Novel in vivo electrophysiological assay for the effects of cocaine and putative "cocaine antagonists" on dopamine transporter activity of substantia nigra and ventral tegmental area dopamine neurons
by
Hinerth MA, Collins HA, Baniecki M, Hanson RN, Waszczak BL.
Department of Pharmaceutical Sciences,
Bouve College of Health Sciences,
Northeastern University, Boston, Massachusetts 02115, USA.
Synapse 2000 Dec 1; 38(3):305-12

ABSTRACT

The aim of these studies was to establish a rapid in vivo assay for evaluating potential "cocaine antagonists," i.e., drugs postulated to block cocaine binding to the dopamine transporter (DAT) without corresponding blockade of dopamine reuptake. The assay is based on the ability of dopamine, and drugs that elevate synaptic dopamine levels, to inhibit the extracellular single unit activities of midbrain dopamine neurons in chloral hydrate-anesthetized rats. As expected, cocaine itself (0.06-16 mg/kg, i.v.) caused a dose-dependent inhibition of firing of both substantia nigra and ventral tegmental area (VTA) dopamine neurons, but had a significantly higher potency on VTA than nigral dopamine cells (ED(50)'s 1.2 and 8.8 mg/kg, respectively). VTA cells were also inhibited to a greater extent (to 4.7 +/- 4.5% vs. 41.3 +/- 6.3% of baseline rates at 16 mg/kg, respectively). We next evaluated GBR12909, a piperazine analog promoted as a "cocaine antagonist" because of its ability to bind with high affinity to the DAT, while only modestly elevating extracellular dopamine levels. The agonist- and antagonist-like properties of GBR12909 were evaluated on only VTA dopamine cells since these neurons were more fully inhibited by cocaine and have been implicated in its rewarding effects. Given alone, GBR12909 exhibited modest "cocaine-like" activity insofar as it partially inhibited VTA dopamine neurons (to 59.0 +/- 4.6% of baseline at 8 mg/kg). However, consistent with an antagonist profile, pretreatment with a low (0.5 mg/kg) dose of GBR12909, which depressed firing only slightly, resulted in a >2-fold rightward shift in the dose-response curve to cocaine (ED(50) 2.6 mg/kg). We conclude that electrophysiological testing of putative "anti-cocaine" drugs for their abilities to inhibit the firing of VTA dopamine neurons, and to block their inhibitory responses to cocaine, may provide a rapid in vivo screen for compounds expected to behave as functional cocaine antagonists in the dopamine reward system.

CART
GBR12909
Cocaine hotspots
Dopaminergic flies?
Dopaminergic agents
GBR12909 and MDMA
GBR12909 and the rat
The coke-craving brain
Monoamines, cocaine and rats
GBR12909 and normal subjects
Freebasing flies go hyperkinetic
GBR12909: a dopaminergic antidepressant?

01 02 03 04 05 06 07 08 09 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24

MORE
HedWeb
HerbWeb
BLTC Research
Wirehead Hedonism
Paradise-Engineering
Utopian Pharmacology
The Hedonistic Imperative
When Is It Best to Take Crack Cocaine?

The Good Drug Guide
The Responsible Parent's Guide To
Healthy Mood Boosters For All The Family