Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites

doi:10.1016/0006-8993(80)91325-6

Brain Research

Volume 194, Issue 1, 21 July 1980, Pages 155-170

https://doi.org/10.1016/0006-8993(80)91325-6 Get rights and content

Abstract

The relationship between the action of enkephalin and the reinforcing action of electrical stimulation in the posterior lateral hypothalamus of the rat was studied with the self-administration approach. Adult male albino rats implanted with a combination cannula and stimulation electrode in hypothalamus were presented for the reinforcing effects of electrical stimulation. Only subjects that self-stimulated at moderate to high rates were given self-administration tests. The chamber for the self-administration tests was fitted with one lever at each end of a rectangular plexiglass ☐. In a session, one lever was ‘active’, the other not. The active lever, if depressed, yielded 20 nl of CSF (artificial cerebrospinal fluid), or CSF in which one of the test substances was dissolved.

Each subject was tested repeatedly for the reinforcing effects first of a control solution (CSF), then ofd-Ala²-Met-enkephalin (DALA), a long-acting synthetic analogue of enkephalin, then of morphine, and then of opiods mixed with naltrexone or naloxone. Following these tests, the subjects were once again given self-stimulation tests to ascertain the functional integrity of the ‘reward’ system after the repeated self-administration tests.

The results demonstrate that when the test solution was DALA instead of CSF the subjects pressed the active lever at a higher rate than for CSF, and they exhausted the supply more rapidly than for CSF. The rate on the active lever was also significantly higher than on the inactive lever. DALA at 1 and 5 μg/μl concentrations proved more reinforcing than at 0.1 μg/μl. Naltrexone did not block the reinforcing effect of DALA, whereas naloxone blocked DALA-induced reinforcement. These data extend the report of ventricular methionine-enkephalin positive reinforcement to DALA injected directly into the lateral hypothalamus.

Reference (55)

AtwehS.F. et al.
Autoradiographic localization of opiate receptors in rat brain I. Spinal cord and lower medulla
Brain Research
(1977)
AtwehS.F. et al.
Autoradiographic localization of opiate receptors in rat brain II. The brain stem
Brain Research
(1977)
CrowT.J.
A map of the rat mesencephalon for electrical self-stimulation
Brain Research
(1972)
EspositoR. et al.
Effects of morphine on intracranial self-stimulation to various brain stem loci
Brain Research
(1979)
GermanD.C. et al.
Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis
Brain Research
(1974)
KatzR.J. et al.
Behavioral activation by enkephalins in mice
Pharmacol. Biochem. Behav.
(1978)
LorensS.A. et al.
Naloxone blocks the excitatory effect of ethanol and chlordiazepoxide on lateral hypothalamic self-stimulation behavior
Life Sci.
(1978)
OldsM.E.
Hypothalamic substrate for the positive reinforcing properties of morphine in the rat
Brain Research
(1979)
PasternakG.W. et al.
An endogenous morphine-like factor in mammalian brain
Life Sci.
(1975)
PlotnikoffN.P. et al.
Neuropharmacological actions of enkephalin after systemic administration
Life Sci.
(1976)

TereniusL. et al.

Morphine like ligand for opiate receptors in human CSF

Life Sci.

(1975)

UhlG.R. et al.

Immunohistochemical mapping of enkephalin containing cell bodies, fibers and nerve terminals in the brain stem of the rat

Brain Research

(1979)

YakshT.L. et al.

Narcotic analgesics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques

Pain

(1978)

AdamsW.J. et al.

Morphine enhances lateral hypothalamic self-stimulation in the rat

AmitZ. et al.

Intraventricular self-adminstration of morphine in naive laboratory rats

Psychopharmacology

(1976)

AtwehS.F. et al.

Autoradiographic localization of opiate receptors in rat brain III. The telencephalon

Brain Research

(1977)

BelluzziJ.D. et al.

Analgesia induced in vivo by central administration of enkephalin in rat

Nature (Lond.)

(1976)

BlasigJ. et al.

Tolerance and dependence induced by morphine-like pituitary peptides in rats

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

(1976)

BroekkampC.L.E. et al.

Stimulant effects of enkephalin microinjection into the dopaminergic A10 area

Nature (Lond.)

(1979)

ChangJ.K. et al.

Opiate receptor affinities and behavioral effects of enkephalin: structure activity relationships of ten synthetic peptide analogues

Life Sci.

(1976)

CrowT.J.

Catecholamine-containing neurones and electrical self-stimulation. A review of some data

Psychol. Med.

(1972)

EldeR. et al.

Immunohistochemical studies using antibodies to leucine-enkephalin initial observations on the nervous system of the rat

Neuroscience

(1976)

FrenkH. et al.

Enkephalin-induced cortical seizures in the rat

Neurosci. Abstr.

(1977)

GlickS.D. et al.

Tolerance to the facilitatory effect of morphine on self-stimulation of the medial forebrain bundle in rats

Res. Commun. Chem. Path. Pharmacol.

(1974)

HallR.D. et al.

Neuronal and neurochemical substrates of reinforcement

Neurosci. Res. Prog. Bull.

(1977)

HillerJ.M. et al.

Distribution of stereospecific binding of the potent narcotic analgesic etorphine in the human brain: predominance in the limbic system

Res. Commun. Chem. Path. Pharmacol.

(1973)

Ho¨kfeltT. et al.

Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enekephalin and substance P

Cited by (65)

Mapping of methionine-enkephalin-arg6-gly7-leu8 in the human diencephalon
2016, Neuroscience
Citation Excerpt :
In addition to an essential involvement in food reinforcement, the hypothalamus might modulate drug intake (Le Merrer et al., 2009). Thus, in both rats and mice, the lateral hypothalamic area has been implicated in morphine self-administration (Olds and Williams, 1980; David and Cazala, 2000). Opioid receptors located in the lateral hypothalamic area contribute to opiate reinforcement (Le Merrer et al., 2009).
Using an immunohistochemical technique, we mapped the immunoreactive structures containing methionine-enkephalin-Arg⁶-Gly⁷-Leu⁸ (Met-8) (a marker for the pro-enkephalin system) in the human diencephalon. Compared with previous studies, we observed a more widespread distribution of Met-8 in the human diencephalon. Met-8-immunoreactive cell bodies and fibers exhibited a more widespread distribution in the hypothalamus than in the thalamus. We observed six populations of Met-8-immunoreactive cell bodies. These perikarya were observed in the paratenial thalamic nucleus, ventromedial and dorsomedial hypothalamic nuclei, lateral hypothalamic area, pallidohypothalamic nucleus and in the paraventricular hypothalamic nucleus (posterior part). In the thalamus, Met-8-immunoreactive fibers were primarily observed in the midline region, whereas in the hypothalamus, these fibers were widely distributed. In general, a moderate/low density of Met-8-immunoreactive fibers was observed in the diencephalic nuclei. A moderate density was observed in the paraventricular thalamic nucleus, reuniens thalamic nucleus, lateral and medial geniculate nuclei, dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus (posterior part) and ventromedial hypothalamic nucleus. The present study is the first to demonstrate the presence of clusters of Met-8-immunoreactive cell bodies in the human thalamus and hypothalamus, the distribution of fibers containing neuropeptides in the hypothalamus and the presence of these fibers in several thalamic nuclei. This neuroanatomical study will serve to elucidate the physiological roles of Met-8 in future studies of the human diencephalon.
Hypothalamic neuropeptide signaling in alcohol addiction
2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Injection of a DOR agonist into the PVN increases extracellular levels of DA in the NAc, although it leaves ACh unaffected (Rada et al., 2010). Further, rats will voluntarily self-administer a DOR agonist into the posterior LH, the same brain region where they press for electrical self-stimulation (Olds and Williams, 1980). These results support the idea that hypothalamic ENK promotes alcohol drinking in part due to its ability to increase positive reinforcement.
The hypothalamus is now known to regulate alcohol intake in addition to its established role in food intake, in part through neuromodulatory neurochemicals termed neuropeptides. Certain orexigenic neuropeptides act in the hypothalamus to promote alcohol drinking, although they affect different aspects of the drinking response. These neuropeptides, which include galanin, the endogenous opioid enkephalin, and orexin/hypocretin, appear to stimulate alcohol intake not only through mechanisms that promote food intake but also by enhancing reward and reinforcement from alcohol. Moreover, these neuropeptides participate in a positive feedback relationship with alcohol, whereby they are upregulated by alcohol intake to promote even further consumption. They contrast with other orexigenic neuropeptides, such as melanin-concentrating hormone and neuropeptide Y, which promote alcohol intake under limited circumstances, are not consistently stimulated by alcohol, and do not enhance reward. They also contrast with neuropeptides that can be anorexigenic, including the endogenous opioid dynorphin, corticotropin-releasing factor, and melanocortins, which act in the hypothalamus to inhibit alcohol drinking as well as reward and therefore counter the ingestive drive promoted by orexigenic neuropeptides. Thus, while multiple hypothalamic neuropeptides may work together to regulate different aspects of the alcohol drinking response, excessive signaling from orexigenic neuropeptides or inadequate signaling from anorexigenic neuropeptides can therefore allow alcohol drinking to become dysregulated.
Opioids in the perifornical lateral hypothalamus suppress ethanol drinking
2013, Alcohol
Citation Excerpt :
These new findings show that the opioids, instead of consistently promoting appetitive behaviors, may have different roles that vary as a function of the specific brain area and specific opioid receptor subtype. There is some evidence that the perifornical lateral hypothalamus (PF/LH), which contains functional δ-, μ-, and κ-receptors (Li & van den Pol, 2006, 2008; Olds & Williams, 1980) and integrates motivational signals with ingestive behavior (Berthoud & Munzberg, 2011), may be another site where the opioids are behaviorally inhibitory. In this area, the excitatory amino acid glutamate has recently been shown to stimulate the consumption of ethanol (Chen, Barson, Chen, Hoebel, & Leibowitz, 2012), similar to its effect on food intake (Stanley, Urstadt, Charles, & Kee, 2011), suggesting that the opioid peptides ENK and DYN which are neuronally inhibitory (Li & van den Pol, 2006; Nicoll, Siggins, Ling, Bloom, & Guillemin, 1977; Singh et al., 1997) may induce the opposite effect, a suppression of ethanol drinking behavior.
The opioid system is known to enhance motivated behaviors, including ethanol drinking and food ingestion, by acting in various reward-related brain regions, such as the nucleus accumbens, ventral tegmental area and medial hypothalamus. There is indirect evidence, however, suggesting that opioid peptides may act differently in the perifornical lateral hypothalamus (PF/LH), causing a suppression of consummatory behavior. Using brain-cannulated Sprague–Dawley rats trained to voluntarily drink 7% ethanol, the present study tested the hypothesis that opioids in the PF/LH can reduce the consumption of ethanol, with animals receiving PF/LH injections of the δ-opioid receptor agonist D-Ala2-met-enkephalinamide (DALA), the μ-receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), the κ-receptor agonist (±)-trans-U-50,488 methanesulfonate (U-50,488H), or the general opioid antagonist methylated naloxone (m-naloxone). The consumption of ethanol, lab chow, and water was monitored for 4 h after injection. The results showed that the three opioid receptor agonists injected into the PF/LH specifically and significantly reduced ethanol intake, while causing little change in chow or water intake, and the opposite effect, enhanced ethanol intake, was observed with the opioid antagonist. Of the three opioid agonists, the δ-agonist appears to produce the most consistent and long-lasting suppression of consumption. This effect was not observed with injections 2 mm dorsal to this area, focusing attention on the PF/LH as the main site of action. These results suggest that the opioid peptides have a specific role in the PF/LH of reducing ethanol drinking, which is distinct from their more commonly observed appetitive actions in other brain areas. The additional finding, that m-naloxone in the PF/LH stimulates ethanol intake in contrast to its generally suppressive effect in other regions, focuses attention on this hypothalamic area and its distinctive role in contributing to the variable effects sometimes observed with opioid antagonist therapy for alcoholism.
Critical assessment of how to study addiction and its treatment: Human and non-human animal models
2005, Pharmacology and Therapeutics
Laboratory models, both animal and human, have made enormous contributions to our understanding of addiction. For addictive disorders, animal models have the great advantage of possessing both face validity and a significant degree of predictive validity, already demonstrated. Another important advantage to this field is the ability of reciprocal interplay between preclinical and clinical experiments. These models have made important contributions to the development of medications to treat addictive disorders and will likely result in even more advances in the future. Human laboratory models have gone beyond data obtained from patient histories and enabled investigators to make direct observations of human drug self-administration and test the effects of putative medications on this behavior. This review examines in detail some animal and human models that have led not only to important theories of addiction mechanisms but also to medications shown to be effective in the clinic.
Localization of brain reinforcement mechanisms: Intracranial self- administration and intracranial place-conditioning studies
1999, Behavioural Brain Research
Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC) methodologies have been mainly used to study drug reward mechanisms, but they have also been applied toward examining brain reward mechanisms. ICSA studies in rodents have established that the ventral tegmental area (VTA) is a site supporting morphine and ethanol reinforcement. ICPC studies confirmed that injection of morphine into the VTA produces conditioned place preference (CPP). Further confirmation that activation of opioid receptors within the VTA is reinforcing comes from the findings that the endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA. Activation of the VTA dopamine (DA) system may produce reinforcing effects in general because (a) neurotensin is self-administered into the VTA, and injection of neurotensin into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC), and (b) GABA_A antagonists are self-administered into the anterior VTA and injections of GABA_A antagonists into the anterior VTA enhance DA release in the NAC. The NAC also appears to have a major role in brain reward mechanisms, whereas most data from ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement processes. Rodents will self-infuse a variety of drugs of abuse (e.g. amphetamine, morphine, phencyclidine and cocaine) into the NAC, and this occurs primarily in the shell region. ICPC studies also indicate that injection of amphetamine into the shell portion of the NAC produces CPP. Activation of the DA system within the shell subregion of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D₂ antagonist can block this behavior. In addition, rats will self-administer a mixture of a D₁ plus a D₂ agonist into the shell, but not the core, region of the NAC. The ICSA of this mixture can be blocked with the co-infusion of either a D₁ or a D₂ antagonist. However, the interactions of other transmitter systems within the NAC may also play key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused into the NAC. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and phencyclidine. The DA system also seems to play a role in this behavior since cocaine self-infusion into the MPF cortex can be blocked by co-infusing a D₂ antagonist, or with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus. Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis) and serotonin systems of the dorsal and median raphe nuclei may also be important anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC studies indicate that there are a number of receptors, neuronal pathways, and discrete CNS sites involved in brain reward mechanisms.
Enhanced sensitivity of the nucleus accumbens proenkephalin system to alcohol in rats selectively bred for alcohol preference
1998, Brain Research
Evidence suggests that alcohol-induced activation of the endogenous opioid system is part of a neurobiological mechanism that may be functionally involved in alcohol reinforcement and high alcohol drinking behavior. We postulate that a genetic predisposition toward alcohol drinking is accompanied by increased responsiveness of the opioid system to alcohol. To test this hypothesis, the present study compared the effect of an acute alcohol challenge on enkephalin gene expression in discrete brain regions which are high in preproenkephalin (PPENK) mRNA content and/or are important in mediating alcohol reward in rats selectively bred for alcohol preference (P) or nonpreference (NP). PPENK mRNA content was measured by in situ hybridization performed with a 36 base oligonucleotide probe for PPENK mRNA and was quantified using a computerized image-analysis system. Blood alcohol concentration (BAC) and rate of alcohol elimination following alcohol infusion were similar in P and NP rats. P and NP rats did not differ in basal content of PPENK mRNA in any of the brain areas examined prior to onset of infusion. An intragastric (I.G.) infusion of alcohol (2.5 g/kg b.wt) produced a significant increase in PPENK mRNA in the nucleus accumbens (both shell and core) of P but not NP rats at 1 h after the onset of infusion which coincided with the time at which peak BAC was attained. In contrast, at 8 h after the onset of the alcohol infusion, when BAC was falling toward baseline, PPENK mRNA was decreased in the nucleus accumbens of both P and NP rats and in the anterior striatum and amygdala of NP rats. The results suggest that enhanced responsiveness of the enkephalinergic system to alcohol is associated with, and may be functionally involved in, mediating high alcohol drinking behavior.

View all citing articles on Scopus

View full text

Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites

Abstract

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Pharmacol. Biochem. Behav.

Life Sci.

Brain Research

Life Sci.

Life Sci.

Life Sci.

Brain Research

Pain

Morphine enhances lateral hypothalamic self-stimulation in the rat

Intraventricular self-adminstration of morphine in naive laboratory rats

Psychopharmacology

Autoradiographic localization of opiate receptors in rat brain III. The telencephalon

Brain Research

Analgesia induced in vivo by central administration of enkephalin in rat

Nature (Lond.)

Tolerance and dependence induced by morphine-like pituitary peptides in rats

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

Stimulant effects of enkephalin microinjection into the dopaminergic A10 area

Nature (Lond.)

Opiate receptor affinities and behavioral effects of enkephalin: structure activity relationships of ten synthetic peptide analogues

Life Sci.

Catecholamine-containing neurones and electrical self-stimulation. A review of some data

Psychol. Med.

Immunohistochemical studies using antibodies to leucine-enkephalin initial observations on the nervous system of the rat

Neuroscience

Enkephalin-induced cortical seizures in the rat

Neurosci. Abstr.

Tolerance to the facilitatory effect of morphine on self-stimulation of the medial forebrain bundle in rats

Res. Commun. Chem. Path. Pharmacol.

Neuronal and neurochemical substrates of reinforcement

Neurosci. Res. Prog. Bull.

Distribution of stereospecific binding of the potent narcotic analgesic etorphine in the human brain: predominance in the limbic system

Res. Commun. Chem. Path. Pharmacol.

Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enekephalin and substance P

Self-administration of D-Ala²-Met-enkephalinamide at hypothalamic self-stimulation sites