Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions.

Abstract

,-Endorphin in nanomole quantities produced a stimulation of locomotor activity when infused into the region of the dopamine cell bodies of the ventral tegmental area (VTA) in rats. a-, -y-, and des-Tyr-y-endorphin produced similar effects, but the D-alanine analogues of a-and y-endorphin produced a larger and longer-lasting activation, presumably reflecting their resistance to degradation. This locomotor activation was reversible by pretreatment with naloxone and b destruction of the terminal projections of the mesocorticolimzic dopamine system originating in the VTA. These results demonstrate that locally infused endorphin can interact with the opioid receptors in the VTA, and they suggest a means by which endorphins activate limbic excitability. The identification and localization within the central nervous system of endogenous peptides with opiate-like actions suggested that these substances may act as central neurotransmitters (1, 2). Both [Metlenkephalin [/3-lipotropin-(61-65)] and f3-endorphin (3-END) [/3-lipotropin-(61-91)] exhibit opiate-like activity when injected into the ventricles (3, 4). These effects have included analgesia, catatonia, loss of corneal and tail pinch reflexes, and wet-dog shakes (3), and :3-END appeared to be more potent than [Met]enkephalin (5-7). In addition, most of these effects are reversible by naloxone. These preliminary results suggested to some that-the endorphins could be an etiological factor in mental illness (3,8), but the nature and specification of this action remains to be determined.Opiate receptors and enkephalin-like peptides have been found in the region of the ventral tegmental area (VTA) (9), and in at least some accounts receptors appear to be localized on mesolimbic dopamine neurons (9, 10). These mesolimbic dopamine neurons are thought to be involved in the locomotor stimulation produced by psychomotor stimulants (11, 12) but also may have a role in general activation and the actual organization of behavior (13,14). In fact, some authors have suggested that the activation of the mesolimbic dopamine system may be an important model of schizophrenia (15). This intriguing similarity of the putative function for the mesolimbic dopamine system and the endogenous opiate systems requires further analysis of their interaction at the behavioral level, and our initial studies have concentrated on the activation of the mesolimbic dopamine system as measured by simple locomotor activity.Recent work has demonstrated that morphine and [D-Ala2, Met]enkephalin when injected into the VTA can produce significant increases in locomotor activity that may reflect an activation of these mesolimbic dopamine neurons (16,17). The purpose of the present study was to determine whether 1-END also interacts with the opiate receptors in the VTA to produceThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 2323 locomot...

Lack of Cross-Sensitization of the Locomotor Effects of Morphine in Amphetamine-Treated Rats

“…A marked difference with systemic administration is that upon intra-VTA administration, the locomotor effects of opioids seem to be completely dopamine-dependent (Kelley et al 1980;Stinus et al 1980;Joyce et al 1981;Kalivas et al 1983), mediated by indirect stimulation of mesolimbic dopaminergic neurons (Johnson and North 1992;Klitenick et al 1992). Given the findings that the mesolimbic dopaminergic system becomes hyperreactive upon repeated treatment with psychostimulant drugs (see introduction), it is therefore not surprising that in these studies cross-sensitization to intra-VTA morphine was observed.…”

“…The locomotor activating properties of psychostimulant drugs are generally thought to be due to an increase in nucleus accumbens dopaminergic neurotransmission (Kelly et al 1975;Pijnenburg et al 1975;Delfs et al 1990; for review see Amalric and Koob 1993). On the other hand, the psychomotor effects of opioid drugs have been shown to involve both dopamine-dependent and dopamine-independent components (Pert and Sivit 1979;Kelley et al 1980;Stinus et al 1980;Joyce et al 1981;Kalivas et al 1983;Vaccarino et al 1986). This leaves open as to whether expression of opioid sensitization involves hyperresponsiveness of dopaminergic and/or non-dopaminergic mechanisms, and whether sensitization to opioids and psychostimulant requires different neuroadaptive phenomena.…”

Sexual Behavior and Sex-Associated Environmental Cues Activate the Mesolimbic System in Male Rats

“…Furthermore, the specific opioid ligand involved in MOR activation in VTA has not been identified. Anatomical studies show both beta-endorphin (Mansour et al, 1988) and enkephalin (Johnson et al, 1980;Fallon and Leslie, 1986) terminals in the VTA, and pharmacological evidence shows that both of these peptides can activate the mesolimbic DA system (Broekkamp et al, 1979;Stinus et al, 1980;Dauge et al, 1992). In addition, recent reports have indicated the presence of the highly MOR-specific ligands endomorphin-1 and -2 in the VTA (Greenwell et al, 2002).…”

Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

“…As pioneered by the Segal laboratory and others, animal models of locomotor behavior have been critical tools for understanding the relationships between monoamines and behavior (Geyer and Segal, 1991;Kelly and Iversen, 1976;Lat, 1965;Schiorring, 1979;Segal et al, 1975Segal et al, , 1971Segal and Mandell, 1970;Stinus et al, 1980). Such behavioral models have provided a foundation for much of what we know regarding the neural correlates of behavioral effects of drugs of abuse, in particular psychotomimetics such as stimulants and hallucinogens (Adams and Geyer, 1982;Bankson and Cunningham, 2001;Creese, 1983;Eilam et al, 1989;Fink and Morgenstern, 1985;Geyer, 1990;Lehmann-Masten and Geyer, 1991;Segal, 1975;Segal et al, 1981Segal et al, , 1980Swerdlow and Koob, 1985).…”