Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents

Abstract

Amphetamine-like compounds are commonly used to enhance cognition and to treat attention deficit/hyperactivity disorder, but they also function as positive reinforcers and are self-administered at doses far exceeding clinical relevance. Many of these compounds (including methamphetamine) are substrates for dopamine reuptake transporters, elevating extracellular dopamine by inhibiting uptake and promoting reverse transport. This produces an increase in extracellular dopamine that inhibits dopamine neuron firing through autoreceptor activation and consequently blunts phasic dopamine neurotransmission, an important learning signal. However, these mechanisms do not explain the beneficial behavioral effects observed at clinically useful concentrations. In the present study, we have used patch-clamp electrophysiology in slices of mouse midbrain to show that, surprisingly, low concentrations of methamphetamine actually enhance dopamine neurotransmission and increase dopamine neuron firing through a dopamine transporter-mediated excitatory conductance. Both of these effects are reversed by higher concentrations of methamphetamine, which inhibit firing through dopamine D2 autoreceptor activation and decrease the peak amplitude of dopamine-mediated synaptic currents. These competing, concentration-dependent effects of methamphetamine suggest a mechanistic interplay by which lower concentrations of methamphetamine can overcome autoreceptor-mediated inhibition at the soma to increase phasic dopamine transmission.

Methamphetamine Regulation of Firing Activity of Dopamine Neurons

“…BK channels are involved in AP repolarization in several neuronal types (Adams et al, 1982;Lancaster and Nicoll, 1987;Storm, 1990;Lin et al, 2014). Consistent with these reports, we found BK channels are expressed in dopamine neurons (Fig.…”

“…In addition, METH exposure broadened the spike halfwidth measured at the half-maximal voltage (Fig. 1 D METH and paxilline blockade of BK channels regulate the repolarization and AHP of APs Activation of BK channels has been shown to contribute to AP repolarization and AHP (Adams et al, 1982;Lancaster and Nicoll, 1987;Faber and Sah, 2002;Lin et al, 2014). Thus, to understand whether METH regulation of intrinsic firing behavior of dopamine neurons involves BK channel activity, we examined the influence of METH and a BK channel blocker paxilline on single spike amplitudes, repolarization, and AHP in spontaneously active dopamine neurons (Fig.…”

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

“…As expected from the actions of methamphetamine or COC (61,63), the amplitude, time to peak, and duration of evoked D2R-mediated IPSCs in WT slices treated with AMPH increased significantly relative to no-drug conditions and remained elevated throughout the AMPH application. However, the AMPH-induced increase in D2R-mediated IPSC amplitude was blunted in DAT Val559 slices (Fig.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…5). Recently, it has become clear that, aside from these traditional mechanisms, amphetamines are also capable of modulating action potential-dependent neurotransmitter release (Branch and Beckstead, 2012;Daberkow et al, 2013). Furthermore, amphetamines regulate DA neurotransmission via inhibition of monoamine oxidase (MAO) and enhancement of tyrosine hydroxylase (TH) and have numerous other receptor targets, including the a2-adrenergic receptor, the sigma receptor, and the trace amine-associated receptor 1 (TA 1 ) receptor (Fung and Uretsky, 1982;Robinson, 1985;Ritz and Kuhar, 1989;Matsumoto et al, 2014;Reese et al, 2014).…”

“…Unlike AMPH, MPH was recently shown to decrease exocytotic DA release (Federici et al, 2014), which may help explain the differing subjective effects of this drug. The exact mechanism by which AMPH increases the exocytotic release of DA is unknown, but may be related to the ability of AMPH to induce persistent transporter-mediated ionleakage and excitatory conductance (Ingram et al, 2002;Branch and Beckstead, 2012;Rodriguez-Menchaca et al, 2012). It has been suggested that reuptake inhibition is primarily associated with lower drug concentrations, possibly corresponding to those in the therapeutic range, whereas doses in the recreational range shift the importance to AMPH-mediated DA release (Calipari and Ferris, 2013).…”