Cocaine Administered in Vitro to Brain Slices from Rats Treated with Cocaine Chronically in Vivo Results in a γ-Aminobutyric Acid Receptor-Mediated Hyperpolarization Recorded from the Dorsolateral Septum1
- Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, Galveston, Texas
Abstract
Previous reports of membrane hyperpolarizations, associated with acute application of cocaine, have been recorded from brain slice preparations containing aminergic nuclei and have always been attributed to cocaine’s ability to elevate levels of local biogenic amines followed by activation of their receptors. The majority of these studies were conducted with brain slices obtained from rats that had not received prior chronic in vivo treatment with cocaine. We observed that cocaine alone, at 3 μM, could induce a membrane hyperpolarization (COC-HYP) in 100% of rat dorsolateral septal nucleus (DLSN) neurons from brain slices of rats treated chronically with cocaine for either 14 or 28 days in vivo. The DLSN is a nucleus absent of biogenic amine cell bodies, but does contain biogenic amine terminals with GABAergic cell bodies and terminals. Cocaine applied to brain slices from rats not previously administered cocaine or administered cocaine for up to seven days in vivo yielded a maximum incidence of COC-HYPs at only 50%. COC-HYPs recorded from DLSN neurons were not blocked by previous treatment with amine receptor antagonists or by a TTX and zero calcium medium. Based on these results, the ability of DLSN neurons to respond to a cocaine challenge with a COC-HYP did not involve inhibition of amine reuptake/uptake or action potential release of neuroactive substances. Rather, the COC-HYP, with an apparent reversal potential of -80 mV, was reduced by the GABA receptor antagonists-bicuculline and CGP-55845A. Lowering extracellular Na+ or Cl− , lowering of temperature, or previous superfusion with the GABA uptake blocker NO-711 could block the COC-HYP. In summary, our data suggest that COC-HYPs, after application of a cocaine challenge to brain slices from rats treated chronically (14 - 28 days, but not acutely, 7 days) with cocaine are due to cocaine-induced changes in GABA release and/or transporter function. The latter changes in transporter function may involve the reversal of the GABA transporter with release of GABA and subsequent activation of postsynaptic GABAA and GABAB receptors.
Footnotes
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Send reprint requests to: Dr. Joel P. Gallagher, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031.
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↵1 This work was supported by National Institutes of Health, National Institutes of Drug Abuse Grant DA-07190 and Training Grant T32-DA07287
- Abbreviations:
- DLSN
- dorsolateral septal nucleus
- COC-HYP
- membrane hyperpolarization associated with cocaine challenge
- TTX
- tetrodotoxin
- GABA
- γ-aminobutyric acid
- GABAA
- GABAA receptor
- GABAB
- GABABreceptor
- COC-7
- chronic in vivo 7-day, twice daily, cocaine treatment
- COC-14
- chronic in vivo 14-day, twice daily, cocaine treatment
- COC-28
- chronic in vivo28-day, twice daily, cocaine treatment
- Ri
- membrane input resistance
- f-ipsp
- fast inhibitory synaptic potential
- s-ipsp
- slow inhibitory synaptic potential
- EPSP
- excitatory postsynaptic potential
- CPT
- 8-cyclopentyl-1, 3-dimethylxanthine
- ACSF
- artificial cerebrospinal fluid
- d-AP5
- (d)-2-amino-5-phosphonovaleric acid
- CNQX
- cyano-7-nitroquinoxaline-2,3-dione
- MP
- membrane potential
- DA
- dopamine
- NE
- norepinephrine
- 5-HT
- serotonin
- NIDA
- National Institute of Drug Abuse
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- Received August 11, 1997.
- Accepted March 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
