Rewarding and Psychomotor Stimulant Effects of Endomorphin-1: Anteroposterior Differences within the Ventral Tegmental Area and Lack of Effect in Nucleus Accumbens

Abstract

Endomorphin-1 (EM-1) is a recently isolated endogenous peptide having potent analgesic activity and high affinity and selectivity for the mu-opioid receptor. The present study was designed to investigate the rewarding and psychomotor stimulant effects of EM-1 in specific brain regions. We found that rats would learn without priming or response shaping to lever-press for microinjections of EM-1 into the ventral tegmental area (VTA); responding was most vigorous for high-dose injections into the posterior VTA. Rats did not learn to lever-press for microinjections of EM-1 into the nucleus accumbens (NAS) or regions just dorsal to the VTA. Lever-pressing for EM-1 in the VTA was extinguished when vehicle was substituted for the peptide and was reinstated when EM-1 reinforcement was re-established. Conditioned place preference was established by EM-1 injections into the posterior but not the anterior VTA or the NAS. Injection of EM-1 (0.1-1.0 nmol) into the posterior VTA induced robust increases in locomotor activity, whereas injections into the anterior VTA had very weak locomotor-stimulating effects. When injected into the NAS, EM-1 (0.1-10.0 nmol) did not affect locomotor activity. The present findings implicate the posterior VTA as a highly specific and sensitive site for opioid reward and suggest a role for EM-1-containing projections to the posterior VTA in the rewarding effects of other reinforcers.

Dual Role of Medial A10 Dopamine Neurons in Affective Encoding

“…Guide tips for microinjection and microdialysis ended 1.0 and 2.0 mm, respectively, above the target sites. We studied two regions within the ventral tegmental area (VTA) because of previous functional studies (Ikemoto et al, 1997(Ikemoto et al, , 1998Carlezon et al, 2000;Rodd-Henricks et al, 2000;Ikemoto and Wise, 2002;Zangen et al, 2002) that divided the VTA into the anterior and posterior portions. The present study divided the VTA into anterolateral and posteromedial portions, because recent neuron tracer data suggest that the cell bodies of dopaminergic neurons projecting to the ventral striatum distribute from the posteromedial to anterolateral dimensions at an approximate 451 angle to the anteroposterior axis (Ikemoto, 2007).…”

“…Local administration of psychomotor stimulants such as amphetamine or cocaine into the ventral striatum, or administration of drugs like carbachol or opiates into the A10 area, increases dopamine concentration in the ventral striatum (Carboni et al, 1989;Devine et al, 1993;Westerink et al, 1996) and somatomotor activity (Ikemoto, 2002;Zangen et al, 2002;Ikemoto et al, 2003) and leads to conditioned place preference (Carr and White, 1986;Ikemoto and Wise, 2002;Zangen et al, 2002;Ikemoto, 2003). Conditioned place preference has been shown to depend on stimulus-positive incentive learning (Perks and Clifton, 1997;Yin and Knowlton, 2002).…”

“…Conditioned place preference has been shown to depend on stimulus-positive incentive learning (Perks and Clifton, 1997;Yin and Knowlton, 2002). In addition, rats learn to lever-press for administration of cocaine or amphetamine into the ventromedial striatum (Ikemoto, 2003;Ikemoto et al, 2005), and various other drugs into medial A10 Zangen et al, 2002Zangen et al, , 2006Rodd et al, 2004;Ikemoto et al, 2006). Further, blockade of dopamine receptors or lesions of dopaminergic terminals in the ventromedial striatum, but not the ventrolateral striatum, disrupts the establishment of conditioned place preference induced by systemic administration of cocaine, amphetamine, nicotine, or morphine (Sellings and Clarke, 2003;Fenu et al, 2006;Sellings et al, 2006a, b;Spina et al, 2006).…”

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

“…The ventral tegmental area (VTA) has been implicated in the motivational actions of opioids (Bozarth and Wise, 1984) and EtOH (McBride et al, 1991): injection of a -opioid receptor (MOR) agonist into the VTA is reinforcing (Bals-Kubik et al, 1993;Olmstead and Franklin, 1997;Zangen et al, 2002;Terashvili et al, 2004) while MOR antagonists in the VTA block both opioid and EtOH place preference (Phillips and LePiane, 1980;Bechtholt and Cunningham, 2005). The major reinforcing process in the VTA is thought to be excitation of dopamine (DA) neurons (Schultz, 2007) and MOR agonist-mediated reinforcement in the VTA is thought to be due to inhibition of GABA release onto DA neurons (Johnson and North, 1992).…”

Heroin Self-Administration Experience Establishes Control of Ventral Tegmental Glutamate Release by Stress and Environmental Stimuli

“…Opiates have rewarding actions in the VTA Devine and Wise, 1994;Phillips and LePiane, 1980;Zangen et al, 2002), and the rewarding actions of m-and d-opioids are in proportion to their ability to activate the dopamine system (Devine et al, 1993). However, the ability of opiates to activate the dopamine system is thought to be mediated by inhibition of GABAergic input (Johnson and North, 1992;Matsui and Williams, 2011) rather than by excitation of glutamate input to the dopamine system.…”