, but in view of the limited distribution of cholinergic cells expressing the classical estrogen receptor, it is unlikely that these cells can account for a memory enhancing effect of estrogen replacement.

Aging↗

PubMed1999

Theoretical basis for the benefit of postmenopausal estrogen substitution.

Women are being presented with an increasing number of choices for health care management as they move through the aging process. Estrogen has positive effects on mood, sexual function, target end organs and cognitive function, and may play an important role in the etiology of Alzheimer's Disease by acting to prevent amyloid plaque formation, oxidative stress, or deterioration of the cholinergic neurotransmitter system. The benefits of estrogen therapy for osteoporosis, the cardiovascular system, and lipid metabolism are far reaching, but the possibility of developing breast cancer later in life is also relevant. Understanding the mechanisms for the action of the estrogens, anti-estrogens, and the selective estrogen receptor modulators, and possible alternative routes of symptom management for some menopausal events is important to make appropriate decisions on choice of therapy. This review discusses the theoretical basis for estrogen's actions in the management of the postmenopausal stage of the life cycle.

Alzheimer Disease↗

PubMed1999

Use of stress echocardiography for risk assessment of patients after myocardial infarction.

The main predictors of outcome after infarction (exercise capacity, ejection fraction, and extent of jeopardized myocardium) can all be identified using stress echocardiography. This review addresses the place of stress echocardiography in postinfarct risk evaluation, relative to clinical evaluation, and other technologies. The test is accurate for identification of multivessel disease and for predicting outcomes, is versatile, and can be used early after infarction.

Adrenergic beta-Agonists↗

PubMed1999

Long-lasting increase in anxiety after electrolytic lesions of the pedunculopontine tegmental nucleus.

This study examined the effect of electrolytic lesions of the pedunculopontine tegmental nucleus (PPTg) on emotionality in rats. Rats with PPTg or sham lesions were tested in the elevated plus-maze, the social interaction test, the open-field test, and the conditioned fear paradigm. Histology showed that lesions were concentrated on the caudal half of the PPTg. In the plus-maze, behavioral scores were biased toward increased "anxiety" on the 1st testing day. Five consecutive exposures to the apparatus led to marked habituation in sham-lesioned but not in PPTg-lesioned rats. On the 5th day, most indexes of emotionality indicated elevated anxiety in PPTg-lesioned rats. Increased anxiety was also found in PPTg-lesioned rats in the social interaction test. In the conditioned fear paradigm, movement suppression during the postconditioned stimulus period was found in both groups on the 1st day of extinction but only in PPTg-lesioned rats on the 2nd extinction day, indicating extinction was slower in PPTg-lesioned rats. Lesions of the caudal PPTg appear to produce long-lasting anxiety in rats.

Animals↗

PubMed1998

Learning impairments caused by lesions to the pedunculopontine tegmental nucleus: an artifact of anxiety?

Bilateral N-methyl-d-aspartate lesions of the pedunculopontine tegmental nucleus (PPTg) blocked the acquisition of a delayed non-matching to position task (DNMP) performed in a T-maze. This acquisition impairment, however, was reversed by pre-testing injections of diazepam (1 mg/kg). These results, in addition to the finding that PPTg lesions elevated anxiety as measured by the elevated plus maze, suggest that PPTg is not involved in learning or memory, but in the regulation of anxiety.

Animals↗

PubMed1998

Effects of pedunculopontine tegmental nucleus lesions on responding for intravenous heroin under different schedules of reinforcement.

The pedunculopontine tegmental nucleus (PPTg) is believed to play important roles in reward and learning. We examined the effect of PPTg lesions (0.5 microl of 0.1 M NMDA injected bilaterally over 10 min) on the learning of an operant response for opiate reward. In 14 adult male Long-Evans rats, bilateral lesions of the PPTg disrupted the acquisition of responding for intravenous heroin (0.1 mg/kg infused at a rate of 0.25 ml/28 sec) on a fixed ratio-1 (FR-1) schedule of reinforcement. The 12 remaining lesioned animals increased their heroin intake over the acquisition sessions but did not reach the response levels of sham-lesioned animals on the 15th and final session. The sham- and PPTg-lesioned animals that learned the FR-1 task exhibited similar patterns of responding during extinction and reacquisition sessions. When tested on a progressive ratio (PR) schedule of reinforcement, however, PPTg-lesioned animals had lower break points than sham-lesioned animals. Asymmetric lesions, which destroyed the majority of the nucleus in one hemisphere only, did not produce any behavioral deficits. Rats that were lesioned after training also did not show deficits in responding under either FR or PR schedules. These findings suggest that PPTg lesions reduce the rewarding effect of opiates but do not disrupt the ability either to learn an operant response or the response requirements of a PR schedule.

Animals↗

PubMed1998

Lesions of the pedunclopontine tegmental nucleus increase anxiety in rats.

To test the hypothesis that the pedunclopontine tegmental nucleus (PPTg) plays a role in anxiety, rats with electrolytic lesions of the PPTg were tested in two animal models of anxiety, the elevated plus maze and the social interaction tests. Histological analysis showed that lesions were concentrated on the caudal half of the PPTg. In the elevated plus maze, traditional as well as 'risk assessment' measures indicated significantly increased anxiety in the PPTg-lesioned rats vs sham-operated controls. In the social interaction test, behavioural scores were biased towards elevated anxiety in the PPTg-lesioned rats but only the number of social sniffs reached significance. Our results confirm that electrolytic lesions of the caudal PPTg produce increased anxiety.

Animals↗

PubMed1998

Analgesia and abuse potential: an accidental association or a common substrate?

The fact that centrally acting analgesics have abuse potential commensurate with their analgesic activity raises the question of whether these effects are related. The abuse potential of drugs depends on their ability to produce reinforcing effects, which are mediated by a neural system that includes the ventral tegmental dopamine cells and their connections with the ventral striatum. Morphine and amphetamine are both powerful analgesics and have high abuse potential. Their analgesic and reinforcing effects are mediated by similar receptors, similar sites of action, and overlapping neural substrates. These coincidences suggest that reinforcers may produce analgesia by transforming the aversive affective state evoked by pain into a more positive affective state. The implications of this hypothesis and its relation to other known mechanisms of analgesia are discussed. The hypothesis predicts that drugs with reinforcing effects should produce analgesia. A survey of drugs acting through 21 classes of receptors reveals that in 13 classes there is evidence for both analgesic and reinforcing effects that are approximately equipotent. The GABA(A) agonists were found to be the only drugs with confirmed abuse potential that lack analgesic activity. The interpretation of this and several other anomalous cases is discussed.

Analgesics↗

PubMed1998

Morphine analgesia in the formalin test: reversal by microinjection of quaternary naloxone into the posterior hypothalamic area or periaqueductal gray.

Bilateral microinjection of 5 nmol morphine into the posterior hypothalamic area (PHA), periaqueductal gray matter (PAG) or ventral tegmental area (VTA) elicits powerful suppression of nociceptive behaviors in the formalin test, an animal model of injury produced pain. The object of the present study was to determine whether analgesia in the formalin test (50 microl 2.5% formalin injected s.c. in one hindpaw) induced by systemically administered morphine requires opioid action at these sites, or other putative sites of opioid action. Morphine sulphate (6 mg/kg s.c.) produced almost complete analgesia in the second phase of the formalin test (30-50 min after formalin). Bilateral microinjection of the quaternary opioid antagonist naloxone methobromide (NxBr, 28 ng in 0.5 microl, 22 min after morphine) into the PHA completely abolished morphine analgesia, while NxBr into PAG partially reversed analgesia. Microinjection of NxBr into the VTA, central nucleus of the amygdala, habenula, striatum, nucleus accumbens or hypothalamic sites outside the PHA did not antagonize morphine analgesia, although microinjections into some of these sites appeared to reduce the cataleptogenic effects of morphine. The data indicate that the PHA and PAG are probably the primary sites of action of morphine in the formalin test.

Analgesics, Opioid↗

PubMed1997

The development of a conditioned place preference to morphine: effects of lesions of various CNS sites.

This study examined the neural substrates underlying the development of a conditioned place preference (CPP) to morphine (2 mg/kg x 3 pairings) by testing whether lesions of 7 different neural sites block a morphine-induced CPP. Lesions of the pedunculopontine tegmental nucleus (PPTg), the periaqueductal gray (PAG), or the fornix reduced the preference for a morphine-paired compartment. When they were retested following morphine administration, fornix- or PAG-lesioned animals exhibited a CPP indicating that lesions did not block morphine-induced reward or the ability to associate this effect with salient environmental cues. PPTg-lesioned animals did not express a CPP during state-dependent testing, suggesting that the lesions may attenuate the rewarding effect of the drug. Lesions of the mesolimbic dopamine system, the ventral pallidum, the lateral nucleus of the amygdala, or the caudate putamen had no effect on a morphine-induced CPP.

Animals↗

PubMed1997

The development of a conditioned place preference to morphine: effects of microinjections into various CNS sites.

Experiment 1 examined whether microinjections of morphine (1 microg in 0.5 microl over 1 min x 2 pairings) into 13 different CNS sites produced a conditioned place preference (CPP). Injections into the lateral ventricles (LV), ventral tegmental area (VTA), or periaqueductal gray (PAG) produced a CPP; injections 1 mm dorsal to the PAG or VTA, or into the caudate putamen, medial frontal cortex, hippocampus, lateral nucleus of the amygdala, lateral hypothalamus, pedunculopontine tegmental nucleus, posterior hypothalamus, ventral palladium, or nucleus accumbens septi (core or shell) did not. In Experiment 2, morphine 0.2 microg produced a CPP when injected into the VTA but not in the PAG, while 5.0 microg was effective in both sites. The CPP induced by systemic morphine (4 mg/kg x 1 pairing) was blocked by naloxone methiodide (NM) injected (2 nmol in 0.5 microl) into the VTA. PAG injections of 2 nmol reduced, and 5 nmol NM eliminated, the CPP. The results confirm that morphine injections into the VTA or the PAG are rewarding, that blockade of opioid receptors in either site disrupts a morphine-induced CPP, and that the VTA is more sensitive to both effects.

Animals↗