Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats

Grubb, Michele C.; Welch, James R.; Finn, Deborah A.; Mark, Gregory P.

doi:10.1016/s0006-8993(02)03192-x

Cited by 6 publications

(7 citation statements)

References 42 publications

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“…Careful consideration was given regarding probe placement across our age groups, and was verified visually. In addition, an intra-VTA perfusion of bicuculline-methochloride (100 lM) using reverse dialysis procedures produced strong ipsilateral turning in all of our animals, and this effect provided neuroanatomical verification as other studies have reported similar results (Westerink et al 1996;Grubb et al 2002).…”

Section: Dialysis Testingsupporting

confidence: 88%

Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

Natividad

Buczynski

Parsons

et al. 2012

Journal of Neurochemistry

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Adolescent smokers report enhanced positive responses to tobacco and fewer negative effects of withdrawal from this drug than adults, and this is believed to propel higher tobacco use during adolescence. Differential dopaminergic responses to nicotine are thought to underlie these age-related effects, since adolescent rats experience lower withdrawal-related deficits in nucleus accumbens (NAcc) dopamine versus adults. This study examined whether age differences in NAcc dopamine during withdrawal are mediated by excitatory or inhibitory transmission in the ventral tegmental area (VTA) dopamine cell body region. In vivo microdialysis was used to monitor extracellular levels of glutamate and gamma-aminobutyric acid (GABA) in the VTA of adolescent and adult rats experiencing nicotine withdrawal. In adults, nicotine withdrawal produced decreases in VTA glutamate levels (44% decrease) and increases in VTA GABA levels (38% increase). In contrast, adolescents did not exhibit changes in either of these measures. Naïve controls of both ages did not display changes in NAcc dopamine, VTA glutamate or VTA GABA following mecamylamine. These results indicate that adolescents display resistance to withdrawal-related neurochemical processes that inhibit mesolimbic dopamine function in adults experiencing nicotine withdrawal. Our findings provide a potential mechanism involving VTA amino acid neurotransmission that modulates age differences during withdrawal.

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Section: Dialysis Testingsupporting

confidence: 88%

Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

Natividad

Buczynski

Parsons

et al. 2012

Journal of Neurochemistry

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“…Furthermore, Grubb et al [2] have demonstrated alterations in rotational behavior induced by intra-VTA injections of the GABA-A antagonist bicuculline in rats with a cocaine self-administration history. If the changes in subunit expression resulting from cocaine selfadministration shift the balance such that GABA-A receptors on non-dopaminergic cells exert a greater influence than on dopaminergic cells in the VTA, one would expect the results seen in the present study.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Ventral Tegmental GABA Receptors to Cocaine Self-administration in Rats

Backes

Hemby

2007

Neurochem Res

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Recent evidence has suggested that compounds affecting GABAergic transmission may provide useful pharmacological tools for the treatment of cocaine addiction. Using a rat model of self-administration, the present study examined the effects of GABA agonists and antagonists injected directly into the ventral tegmental area (VTA) on cocaine intake in rats trained to self-administer cocaine (0, 125, 250 and 500 microg/infusion) under an FR5 schedule of reinforcement. Separate groups of rats received bilateral intra-VTA injections of the GABA-A antagonist picrotoxin (34 ng/side, n = 7; 68 ng/side, n = 8), GABA-A agonist muscimol (14 ng/side, n = 8), GABA-B agonist baclofen (56 ng/side, n = 7; 100 ng/side, n = 6), picrotoxin (68 ng/side) co-injected with the GABA-B antagonist 2-hydroxysaclofen (100 ng/side, n = 7; 2 microg/side, n = 8) or artificial cerebrospinal fluid (aCSF, n = 6) to assess the effects of the various compounds on the cocaine self-administration dose-response curve. Both picrotoxin and baclofen reduced responding maintained by cocaine, whereas muscimol had no effect on responding. In contrast, neither picrotoxin (n = 6) nor baclofen (n = 8) affected responding maintained by food. Interestingly, 2-hydroxysaclofen effectively blocked the suppression of responding produced by picrotoxin, suggesting that both picrotoxin and baclofen exert their effects via activation of GABA-B receptors. Additionally, these effects appear to be specific to cocaine reinforcement, supporting current investigation of baclofen as a treatment for cocaine addiction.

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“…Although reinstatement by intra-VTA bicuculline or 2-hydroxysaclofen has not, to our knowledge, been previously reported, these results were somewhat surprising to us, particularly in the case of bicuculline, which has been found to elevate nucleus accumbens dopamine levels (Ikemoto et al 1997), increase locomotor activity (Grubb et al 2002; Lavezzi et al 2015), and produce conditioned place preference (Laviolette and van der Kooy, 2001) when injected into the VTA and has been reported to be self-administered directly into the VTA in mice (David et al 1997). As elevated dopamine in the nucleus accumbens (Cornish and Kalivas, 2000) and intra-accumbens delivery of dopamine receptor agonists (Bachtell et al 2005; Schmidt et al 2006) have been reported to be sufficient for reinstatement of cocaine seeking, we predicted that intra-VTA GABA receptor antagonism would induce cocaine seeking, especially considering that GABA receptor agonist injections into the VTA suppress dopamine release (Yoshida et al 1994), drug self-administration (Xi and Stein, 1999; Brebner et al 2000; Backes and Hemby, 2008), and reinstatement (McFarland et al 2001; Di Ciano and Everitt, 2004; McFarland et al 2004).…”

Section: Discussionmentioning

confidence: 59%

“…The GABA A receptor antagonist (−)-bicuculline methiodide was purchased from Tocris Bioscience and was administered at doses of 1, 10 and 20 ng/side (0.002 and 0.02 and 0.04 nmol/side) dissolved in aCSF (0.25 µl/side). The doses used were selected based on prior reports assessing VTA effects (Sandner et al 1996; Trojniar and Klejbor, 1999; Laviolette and van der Kooy, 2001; Grubb et al 2002; Echo et al 2002; Lavezzi et al 2015). The occurrence of seizures prevented testing for effects of higher doses.…”

Section: Methodsmentioning

confidence: 99%

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

et al. 2016

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Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 sec; range 10–70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 µg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts.

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Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats

Cited by 6 publications

References 42 publications

Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

Contribution of Ventral Tegmental GABA Receptors to Cocaine Self-administration in Rats

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

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