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P W Kalivas

Publications and source records attributed to P W Kalivas.

At least 19 recordsLinked to original sources
PubMed1992

Effect of inhibiting enkephalin catabolism in the VTA on motor activity and extracellular dopamine.

The mixed inhibitor of enkephalin catabolism, kelatorphan, was microinjected into the ventral tegmental area (VTA) of rats to determine if endogenous enkephalins can modulate dopamine transmission in the mesoaccumbens projection. The concentration of extracellular dopamine content in the nucleus accumbens was monitored using in vivo microdialysis simultaneously with measuring motor behavior. Kelatorphan microinjection into the VTA produced a dose-related increase in motor activity and extracellular dopamine in the nucleus accumbens. While the change in extracellular dopamine was modest as compared to exogenous stimulation by a mu agonist such as DAMGO, there was a marked increase in the extracellular content of dopamine and serotonin metabolites. This suggests that mesoaccumbens dopamine transmission is under tonic control of endogenous enkephalins at the ventral tegmental area level.

Amino Acid Sequence↗
PubMed1992

Patterns of glucose use after bicuculline-induced convulsions in relationship to gamma-aminobutyric acid and mu-opioid receptors in the ventral pallidum--functional markers for the ventral pallidum.

Bicuculline-induced convulsions increased glucose use throughout the brain and sharply demarcated the ventral pallidum and globus pallidus. Glucose use in the nucleus accumbens also increased after bicuculline-induced convulsions, except for a circumscribed region in the dorsomedial shell. Since the projection from the nucleus accumbens to the ventral pallidum contains gamma-aminobutyric acid (GABA) and the opioid peptide, enkephalin, the pattern of increased glucose use in the ventral pallidum and nucleus accumbens after bicuculline-induced convulsions was compared to the topography of GABAA and mu-opioid receptors. The pattern of glucose use in the nucleus accumbens and ventral pallidum resembled the topography of GABAA, but differed from that of mu-opioid receptors. Bicuculline may disinhibit GABAergic efferents to the ventral pallidum resulting in a dramatic increase in glucose use within striatopallidal synaptic terminals as well as in local terminals of the pallidal projection neurons.

Animals↗
PubMed1992

Correlation between behavioral sensitization to cocaine and G protein ADP-ribosylation in the ventral tegmental area.

The ventral tegmental area is a site of action by psychostimulants in the production of behavioral sensitization. Recently, G proteins of the ventral tegmental area have been implicated in behavioral sensitization to cocaine. To further investigate the specific role of G proteins, rats were treated with either 15 or 30 mg/kg, i.p., of cocaine (x 5 days), and at 1, 6 or 24 h after the last injection in vitro pertussis toxin catalyzed adenosine diphosphate (ADP)-ribosylation was used to measure the G proteins in the ventral tegmental area, nucleus accumbens, prefrontal cortex, substantia nigra, and striatum. A significant decline in the ADP-ribosylation of G proteins, specific for the ventral tegmental area, was observed at 1 and/or 6 h but had returned to normal by 24 h. A significant negative correlation was found between the percent of G proteins ADP-ribosylated in the ventral tegmental area and the behavioral activity elicited in sensitized but not acute cocaine-treated animals at 1 h after injection. These data suggest that the G proteins ADP-ribosylated by pertussis toxin may be involved in the sensitized motor response produced by repeated cocaine administration in rats.

Adenosine Diphosphate Ribose↗
PubMed1992

Apomorphine decreases extracellular GABA in the ventral pallidum of rats with 6-OHDA lesions in the nucleus accumbens.

Inhibition of a tonically active gamma-aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is thought to mediate the locomotor response elicited by dopamine in the nucleus accumbens. To evaluate this hypothesis, dopamine was depleted in the nucleus accumbens using 6-hydroxydopamine which produced an upregulated locomotor response to systemic apomorphine (0.2 mg/kg, s.c.). Simultaneously, the level of extracellular GABA in the VP was monitored using microdialysis. Apomorphine injection produced an elevation in locomotor activity only in the lesioned rats. While apomorphine reduced extracellular GABA in both control and lesioned rats, the reduction had an earlier onset and was more consistent in lesioned animals. Although the onset of the decline in extracellular GABA in the VP of lesioned rats corresponded to the onset of apomorphine-induced motor activity, a significant reduction in GABA persisted for 180 min, while the behavior returned to control levels by 60 min after injection. These data support a possible role for dopamine receptor-mediated inhibition of accumbal GABA neurons projecting to the VP in the initiation of locomotor activity.

Animals↗
PubMed1992

Dopamine depletion produces augmented behavioral responses to a mu-, but not a delta-opioid receptor agonist in the nucleus accumbens: lack of a role for receptor upregulation.

Microinjection of either mu- or delta-opioid agonists into the nucleus accumbens produces an increased locomotor activity, and when the dopaminergic innervation of the nucleus accumbens is bilaterally lesioned, the locomotor response to the microinjection of mixed mu- and delta-opioid agonists is augmented. To determine whether the lesion-induced augmentation to opioids is specific to mu- or delta-opioid receptor activation, dopamine innervation of the nucleus accumbens was lesioned with 6-hydroxydopamine (6-OHDA), and the motor stimulant response to intra-accumbens microinjection of the selective mu-opioid agonist, Tyr-D-Ala-Gly-mePhe-Gly-OH (DAMGO), was compared to that of the delta-opioid agonist, [D-penicillamine2,5]-enkephalin (DPDPE). The lesions caused a 95% depletion of tissue dopamine levels in the nucleus accumbens of the DAMGO-injected rats compared to sham-lesioned rats. Horizontal and vertical photocell counts were significantly increased in response to DAMGO in 6-OHDA-lesioned compared to the sham-lesioned rats. This behavioral augmentation was dose dependent and blocked by naloxone. In rats with similar accumbal dopamine depletions (94%), the locomotor response to DPDPE was not enhanced. The augmentation in the behavioral response to DAMGO was not associated with a change in the Bmax or Kd of [125I]DAMGO binding in nucleus accumbens homogenates from lesioned rats. Likewise, using quantitative receptor autoradiography, no difference between 6-OHDA- and sham-lesioned rats was observed in [125I]DAMGO or [125I]DPDPE binding. Therefore, the augmented behavioral response to opioids in the nucleus accumbens following dopamine depletion relies predominately on mu-opioid receptor stimulation. However, this augmentation is not mediated by an alteration in the number or affinity of these receptors.

Animals↗
PubMed1992

Autoradiographic localization of gamma-aminobutyric acidA receptors within the ventral tegmental area.

Destruction of intrinsic neurons in the ventral tegmental area (VTA) with the excitotoxin, quinolinic acid produced a significant decrease (80%) in [3H]muscimol binding to GABAA receptors within the parabrachial pigmented and paranigral nuclei of the VTA. Selective destruction of the dopaminergic neurons with 6-hydroxydopamine (6-OHDA) did not reduce [3H]muscimol binding within the VTA. However, the destruction of dopaminergic neurons did produce an increase (20%) in [3H]muscimol binding contralateral to the lesion, suggesting a reduction in the GABAergic innervation to this region. Additionally, destruction of the VTA afferents with quinolinic acid injections in the medial accumbens failed to produce alterations in [3H]muscimol binding within the VTA. These results are consistent with the predominant localization of GABAA receptors to non-dopaminergic neurons intrinsic to the VTA.

Animals↗
PubMed1992

Dopamine and endogenous opioid regulation of picrotoxin-induced locomotion in the ventral pallidum after dopamine depletion in the nucleus accumbens.

Microinjection of picrotoxin or the mu-opioid agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO), into the ventral pallidum (VP) produces an increase in locomotor activity that is antagonized by dopamine receptor blockade. To investigate the regulation of VP-induced locomotion by the dopaminergic innervation of the nucleus accumbens (NA) and the role of opioid receptors in this regulation, dopamine innervation of the NA was bilaterally lesioned with 6-hydroxydopamine (6-OHDA). The lesions resulted in an 89-97% depletion of tissue dopamine levels in the nucleus accumbens compared with sham-lesioned rats. Dopamine depletion in the NA failed to significantly antagonize picrotoxin or DAMGO injected into the VP. However, the dopamine receptor antagonist, haloperidol (0.1 mg/kg, IP), blocked the picrotoxin-initiated increase in horizontal photocell counts in both sham- and 6-OHDA-lesioned rats. The opioid receptor antagonist, naloxone (1.0 mg/kg, SC), also blocked the picrotoxin-induced locomotion in 6-OHDA-lesioned rats but did not block locomotion in the sham-lesioned rats. At a higher dose (3.0 mg/kg, SC), naloxone blocked picrotoxin-induced locomotion in both sham- and 6-OHDA-lesioned rats. These results indicate that although dopamine depletion in the NA does not affect the permissive role of dopamine transmission on locomotion elicited from the VP, it results in an increased sensitivity to enkephalinergic transmission.

Animals↗
PubMed1992

The role of the nucleus accumbens in sensitization to drugs of abuse.

1. Male rats received cannula implants above the nucleus accumbens for monitoring extracellular concentrations of dopamine via in vivo microdialysis. 2. Daily injections with cocaine led to an augmentation in both the behavioral response and the neurochemical response (i.e. cocaine-induced increase in extracellular dopamine within the nucleus accumbens) to this drug. 3. Pertussis toxin injections into the A10 region led to sensitized behavioral and neurochemical responses to an acute injection of cocaine. 4. Prior exposure to footshock stress augmented the cocaine-induced increase of motor activity and of extracellular dopamine within the nucleus accumbens. 5. These data suggest that treatments which lead to behavioral sensitization also lead to sensitization within the mesolimbic dopamine system as measured by an augmented dopamine release in the nucleus accumbens.

Animals↗
PubMed1992

Topography and functional role of dopaminergic projections from the ventral mesencephalic tegmentum to the ventral pallidum.

A dopaminergic projection from the ventral tegmental area to the ventral pallidum was identified in the rat using anterograde tract tracing and combined retrograde tracing-immunocytochemistry. The projection was found to be topographically organized such that fibers innervating the ventromedial ventral pallidum arose from neurons located along the midline nuclei of the ventral mesencephalon, including the nucleus interfascicularis and nucleus linearis caudalis. Ventral tegmental neurons situated more laterally, in the nucleus parabrachialis pigmentosus and nucleus paranigralis, projected to the ventromedial and dorsolateral ventral pallidum. The substantia nigra did not supply a major contribution to this projection. The proportion of ventral tegmental area dopaminergic neurons projecting to the ventral pallidum ranged from approximately 30% to 60%. The functional significance of the projection is indicated since intra-ventral pallidum microinjections of dopamine elicited a dose-dependent increase in locomotor activity. Furthermore, whereas pretreatment of the ventral pallidum with the GABAA agonist muscimol has been shown to attenuate opioid-induced locomotor activity elicited from the ventral pallidum, it did not attenuate the dopamine-induced motor response. Thus, while mu-opioids in the ventral pallidum may presynaptically regulate GABAergic efferents from the nucleus accumbens, it appears that the dopaminergic input directly influences the ventral pallidal output neuron which is involved in locomotion.

Afferent Pathways↗
PubMed1992

Pertussis toxin in the A10 region increases dopamine synthesis and metabolism.

Inhibitory regulation of dopamine neurons is mediated by dopamine autoreceptor and gamma-aminobutyric acidB receptor opening of potassium channels. Increased potassium conductance by either receptor is G protein dependent. To evaluate the role of G proteins in vivo, pertussis toxin (PTX) was microinjected into the A10 dopamine region and changes in dopamine metabolism and synthesis measured. PTX produced an elevation in dopamine metabolism and synthesis in the A10 region and nucleus accumbens for up to 4 days after injection. By day 7 the levels of the dopamine precursor and metabolites had returned to normal. A less consistent increase was also measured in the A9 dopamine region and the prefrontal cortex. Although dopamine synthesis and metabolism had returned to normal by day 7, the in vitro ADP-ribosylation of G proteins in the A10 region by PTX remained depressed by approximately 50% from day 1 to day 14 after administration, returning to normal by day 30. The data suggest that in vivo ribosylation of G proteins may lead to a short-term attenuation of the tonic inhibitory control of dopamine neurons, which can be compensated for by PTX-insensitive mechanisms.

Adenosine Diphosphate Ribose↗
PubMed1992

Modulation of extracellular gamma-aminobutyric acid in the ventral pallidum using in vivo microdialysis.

Intracranial microdialysis was used to investigate the origin of extracellular gamma-aminobutyric acid (GABA) in the ventral pallidum. Changes in basal GABA levels in response to membrane depolarizers, ion-channel blockers, and receptor agonists were determined. Antagonism of Ca2+ fluxes with high Mg2+ in a Ca(2+)-free perfusion buffer decreased GABA levels by up to 30%. Inhibition of voltage-dependent Na+ channels by the addition of tetrodotoxin also significantly decreased basal extracellular GABA concentrations by up to 45%, and blockade of Ca2+ and Na+ channels with verapamil reduced extracellular GABA by as much as 30%. The addition of either the GABAA agonist, muscimol, or the GABAB agonist, baclofen, produced a 40% reduction in extracellular GABA. GABA release was stimulated by high K+ and the addition of veratridine to increase Na+ influx. High K(+)-induced release was predominantly Ca(2+)-dependent, whereas the effect of veratridine was potentiated in the absence of extracellular Ca2+. Both high K(+)- and veratridine-induced elevations in extracellular GABA were inhibited by baclofen, whereas only veratridine-induced release was antagonized by muscimol. These results demonstrate that at least 50% of basal extracellular GABA in the ventral pallidum is derived from Ca(2+)- or Na(+)-dependent mechanisms. They also suggest that Na(+)-dependent release of GABA via reversal of the uptake carrier can be shown in vivo.

Animals↗
PubMed1992

Regulation of somatodendritic dopamine release in the ventral tegmental area by opioids and GABA: an in vivo microdialysis study.

Microdialysis of the ventral tegmental area in conscious rats was used to evaluate the influence of opioids and GABA agonists on extracellular levels of GABA and somatodendritically released dopamine. The administration of morphine through the dialysis probe elicited significant, dose-dependent increases in the levels of extracellular dopamine and significantly reduced the extracellular concentration of GABA. In contrast, a dose-dependent decrease in somatodendritic extracellular dopamine was produced following the administration of the GABAB agonist baclofen. The increase in dopamine levels elicited by morphine (100 microM) was completely blocked by either baclofen (100 microM) coadministration or peripheral injection of naloxone (2 mg/kg, i.p.). Application of the GABAA agonist muscimol produced a significant increase in both extracellular levels of dopamine and locomotor activity. The present results, together with other electrophysiological, neurochemical, and behavioral data, support a hypothesis that stimulation of mu-opioid or GABAA receptors inhibits the activity of GABAergic afferents to dopamine neurons, thereby removing tonic inhibitory regulation, whereas stimulation of GABAB receptors directly inhibits dopamine neurons.

Afferent Pathways↗
PubMed1992

Microinjection of the D2 agonist quinpirole into the A10 dopamine region blocks amphetamine-, but not cocaine-stimulated motor activity.

Dopamine neurons in the ventral mesencephalon are under the inhibitory influence of dopamine D2 and gamma-aminobutyric acidB receptors. In a previous report, we demonstrated that intra-A10 injections of baclofen, a gamma-aminobutyric acidB agonist, could inhibit the motor-stimulant response to cocaine and amphetamine. In order to further extend these results, we examined the effects of injection of the D2 agonist quinpirole into the A10 region on cocaine- and amphetamine-stimulated motor activity. The results of this study showed that intra-A10 quinpirole dose-dependently decreased locomotor activity. In addition, an intra-A10 injection of 0.3 nmol/microliter quinpirole, a dose chosen for its near threshold effect, could block the motor-stimulant response to a low dose of amphetamine (0.5 mg/kg) and attenuate the response to moderate doses (1.0 and 2.0 mg/kg). Cocaine-stimulated motor activity, at all doses tested (7.5, 15.0 and 30.0 mg/kg), was not altered by intra-A10 quinpirole pretreatment. In vivo microdialysis revealed that quinpirole was unable to block the amphetamine-induced increase in extracellular dopamine concentrations within the nucleus accumbens, despite blocking the motor-stimulant response. It is suggested that the different mechanisms of action of cocaine and amphetamine, uptake blocker vs. releaser or longloop vs. shortloop feedback inhibition of A10 dopamine neurons, respectively, may account for the differential effects that quinpirole had in blocking the motor-stimulant response to these psychostimulants.

Amphetamine↗
PubMed1991

Effects of cocaine and footshock stress on extracellular dopamine levels in the ventral striatum.

Behavioral and neurochemical cross-sensitization between cocaine and stress was examined. The effects of stress and cocaine on extracellular levels of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis in the rostral ventral striatum, including the nucleus accumbens. Pretreatment with a daily 20 min footshock stress (0.45 mA/200 ms/s) for 5 days enhanced the cocaine-induced increase in extracellular dopamine levels in shock compared to sham shock-pretreated rats. The motor stimulant response to acute cocaine was also augmented in shock-pretreated rats. There was a slight but significant decrease in the levels of DOPAC and HVA in both groups following cocaine but no differences between shock and sham shock animals. In contrast, in the converse experiment, pretreatment with daily cocaine (15 mg/kg, i.p.) for 5 days did not significantly alter the stress-induced levels of extracellular dopamine compared to controls. The levels of DOPAC and HVA were not different between cocaine- and saline-pretreated groups although there was a trend towards enhanced metabolite levels in cocaine-pretreated animals. These data in part support a role for enhanced dopamine neutrotransmission in mediating behavioral cross-sensitization between psychostimulants and stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Effects of 5-hydroxytryptophan on extracellular serotonin in the spinal cord of rats with experimental allergic encephalomyelitis.

Serotonin (5-HT) and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were collected by in vivo dialysis in the lumbar spinal cord of control rats and rats with hindlimb paralysis induced by experimental allergic encephalomyelitis (EAE). Both 5-HT and 5-HIAA were significantly decreased in baseline samples from EAE rats compared to controls. This decrease in extracellular 5-HT and 5-HIAA in the EAE rats was accompanied by marked morphological changes in spinal cord axons and axon terminal plexuses that were stained for 5-HT-like immunoreactivity. The 5-HT precursor, 5-hydroxytryptophan (5-HTP)-increased 5-HT and 5-HIAA levels in dialysate samples from both control and EAE animals. However, the 5-HTP-induced increase in extracellular 5-HT was significantly greater in the EAE rats than in the controls, despite a lower baseline 5-HT level in the EAE animals. In contrast to 5-HT, both baseline and post-5-HTP levels of 5-HIAA were significantly higher in control animals than in EAE animals. The decreased extracellular 5-HT and 5-HIAA in baseline samples from the EAE rats compared to controls is probably a consequence of the damage to descending 5-HT axons and axon terminals that occurs during the disease. The larger increase in extracellular 5-HT in EAE animals after precursor injection may reflect both decreased 5-HT reuptake from the extracellular space by damaged 5-HT terminals and disruption of the blood-brain barrier that allows entry into the central nervous system of 5-HT that was synthesized from 5-HTP in the periphery.

5-Hydroxytryptophan↗