Antisense inhibition of striatal GABAA receptor proteins decreases GABA-stimulated chloride uptake and increases cocaine sensitivity in rats

Peris, Joanna; Jung, Bruce J.; Resnick, Adam; Walker, Paul D.; Malakhova, O. E.; Bokrand, Yvonne; Wielbo, Donna

doi:10.1016/s0169-328x(98)00102-8

Cited by 19 publications

(15 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data are supported by previous studies demonstrating significant decreases in ␣1, ␣6, ␤2, ␤3, and ␥2 mRNAs in the striatum and NAc Yamaguchi et al, 2000), along with decreased receptor number and function in this region (Peris, 1996;Yamaguchi et al, 2002). Cocaine-induced alterations in these subunits alter subsequent responsivity to the drug (Peris et al, 1998). Decreased expression of the ␥2 subunit could also have a potentially profound effect on normal receptor function, because ␥2 subunits are essential for receptor clustering (Essrich et al, 1998).…”

Section: Discussionsupporting

confidence: 84%

Discrete Cell Gene Profiling of Ventral Tegmental Dopamine Neurons after Acute and Chronic Cocaine Self-Administration

Backes

Hemby²

2003

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Chronic cocaine administration induces a number of biochemical alterations within the mesolimbic dopamine system that may mediate various aspects of the addictive process such as sensitization, craving, withdrawal, and relapse. In the present study, rats were allowed to self-administer cocaine (0.5 mg/ infusion) for 1 or 20 days. Tyrosine hydroxylase immunopositive cells were microdissected from the ventral tegmental area (VTA) using laser capture microdissection, and changes in the abundances of 95 mRNAs were assessed using cDNA macroarrays. Five GABA-A receptor subunit mRNAs (␣4, ␣6, ␤2, ␥2, and ␦) were down-regulated at both 1 and 20 days of cocaine selfadministration. In contrast, the catalytic subunit of protein phosphatase 2A (PP2␣), GABA-A ␣1, and G␣ i2 were significantly increased at both time points. Additionally, calcium/ calmodulin-dependent protein kinase II␣ mRNA levels were increased initially followed by a slight decrease after 20 days, whereas neuronal nitric-oxide synthase mRNA levels were initially decreased but returned to near control levels by day 20. These results indicate that alterations of specific GABA-A receptor subtypes and other signal transduction transcripts seem to be specific neuroadaptations associated with cocaine selfadministration. Moreover, as subunit composition determines the functional properties of GABA-A receptors, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine.

show abstract

Section: Discussionsupporting

confidence: 84%

Discrete Cell Gene Profiling of Ventral Tegmental Dopamine Neurons after Acute and Chronic Cocaine Self-Administration

Backes

Hemby²

2003

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…5A) is to be expected considering that the half-life of the GABA A channel is estimated to be around 20 hours. 30,31 When mechanical hypersensitivity was assessed, we found similar pattern. Namely, although crush injury produced significant increase in PWRs in both ASODNs [F(11,55)=25.751, p<0.001] (Fig.…”

Section: Resultssupporting

confidence: 63%

Silencing the α2 Subunit of γ-aminobutyric Acid Type A Receptors in Rat Dorsal Root Ganglia Reveals Its Major Role in Antinociception Posttraumatic Nerve Injury

et al. 2015

View full text Add to dashboard Cite

Background Neuropathic pain is likely the result of repetitive high frequency bursts of peripheral afferent activity leading to long-lasting changes in synaptic plasticity in the spinal dorsal horn (DH). Drugs that promote GABA activity in the DH provide partial relief of neuropathic symptoms. We examined how in vivo silencing of the GABAA α2 gene in DRG controls of NPP. Methods After crush injury to the right sciatic nerve of female rats, the α2 GABAA antisense and mismatch oligodeoxynucleotides or NO-711 (a GABA uptake inhibitor) were applied to the L5 DRG. In vivo behavioral assessment of nociception was conducted prior to the injury and ensuing 10 days (n=4–10). In vitro quantification of α2 GABAA protein and electrophysiology studies of GABAA currents were performed on acutely dissociated L5 DRG neurons at relevant time-points (n=6–14). Results NPP post-crush injury of a sciatic nerve in adult female rats coincides with significant down-regulation of the α2 subunit expression in the ipsilateral DRG (about 30%). Selective down-regulation of α2 expression in DRGs significantly worsens mechanical (2.55±0.75 to 5.16±1.16) and thermal (7.97±0.96 to 5.51±0.75) hypersensitivity in crush-injured animals and causes development of significant mechanical (2.33±0.40 to 5.00±0.33) and thermal (10.80±0.29 to 7.34±0.81) hypersensitivity in sham animals (data shown as MEAN±SD). Conversely, up-regulation of endogenous GABA via blockade of its uptake in DRG alleviates NPP. Conclusions The GABAA receptor in the DRG plays an important role in pathophysiology of NPP caused by sciatic nerve injury and represent promising target for novel pain therapies.

show abstract

“…These results suggest a plausible mechanism for these effects in normal subjects although it may be difficult again to separate peripheral from CNS effects. Hallucination induction in normals is consistent with data indicating nasal cocaine inhalation or THC smoking decreased CNS GABA or GABA function [205,206,207,208,209], perhaps also extending to peripheral structures, with subsequent changes in CNS GAD, other moieties, disinhibition of CNS and sensory function [210,211,212] and hallucination onset. It is this decreased GABA we previously hypothesized as consistent in both normals and CUP with onset of hallucinatory activity.…”

Section: Discussionsupporting

confidence: 83%

Olfactory Hallucinations without Clinical Motor Activity: A Comparison of Unirhinal with Birhinal Phantosmia

2013

View full text Add to dashboard Cite

Olfactory hallucinations without subsequent myoclonic activity have not been well characterized or understood. Herein we describe, in a retrospective study, two major forms of olfactory hallucinations labeled phantosmias: one, unirhinal, the other, birhinal. To describe these disorders we performed several procedures to elucidate similarities and differences between these processes. From 1272, patients evaluated for taste and smell dysfunction at The Taste and Smell Clinic, Washington, DC with clinical history, neurological and otolaryngological examinations, evaluations of taste and smell function, EEG and neuroradiological studies 40 exhibited cyclic unirhinal phantosmia (CUP) usually without hyposmia whereas 88 exhibited non-cyclic birhinal phantosmia with associated symptomology (BPAS) with hyposmia. Patients with CUP developed phantosmia spontaneously or after laughing, coughing or shouting initially with spontaneous inhibition and subsequently with Valsalva maneuvers, sleep or nasal water inhalation; they had frequent EEG changes usually ipsilateral sharp waves. Patients with BPAS developed phantosmia secondary to several clinical events usually after hyposmia onset with few EEG changes; their phantosmia could not be initiated or inhibited by any physiological maneuver. CUP is uncommonly encountered and represents a newly defined clinical syndrome. BPAS is commonly encountered, has been observed previously but has not been clearly defined. Mechanisms responsible for phantosmia in each group were related to decreased gamma-aminobutyric acid (GABA) activity in specific brain regions. Treatment which activated brain GABA inhibited phantosmia in both groups.

show abstract

Antisense inhibition of striatal GABAA receptor proteins decreases GABA-stimulated chloride uptake and increases cocaine sensitivity in rats

Cited by 19 publications

References 46 publications

Discrete Cell Gene Profiling of Ventral Tegmental Dopamine Neurons after Acute and Chronic Cocaine Self-Administration

Discrete Cell Gene Profiling of Ventral Tegmental Dopamine Neurons after Acute and Chronic Cocaine Self-Administration

Silencing the α2 Subunit of γ-aminobutyric Acid Type A Receptors in Rat Dorsal Root Ganglia Reveals Its Major Role in Antinociception Posttraumatic Nerve Injury

Olfactory Hallucinations without Clinical Motor Activity: A Comparison of Unirhinal with Birhinal Phantosmia

Contact Info

Product

Resources

About