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Biomedical subjects

Roy A Wise

Publications and source records attributed to Roy A Wise.

At least 19 recordsLinked to original sources
PubMed2006

Role of brain dopamine in food reward and reinforcement.

The ability of food to establish and maintain response habits and conditioned preferences depends largely on the function of brain dopamine systems. While dopaminergic transmission in the nucleus accumbens appears sufficient for some forms of reward, the role of dopamine in food reward does not appear to be restricted to this region. Dopamine plays an important role in both the ability to energize feeding and to reinforce food-seeking behaviour; the role in energizing feeding is secondary to the prerequisite role in reinforcement. Dopaminergic activation is triggered by the auditory and visual as well as the tactile, olfactory, and gustatory stimuli of foods. While dopamine plays a central role in the feeding and food-seeking of normal animals, some food rewarded learning can be seen in genetically engineered dopamine-deficient mice.

Brain↗
PubMed2006

Heteromeric nicotinic acetylcholine-dopamine autoreceptor complexes modulate striatal dopamine release.

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D(2) autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D(2) autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-alpha(7) nACh receptor antagonist dihydro-beta-erythroidine or the D(2-3) receptor agonist quinpirole. Local perfusion of the D(2-3) receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-beta-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D(2) autoreceptor modulating the efficacy of non-alpha(7) nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between beta(2) subunits of non-alpha(7) nicotinic acetylcholine receptors and D(2) autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-alpha(7) nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.

Animals↗
PubMed2006

Two brain sites for cannabinoid reward.

The recent findings that Delta9tetrahydrocannabinol (Delta9THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions of Delta9THC. Microinjections of Delta9THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of Delta9THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1 receptor antagonist caused response cessation. Microinjections of Delta9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of Delta9THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.

Analysis of Variance↗
PubMed2006

A new peptide input to learning and addiction.

In this issue of Neuron, Borgland et al. report that the arousal-associated peptide orexin enhances LTP-like changes in glutamatergic excitability of ventral tegmental dopamine neurons. This parallels a similar effect of corticotropin-releasing factor and suggests a form of neuroadaptation that increases the likelihood of addiction relapse.

Animals↗
PubMed2005

Forebrain substrates of reward and motivation.

Electrical stimulation of the medial forebrain bundle can reward arbitrary acts or motivate biologically primitive, species-typical behaviors like feeding or copulation. The subsystems involved in these behaviors are only partially characterized, but they appear to transsynaptically activate the mesocorticolimbic dopamine system. Basal function of the dopamine system is essential for arousal and motor function; phasic activation of this system is rewarding and can potentiate the effectiveness of reward-predictors that guide learned behaviors. This system is phasically activated by most drugs of abuse and such activation contributes to the habit-forming actions of these drugs.

Afferent Pathways↗
PubMed2005

Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking.

Footshock stress can reinstate cocaine-seeking behavior through a central action of the stress-associated neurohormone corticotropin-releasing factor (CRF). Here we report (1) that footshock stress releases CRF in the ventral tegmental area (VTA) of the rat brain, (2) that, in cocaine-experienced but not in cocaine-naive rats, this CRF acquires control over local glutamate release, (3) that CRF-induced glutamate release activates the mesocorticolimbic dopamine system, and (4) that, through this circuitry, footshock stress triggers relapse to drug seeking in cocaine-experienced animals. Thus, a long-lasting cocaine-induced neuroadaptation, presumably at the level of glutamate terminals in the VTA, appears to play an important role in stress-induced relapse to drug use. Similar neuroadaptations may be important for the comorbidity between addiction and other stress-related psychiatric disorders.

Animals↗
PubMed2004

Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area.

We examined whether injections of the excitatory amino acid AMPA are rewarding when injected into the posterior hypothalamus and ventral tegmental area. Rats quickly learned to lever-press for infusions of AMPA into the supramammillary or posterior hypothalamic nuclei but failed to learn to lever-press for similar injections into the ventral tegmental areas. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, induced conditioned place preference. The rewarding effects of AMPA appear to be mediated by AMPA receptors, because coadministration of the AMPA antagonist CNQX blocked the rewarding effects of AMPA, and administration of the enantiomer R-AMPA did not mimic the rewarding effects. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, also increased extracellular dopamine concentrations in the nucleus accumbens. Pretreatment with the D1 dopamine antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] led to extinction of AMPA self-administration. These findings implicate posterior hypothalamic regions in reward function and suggest that reward mechanisms localized around the ventral tegmental area are more complex than has been assumed recently.

Animals↗
PubMed2004

Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats.

RATIONALE: We have recently found that blockade of dopamine D1-type receptors in the ventral tegmental area reduces the rewarding effects of intravenous cocaine; here, we explored the possibility that blockade of D1 receptors in the adjacent substantia nigra (SN)--not usually considered part of reward circuitry--might have similar effects. OBJECTIVE: To test the hypothesis that blockade of dopamine D1 receptors in the SN reduces the rewarding effects of cocaine. METHODS: Twenty one rats were prepared with intravenous catheters and with bilateral guide cannulae implanted such that injections could be made directly into the SN or just dorsal to the SN. The rats were trained to self-administer intravenous cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR1) schedule of reinforcement. After stable responding developed, 13 of the animals were tested following pretreatment with bilateral microinjections of SCH 23390 at doses of 0, 1, 2 or 4 microg/0.5 microl into the SN and 8 were tested with injections of 0 microg or 4 microg/0.5 microl into a site 2 mm dorsal to the SN site. RESULTS: Microinjections of SCH 23390 in the SN significantly increased rates of cocaine self-administration, while injections dorsal to SN had no significant effect on responding. CONCLUSIONS: These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drug's ability to elevate dopamine levels in the nucleus accumbens.

Animals↗
PubMed2004

Mapping of chemical trigger zones for reward.

Addictive drugs are thought to activate brain circuitry that normally mediates more natural rewards such as food or water. Drugs activate this circuitry at synaptic junctions within the brain; identifying the junctions at which this occurs provides clues to the neurochemical and anatomical characteristics of the circuitry. One approach to identifying the junctions at which drugs interact with this circuitry is to determine if animals will lever-press for site-specific microinjections of addictive drugs. This approach has identified GABAergic, dopaminergic, glutamatergic, and cholinergic trigger zones within meso-corticolimbic circuitry important for natural reward function.

Acetylcholine↗
PubMed2003

Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction.

Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) temperatures were continuously monitored. METH produced dose-dependent hyperthermia, with brain structures (especially the NAcc) showing a more rapid and pronounced temperature increase than the muscle. At the highest dose, brain and body temperatures increased 3.5-4.0 degrees C above basal levels and remained elevated for 3-5 hr. Stressful and other high-activity situations such as interaction with a conspecific female are also known to induce a significant hyperthermic response in the rat. A combination of social interaction and METH administration was tested for additive effects. Male rats were exposed daily to a conspecific female for a total of 120 min, and METH was injected at the same doses 30 min after the initial contact with the female. An initial hyperthermic response ( approximately 1.5 degrees C) to social interaction was followed by a large and prolonged hyperthermic response (3.5-5.0 degrees C, 5-7 hr at 9 mg/kg) to METH, which was again stronger in brain structures (especially in the NAcc) than in the muscle. Although the combined effect of the hyperthermic events was not additive, METH administration during social interaction produced stronger and longer-lasting increases in brain and body temperature than that induced by drug alone, heating the brain in some animals near its biological limit (>41 degrees C).

Amphetamine-Related Disorders↗
PubMed2002

Endomorphin-1 and -2 immunoreactive cells in the hypothalamus are labeled by fluoro-gold injections to the ventral tegmental area.

Endomorphin-1 and -2 (EM1, EM2) are endogenous opioids with high affinity and selectivity for the mu-opioid receptor. Cells expressing EM-like immunoreactivity (EM-LI) are present in the hypothalamus, and fibers containing EM-LI project to many brain regions, including the ventral tegmental area (VTA). The VTA is one of the most sensitive brain regions for the rewarding and locomotor effects of opioids. It contains mu-opioid receptors, which are thought to mediate gamma-aminobutyric acid-dependent disinhibition of dopamine transmission to the nucleus accumbens. We investigated whether hypothalamic EM-LI cells project to the VTA, where they could play a natural role in this circuitry. The retrograde tracer Fluoro-Gold (FG) was microinjected into the anterior or posterior VTA in rats. Nine days later, colchicine was injected, and 24 hours later, the animals were perfused and processed for fluorescence immunocytochemistry. Numerous FG-labeled cells were detected in the hypothalamus. Both EM1-LI and EM2-LI cells were present in the periventricular nucleus, between the dorsomedial and ventromedial hypothalamus and between the ventromedial and arcuate nuclei. Subpopulations of EM1-LI and EM2-LI cells were labeled by FG. Injections of FG to the anterior and posterior VTA were both effective in producing double-labeled cells, and an anterior-posterior topographical organization between the VTA and hypothalamus was observed. The results support the idea that some endomorphin-containing neurons in the hypothalamus project to the VTA, where they may modulate reward and locomotor circuitry.

Animals↗
PubMed2002

Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine.

Although the effects of psychostimulants on brain dopamine systems are well recognized, the direct actions of cocaine on serotonin systems also appear to be important to its addictive properties. For example, serotonin actions at 5-HT1B receptors in the ventral tegmental area (VTA) modulate cocaine-induced dopamine release in the nucleus accumbens (NAcc) and alter the rewarding and stimulant properties of cocaine. However, the mechanisms of these effects have been unclear, because several neuron types in VTA express 5-HT1B receptors. One possibility is that 5-HT1B receptors on the terminals of GABAergic projections from NAcc to VTA inhibit local GABA release, thereby disinhibiting VTA neurons. We tested this hypothesis directly by using viral-mediated gene transfer to overexpress 5-HT1B receptors in NAcc projections to VTA. A viral vector containing either epitope hemagglutinin-tagged 5-HT1B and green fluorescent protein (HA1B-GFP) cassettes or green fluorescent protein cassette alone (GFP-only) was injected into the NAcc shell, which sends projections to the VTA. HA1B-GFP injection induced elevated expression of 5-HT1B receptors in neuronal fibers in VTA and increased cocaine-induced locomotor hyperactivity without affecting baseline locomotion. Overexpression of 5-HT1B receptors also shifted the dose-response curve for cocaine-conditioned place preference to the left, indicating alterations in the rewarding effects of cocaine. Thus, increased expression of 5-HT1B receptors in NAcc efferents, probably in the terminals of medium spiny neurons projecting to the VTA, may contribute to psychomotor sensitization and offer an important target for regulating the addictive effects of cocaine.

Animals↗