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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    257—Opioids: Neural Mechanisms of Addiction

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    257.10: Orexin/hypocretin in the ventral tegmental area is necessary for morphine-induced synaptic plasticity of dopamine neurons

    Location: Halls B-H

    1Univ. of British Columbia, Vancouver, BC, Canada; 2Hotchkiss Brain Inst., Calgary, AB, Canada

    Abstract Body: Dopamine neurons in the ventral tegmental area (VTA) are a key target of addictive drugs and neuroplasticity in this region may underlie some of the core features of addiction. All drugs of abuse induce an LTP-like potentiation of excitatory inputs to VTA dopamine neurons, but it is not well understood how these drugs, despite chemical diversity and differences in molecular targets, bring about a common synaptic change. Orexin (hypocretin) is a lateral hypothalamic neuropeptide released into the VTA that promotes drug-seeking behaviours and potentiates excitatory synaptic transmission in the VTA. Inhibition of systemic orexin signaling blocks both cocaine-induced plasticity and drug seeking behaviours. However, it is unknown how orexin gates drug-induced plasticity in the VTA. We determined if orexin action in the VTA was necessary for morphine-induced strengthening of excitatory synapses onto VTA dopamine neurons. We used whole cell patch clamp electrophysiology in midbrain slices taken from male Sprague Dawley rats 24 hours following a single in vivo injection of morphine (10 mg/kg) or saline to assess excitatory synaptic strength. Morphine potentiated glutamatergic synaptic transmission onto VTA dopamine neurons by a presynaptic increase in glutamate release and by a postsynaptic change in AMPAR number or function, likely including a switch in subunit composition. Systemic or intra-VTA administration of SB 334867, an orexin receptor type 1 antagonist, blocked a morphine- induced increase in the AMPAR/NMDAR ratio, morphine-induced increases in AMPAR mini excitatory postsynaptic current frequency and amplitude, as well as morphine-induced AMPAR subunit redistribution measured by a change in rectification. These results support a role for orexin signaling in both pre-and postsynaptic potentiation of glutamatergic transmission in the VTA by morphine. Because orexin signaling is required for plasticity induced by both morphine and cocaine, orexin may function as a gatekeeper for drug-induced plasticity of glutamatergic inputs to dopamine neurons.

    Lay Language Summary: Our research indicates that blocking orexin (also known as hypocretin) signaling prevents morphine-induced changes in the activity of the ventral tegmental area, a brain region critical for mediating addiction-related behaviors. These results suggest that orexin receptors may be a useful target for the treatment of drug addiction.
    Drug addiction is a devastating illness with wide prevalence that is plagued by relapse. Even when an individual has not taken drugs for years, drug-related cues have a persistent and exaggerated importance for them, and often serve as a trigger for relapse. These cues are thought to retain a powerful influence over drug users because even from the very first drug exposure, the connections between the neurons that carry information about these cues and the neurons of reward-related brain areas like the ventral tegmental area are strengthened by the drugs themselves. However, the way this strengthening occurs is largely unknown. Orexins are protein molecules in the brain that signal arousal and when absent result in narcolepsy. Our results suggest that drugs of abuse manipulate the orexin system to influence the activity of reward-related brain areas.
    To simulate the first drug-taking experience, we gave rats a single injection of morphine. Twenty-four hours later, after the immediate rewarding effects of morphine have worn off, we assessed the relative strength of connections that either excite or inhibit the activity of dopamine neurons in the ventral tegmental area. In rats that were given a placebo with morphine, there was a significant strengthening of the connections that excite dopamine neurons and a weakening of those that inhibit. This suggests that morphine creates an imbalance in the control mechanisms that regulate the activity of dopamine neurons in order to enhance the rewarding nature of the drug-taking experience. However, in rats that were treated with a blocker of the orexin signaling system, the strengthening of excitatory connections to the ventral tegmental area was abolished, and the switch from inhibitory to excitatory control was lost. This means that by inhibiting orexin function in the ventral tegmental area, it is possible to block some of the changes that are thought to mediate drug-seeking behavior.
    These results provide evidence that addictive drugs hijack natural signals in the brain, like orexin, to exaggerate the importance of drug-related cues and drive drug seeking. Because relapse is one of the hardest aspects of addiction to prevent, future studies will determine if modifying orexin function in humans can reduce craving or the propensity to relapse into drug-seeking behavior.