Opioid modulation of ventral pallidal afferents to ventral tegmental area neurons.

Activation of mu opioid receptors within the ventral tegmental area (VTA) can produce reward through the inhibition of GABAergic inputs. GABAergic neurons in the ventral pallidum (VP) provide a major input to VTA neurons. To determine the specific VTA neuronal targets of VP afferents and their sensitivity to mu opioid receptor agonists, we virally expressed channel rhodopsin (ChR2) in rat VP neurons and optogenetically activated their terminals in the VTA. Light activation of VP neuron terminals elicited GABAergic IPSCs in both dopamine (DA) and non-DA VTA neurons, and these IPSCs were inhibited by the mu opioid receptor agonist DAMGO. In addition, using a fluorescent retrograde marker to identify VTA-projecting VP neurons, we found them to be hyperpolarized by DAMGO. Both of these actions decrease GABAergic input onto VTA neurons, revealing two mechanisms by which endogenous or exogenous opioids can activate VTA neurons, including DA neurons

Direct bidirectional μ-opioid control of midbrain dopamine neurons.

The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic μ-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 μM) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 μM, n = 5) and ω-agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca(2+) channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ± 7 mV and inhibitions were blocked by the K(+) channel blocker BaCl2 (100 μM, n = 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons

Opioid modulation of ventral pallidal afferents to ventral tegmental area neurons.

Activation of mu opioid receptors within the ventral tegmental area (VTA) can produce reward through the inhibition of GABAergic inputs. GABAergic neurons in the ventral pallidum (VP) provide a major input to VTA neurons. To determine the specific VTA neuronal targets of VP afferents and their sensitivity to mu opioid receptor agonists, we virally expressed channel rhodopsin (ChR2) in rat VP neurons and optogenetically activated their terminals in the VTA. Light activation of VP neuron terminals elicited GABAergic IPSCs in both dopamine (DA) and non-DA VTA neurons, and these IPSCs were inhibited by the mu opioid receptor agonist DAMGO. In addition, using a fluorescent retrograde marker to identify VTA-projecting VP neurons, we found them to be hyperpolarized by DAMGO. Both of these actions decrease GABAergic input onto VTA neurons, revealing two mechanisms by which endogenous or exogenous opioids can activate VTA neurons, including DA neurons

Direct bidirectional μ-opioid control of midbrain dopamine neurons.

The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic μ-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 μM) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 μM, n = 5) and ω-agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca(2+) channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ± 7 mV and inhibitions were blocked by the K(+) channel blocker BaCl2 (100 μM, n = 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons

Opioid Modulation of Ventral Pallidal Afferents to Ventral Tegmental Area Neurons

Activation of mu opioid receptors within the ventral tegmental area (VTA) can produce reward through the inhibition of GABAergic inputs. GABAergic neurons in the ventral pallidum (VP) provide a major input to VTA neurons. To determine the specific VTA neuronal targets of VP afferents and their sensitivity to mu opioid receptor agonists, we virally expressed channel rhodopsin (ChR2) in rat VP neurons and optogenetically activated their terminals in the VTA. Light activation of VP neuron terminals elicited GABAergic IPSCs in both dopamine (DA) and non-DA VTA neurons, and these IPSCs were inhibited by the mu opioid receptor agonist DAMGO. In addition, using a fluorescent retrograde marker to identify VTA-projecting VP neurons, we found them to be hyperpolarized by DAMGO. Both of these actions decrease GABAergic input onto VTA neurons, revealing two mechanisms by which endogenous or exogenous opioids can activate VTA neurons, including DA neurons

Ventral Tegmental Area Glutamate Neurons: Electrophysiological Properties and Projections

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2(+) VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (I(h)) than more lateral dopamine neurons and less consistent inhibition by dopamine D(2) receptor agonists. In addition, VGLUT2(+) VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2(+) projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons