When it comes to drugs of abuse it seems that all roads lead to the VTA. What local streets those drugs take when they get there is another matter. For example, the dopaminergic activating effects of psychostimulants are modulated by glutamate release in the VTA in a D1-like DA receptor manner. What about other drugs like nicotine? Turns out glutamatergic output is also D1 dependent in this case. But the VTA has a whole bunch of nicotinic receptors, mainly of two varieties. Alpha4beta6, which are high affinity and fast desensitizing, are predominantly post-synaptic on the soma of DA and GABA neurons. Alpha7, which are low affinity and slow desensitizing, are predominantly presynaptic. It is known that nicotine can enhance LTP but there is some evidence that nicotine directly affects synaptic plasticity. The question is, which receptors might mediate such change?
Jin et al. (2011) attempted to answer this question by recording DA cells in horizontal slices from male Wistar rats (14 to 18 days old). Nicotine was bath applied and DA cells were recorded. The authors measured synaptic plasticity by looking at changes in AMPA/NMDA ratios. It gets complicated but the gist is that when the strength of synaptic glutamate transmission increases so does the ratio of these two postsynaptic glutamate receptors.
The researchers found that one hour, but not 10 minutes, of exposure to nicotine elevated AMPA/NMDA ratios. So nicotine directly affects synaptic plasticity without the induction of LTP. This effect occurred even within the same neuron using pre and post nicotine recordings. Cool, but by what means is it doing so? Remember there are two different nicotinic receptor types in this preparation. By including antagonists to the two different receptors in tandem with the nicotine application the authors determined that the alpha7 receptors are responsible for the plasticity. As further confirmation alpha7 knockout mice showed no change in AMPA/NMDA ratio using the same procedure. So, nicotine appears to elevate glutamate input to DA neurons via action on presynaptic alpha7 nicotinic receptors.
But is it really presynaptic? There is a way to test this called the paired pulse ratio. By stimulating the glutamtergic inputs twice in rapid succession we can see a decrease in synaptic transmission with the second pulse. This is due entirely to presynaptic effects namely the probability of vesicular release. And nicotine causes a greater decrease in the paired pulse ratio, i.e. it increases the probability of glutamte release, an effect not seen with the knockout mice. So it is confirmed: nicotine induces synaptic plasticity on DA neurons via action on presynaptic alpha7 receptors
Or does it? That is the subject of my next paper review.
Jin Y, Yang K, Wang H, & Wu J (2011). Exposure of nicotine to ventral tegmental area slices induces glutamatergic synaptic plasticity on dopamine neurons. Synapse (New York, N.Y.), 65 (4), 332-8 PMID: 20730803