Abstract
Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the phosphates will be removed. This balance of phosphorylation control suggests that a D1 receptor agonist and a NMDA glutamate receptor antagonist should have additive or synergistic actions to increase activated DARPP-32 and consequent behavioral effects. This hypothesis was tested in a volitional consumption of ethanol model: the selectively bred Myers’ high ethanol preferring (mHEP) rat. A 3-day baseline period was followed by 3-days of twice daily injections of drug(s) or vehicle(s) and then a 3-day post-treatment period. Vehicle, the D1 agonist SKF 38393, the non-competitive NMDA receptor antagonist memantine, or their combination were injected 2 h before and after lights out. The combination of 5.0 mg/kg SKF 38393 with either 3.0 or 10 mg/kg memantine did not produce an additive or synergistic effect. For example, 5.0 mg/kg SKF reduced consumption of ethanol by 27.3% and 10 mg/kg memantine by 39.8%. When combined, consumption declined by 48.2% and the proportion of ethanol solution to total fluids consumed declined by 17%. However, the consumption of food also declined by 36.6%. The latter result indicates that this dose combination had a non-specific effect. The combination of SKF 38393 with (+)-MK-801, another NMDA receptor antagonist, also failed to show an additive effect. The lack of additivity and specificity suggests that the hypothesis may not be correct for this in vivo model. The interaction of these different receptor systems with intraneuronal signaling and behaviors needs to be studied further.
Highlights
Ethanol interacts with the functioning of many different neurotransmitter systems
Drugs that target this receptor to reduce glutamate activation will reduce the volitional consumption of ethanol by selectively bred high ethanol preferring rats
A drug that directly inhibits the binding of glutamate to this ligand-operated channel, LY 274614 (3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydroisoquinoline-3-carboxylic acid), drugs that inhibit the binding of glycine to an accessory site on the receptor, (+)-HA-966 (3-amino-1-hydroxy-2-pyrrolidone) and ACPC (1-aminocyclo-propane-1carboxylic acid), a drug that binds to the “PCP-site” to potently and non-competitively inhibit, dizolcipine (MK-801), or a drug that blocks the opened channel, memantine, all will decrease volitional consumption at doses with insignificant or small effects on food intake and motor performance [15,16]
Summary
Ethanol interacts with the functioning of many different neurotransmitter systems. These interactions include increased dopaminergic impulse flow likely through an opiate receptor mediated system [1], potentiation of gamma-aminobutyric acid (GABA) at the GABAA receptor, inhibition of excitatory glutamate (NMDA) receptors [2,3], release of angiotensin II [4] and an agonist-like interaction with adenosine receptors [5,6]. The search for drugs that will reduce the desire to consume alcohol involves modification of the function of these neurotransmitter-receptor systems One such example is the use of opiate receptor antagonists such as naltrexone to reduce consumption of ethanol in animal models [7,8] and in humans [9,10]. In addition to the acceptor site for glutamate itself, the glutamate NMDA receptor has several different binding sites that can be targeted to modify the functioning of the receptor Drugs that target this receptor to reduce glutamate activation will reduce the volitional consumption of ethanol by selectively bred high ethanol preferring rats. The influx of Ca2+ will contribute to an excitatory postsynaptic potential that makes the neuron more likely to discharge and the Ca2+ will interact with intracellular proteins One such calcium-activated enzyme is Ca2+-/calmodulin-dependent phosphatase, calcineurin. High ethanol preferring (mHEP) rat [23] that voluntarily consumes large amounts of ethanol solutions and injections of varying doses of a D1 partial agonist, SKF 38393 [(±)-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diol] and either memantine or (+)MK-801, both non-competitive inhibitors of the glutamate NMDA receptor [24]
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