Drug dependence research background
R.J.Walters Ph.D. 1999
Much interest hinges upon the neurophysiological, synaptic and biochemical
basis of dependence upon recreational drugs such as heroine, cocaine and caffeine
(class I), ethanol and nicotene (class II) and cannabis and marijuana (class III).
The fundamental neural mechanisms and pathways associated with the "reward signal"
that leads to drug dependence are poorly understood, but are believed to be due to the
release of dopamine into the nucleus accumbens and forebrain by projections from A10 neurons
of the ventral tegmental area (VTA) which is located in the 'ancient' mid-brain. These A10 neurons are of particular interest
because, even when they are maintained in vitro, they fire at a spontaneous and regular rate that is modulated by other neuronal influences.
For this reason they are known as 'pacemaker' neurons.
The ingestion of drugs of dependence is postulated to cause an increase in dopamine release from the
A10 VTA neurons, influenced by the release of serotonin (5-HT) from incoming terminal projections from
the neurons of the dorsal Raphe nucleus in the (lower) brainstem. This change in dopamine
output to the nucleus accumbens and forebrain, regulated by the local release of
5-HT, GABA and dopamine, thus regulates the sensation of reward that accompanies satiety
induced by a meal, a recreational drug or even, as evidence would suggest, a video game.
Extracellular single-unit recordings were obtained from dopaminergic
A10 neurons from the ventral tegmental area of rat slices to study the
effects of L-type calcium channel antagonists upon the firing kinetics of pacemaker
neurons implicated in drug dependence pathways. Our findings suggested that L-type antagonists,
in conjunction with a local action of dopamine acting via feedback autoreceptors upon the A10 neurons,
provides a possible strategy for blocking reward mechanisms, and hence dependence upon recreational drugs
(or even food or video games). The key objective must be to
develop L-type antagonists that are more specific to this population of neurons.
