Ventral tegmental self‐stimulation selectively induces opioid peptide release in rat CNS

Abstract

Intracranial self-stimulation (ICS) is thought to activate neuronal systems involved in processing natural reinforcing agents. Metabolic mapping studies have previously demonstrated a subset of CNS structures specifically engaged by ICS in animals receiving stimulation actively vs. passively. Since opiates are known to enhance ICS behavior and presumably its reinforcing properties, the current study addressed the question of the role of opioid peptides as mediators of ICS. Rats were trained on a fixed ration (FR) 20 schedule of responding maintained by ICS. Following response stabilization, rats were assigned either to an active or a corresponding yoked stimulation group at 1 of 2 schedules of reinforcement (i.e., FR1-YFR1, FR20-YFR20, or sedentary control), and opioid peptide release was inferred from in vivo receptor occupancy. Autoradiographic analyses identified 3 groups of structures. Treatment-induced alterations in occupancy were seen in the medial dorsal nucleus of the thalamus, basolateral amygdala, ventral pallidum, medial habenula, dorsal raphe, posterior hypothalamus, substantia nigra pars compacta, agranular preinsular cortex, and zona incerta. Depending upon the structure, peptide release was dependent upon stimulus contingency (active vs. yoked) and/or schedule (FR1 vs. FR20). Evidence for ICS-induced inhibition of peptide release was found in the habenula and preinsular cortex. Nine additional structures, all components of, or receiving projections from, the limbic system, revealed complex interactions between ICS treatment and the electrode side. Finally, a widespread ipsilateral increase in receptor binding was seen rostrally from the cingulate, olfactory tubercle, and nucleus accumbens, along the lateral hypothalamus and hippocampus, and extending caudally to the substantia nigra and ventral tegmentum. These later effects appear to be related to stimulation-induced changes in blood flow and subsequent ligant presentation increases. Collectively, these data point towards the ability of rewarding brain stimulation to activate discrete neuronal opioid systems contingent upon specific behavioral as well as stimulus conditions.

Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: Role of μ-opioid receptors

“…Fifth, saturating concentration of a MOR agonist occludes ethanol-induced excitation of VTA DA neurons (Xiao et al, 2007), probably resulted from a maximal inhibition of GABAergic synaptic transmission. These results are in line with previous observations that ethanol increases the release of β-endorphin in the brain, which activates MORs (Stein, 1993, Herz, 1997, Marinelli et al, 2004.…”

“…Acute ethanol increases the release of β-endorphin, an endogenous ligand for MORs in the rat brain (Stein, 1993, Herz, 1997, Marinelli et al, 2004. Our recent study supports the postulation that ethanol might inhibit the activity of VTA GABAergic neurons through the activation of postsynaptic MORs following its enhancement of β-endorphin release (Xiao et al, 2007).…”

“…Activation of MORs hyperpolarizes and inhibits VTA GABAergic neurons (Di Chiara and North, 1992, Johnson and North, 1992a, Margolis et al, 2003. Several lines of evidence indicate that MORs are involved in ethanol-induced excitation of VTA DA neurons: (1) ethanol enhances the release of β-endorphin in several brain regions, which activates MORs (Stein, 1993, Herz, 1997, Marinelli et al, 2004; (2) Naloxone, an opioid receptor antagonist, greatly attenuates ethanolinduced inhibition of VTA GABAergic neurons (Xiao et al, 2007); (3) Both naloxone and MOR agonist attenuated the effect of ethanol on VTA DA neurons (Xiao et al, 2007).…”

Acupuncture Inhibits GABA Neuron Activity in the Ventral Tegmental Area and Reduces Ethanol Self‐Administration

“…As VTA GABA neurons are the primary source of inhibitory input to VTA DA neurons, ethanol inhibition of GABA IPSCs appears to dominate over the potentiating effect of ethanol on other GABAergic or opioidergic inputs to VTA neurons. Third, ethanol enhances the release of β‐endorphin (Herz, 1997; Marinelli et al., 2004; Stein, 1993), which might activate MORs on VTA GABA neurons. Thus, acupuncture effects on VTA GABA neurons might result from combined effects on opiodergic actions on VTA GABA neurons via MORs or on accumbal GABA input to VTA GABA neurons via DORs.…”

Ethanol Blocks Long-Term Potentiation of GABAergic Synapses in the Ventral Tegmental Area Involving μ-Opioid Receptors

“…Several lines of evidence indicate that ethanol's action on neurons in the VTA involves MORs. Ethanol enhances the release of β-endorphin, which activates MORs in the VTA and several other brain regions (Stein, 1993; Herz, 1997; Mendez et al, 2003; Marinelli et al, 2004; Lam et al, 2008; Jarjour et al, 2009). Selective MOR antagonists reduce ethanol consumption (Krishnan-Sarin et al, 1998; Kim et al, 2000; Hyytia and Kiianmaa, 2001; Margolis et al, 2008).…”