Opioid-neuroleptic interaction in brainstem self-stimulation

doi:10.1016/0006-8993(89)91401-7

Brain Research

Volume 477, Issues 1–2, 16 January 1989, Pages 144-151

https://doi.org/10.1016/0006-8993(89)91401-7 Get rights and content

Abstract

Injection of morphine into the ventral tegmental area (but not dorsal to it) induced a dose-dependent decrease in the frequency threshold for midline metencephalic brain stimulation reward. Facilitating doses of ventral tegmental morphine also reversed, in 4 of 6 animals, the threshold-increasing effects of pimozide (0.35 mg/kg, i.p.). This reversal was itself reversed by naloxone (2 mg/kg, i.p.), suggesting a direct action of morphine at ventral tegmental opiate receptors. These data fit with electrophysiological evidence that ventral tegmental morphine stimulates or disinhibits dopamine impulse flow, which would result in increased synaptic dopamine concentrations and decreased synaptic pimozide effectiveness. In the remaining two animals, the combined neuroleptic-opiate treatment resulted in a complete cessation of responding that was not reversed by a 5-fold increase in stimulation frequency. This finding suggested a complete inactivation of the reward mechanism, which might be expected from the interaction of high doses of two drugs that are each known to be capable of producing depolarization inactivation of dopaminergic neurons. These data confirm that brainstem self-stimulation, like medial forebrain bundle self-stimulation, depends critically on the function of the mesocorticolimbic dopamine system.

References (58)

J. Atalay et al.
Time course of pimozide effects on brain stimulation reward
Pharmacol. Biochem. Behav.
(1983)
M. Besson et al.
Dopamine: spontaneous and drug-induced release from the caudate nucleus in the cat
Brain Research
(1971)
M.A. Bozarth
Neuroanatomical boundaries of the reward-relevant opiate-receptor field in the ventral tegmental area as mapped by the conditioned place preference method in rats
Brain Research
(1987)
M.A. Bozarth et al.
Intracranial self-administration of morphine into the ventral tegmental area of rats
Life Sci.
(1981)
C.L. Broekkamp et al.
Separation of inhibiting and stimulating effects of morphine on self-stimulation behavior by intracerebral microinjections
Eur. J. Pharmacol.
(1976)
C.L. Broekkamp et al.
Facilitation of self-stimulation behavior following intracerebral microinjections of opioids into the ventral tegmental area
Pharmacol. Biochem. Behav.
(1979)
G. Fouriezos et al.
Pimozide-induced extinction of intracranial self-stimulation: response patterns rule out motor or performance deficits
Brain Research
(1976)
K.B.J. Franklin
Catecholamines and self-stimulation: reward and performance effects dissociated
Pharmacol. Biochem. Behav.
(1978)
C.R. Gallistel et al.
Affinity for the dopamine D2 receptor predicts neuroleptic potency in blocking the reinforcing effect of MFB stimulation
Pharmacol. Biochem. Behav.
(1983)
C.R. Gallistel et al.
Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation
Pharmacol. Biochem. Behav.
(1987)

C.R. Gallistel et al.

Pimozide and amphetamine have opposing effects on the reward summation function

Pharmacol. Biochem. Behav.

(1984)

T.H. Hand et al.

6-OHDA lesions of the ventral tegmental area block morphine-induced but not amphetamine-induced facilitation of self-stimulation

Brain Research

(1985)

T.H. Hand et al.

Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons

Brain Research

(1987)

L.J. Holmes et al.

Circling from intracranial morphine applied to the ventral tegmental area in rats

Brain Res. Bull.

(1983)

L.J. Holmes et al.

Contralateral circling induced by ventral tegmental morphine: anatomical localization, pharmacological specificity, and phenomenology

Brain Research

(1985)

F. Jenck et al.

Opioid receptor subtypes associated with ventral tegmental facilitation of lateral hypothalamic brain stimulation reward

Brain Research

(1987)

R.P. Johnson et al.

A topographic localization of enkephalin on the dopamine neurons of the rat substantia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunocytochemistry

Brain Research

(1980)

E.M. Joyce et al.

The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat

Neurosci. Lett.

(1979)

E. Miliaressis et al.

The effects of pimozide on the reinforcing efficacy of central grey stimulation in the rat

Behav. Brain Res.

(1986)

E. Miliaressis et al.

Psychophysical method for mapping behavioral substrates using a moveable electrode

Brain Res. Bull.

(1982)

E. Miliaressis et al.

The curve-shift paradigm in self-stimulation

Physiol. Behav.

(1986)

G.J. Mogenson et al.

Self-stimulation of the nucleus accumbens and ventral tegmental area of Tsai attenuated by microinjections of spiroperidol into the nucleus accumbens

Brain Research

(1979)

S. Nakajima et al.

Reduction of the rewarding effect of brain stimulation by a blockade of dopamine D-1 receptor with SCH 23390

Pharmacol. Biochem. Behav.

(1986)

R.D. Oades et al.

Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity

Brain Research Reviews

(1987)

N.L. Ostrowski et al.

The effects of low doses of morphine on the activity of dopamine containing cells and on behavior

Life Sci.

(1982)

A.G. Phillips et al.

Reinforcing effects of morphing microinjection into the ventral tegmental area

Pharmacol. Biochem. Behav.

(1980)

P.P. Rompré et al.

Behavioral determination of refractory periods of the brain stem substrates of self-stimulation

Behav. Brain Res.

(1987)

P.P. Rompré et al.

Pontine and mesencephalic substrates of self-stimulation

Brain Research

(1985)

P.P. Rompré et al.

Behavioral evidence for midbrain dopamine depolarization inactivation

Brain Research

(1989)

Cited by (47)

Illuminating subcortical GABAergic and glutamatergic circuits for reward and aversion
2021, Neuropharmacology
Citation Excerpt :
Optogenetic stimulation of dopaminergic neurons in the VTA and substantia nigra (SN) supports positive ICSS in rats and mice (Bimpisidis et al., 2019; Galaj et al., 2020; Han et al., 2017a, 2017b, 2017b; Ilango et al., 2014; Jing et al., 2019; Keiflin et al., 2018; Kim et al., 2013; McDevitt et al., 2014; Rossi et al., 2013; Saunders et al., 2018; Steinberg et al., 2014; Wang et al., 2017; Witten et al., 2011; Yoo et al., 2016) (but see (Adamantidis et al., 2011)). Also confirming previous theories, reinforcing effects of VTA dopaminergic neuron stimulation are dependent on dopamine receptors in the nucleus accumbens (NAc) (Cheer et al., 2007; Rompré and Wise, 1989; Wise, 1996), as positive ICSS for stimulation of VTA dopaminergic neurons is blocked with systemic dopamine receptor D1 (D1R) (Jing et al., 2019) or intra NAc D1R or dopamine receptor D2 (D2R) antagonists (Steinberg et al., 2014). Use of genetic- and projection-specific optogenetic manipulations has advanced our understanding of the role of specific dopaminergic projections in reinforcement.
Reinforcement, reward, and aversion are fundamental processes for guiding appropriate behaviors. Longstanding theories have pointed to dopaminergic neurons of the ventral tegmental area (VTA) and the limbic systems’ descending pathways as crucial systems for modulating these behaviors. The application of optogenetic techniques in neurotransmitter- and projection-specific circuits has supported and enhanced many preexisting theories but has also revealed many unexpected results. Here, we review the past decade of optogenetic experiments to study the neural circuitry of reinforcement and reward/aversion with a focus on the mesolimbic dopamine system and brain areas along the medial forebrain bundle (MFB). The cumulation of these studies to date has revealed generalizable findings across molecularly defined cell types in areas of the basal forebrain and anterior hypothalamus. Optogenetic stimulation of GABAergic neurons in these brain regions drives reward and can support positive reinforcement and optogenetic stimulation of glutamatergic neurons in these regions drives aversion. We also review studies of the activity dynamics of neurotransmitter defined populations in these areas which have revealed varied response patterns associated with motivated behaviors.
This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.
ΔfosB enhances the rewarding effects of cocaine while reducing the pro-depressive effects of the kappa-opioid receptor agonist U50488
2012, Biological Psychiatry
Citation Excerpt :
First, our method of analysis for measuring θ-zero uses a least-squares line of best fit to estimate the frequency at which stimulation becomes rewarding. Because the regression algorithm discounts extreme values, it is minimally sensitive to treatment-induced alterations in response capabilities; in contrast, alterations in response capabilities alone can cause artifactual shifts in thresholds when using M-50, a measure that is analogous to an ED-50 in pharmacology (36,42,45,46). Second, the increases in maximum response rates above baseline values are evident only at the highest doses of cocaine, twofold higher than those at which ICSS thresholds of ΔFosB-ON animals are significantly lower than in control subjects.
Elevated expression of the transcription factor ΔFosB accompanies repeated exposure to drugs of abuse, particularly in brain areas associated with reward and motivation (e.g., nucleus accumbens). The persistent effects of ΔFosB on target genes might play an important role in the development and expression of behavioral adaptations that characterize addiction. This study examines how ΔFosB influences the responsiveness of the brain reward system to rewarding and aversive drugs.
We used the intracranial self-stimulation paradigm to assess the effects of cocaine in transgenic mice with inducible overexpression of ΔFosB in striatal regions (including nucleus accumbens and dorsal striatum). Mice implanted with lateral hypothalamic stimulating electrodes were trained with the “rate-frequency” procedure for intracranial self-stimulation to determine the frequency at which stimulation becomes rewarding (threshold).
A dose-effect analysis of cocaine effects revealed that mice overexpressing ΔFosB show increased sensitivity to the rewarding (threshold-lowering) effects of the drug, compared with littermate control subjects. Interestingly, mice overexpressing ΔFosB were also less sensitive to the pro-depressive (threshold-elevating) effects of U50488, a kappa-opioid agonist known to induce dysphoria and stress-like effects in rodents.
These data suggest that induction of ΔFosB in striatal regions has two important behavioral consequences—increased sensitivity to drug reward, and reduced sensitivity to aversion—producing a complex phenotype that shows signs of vulnerability to addiction as well as resilience to stress.
Appetite and reward
2010, Frontiers in Neuroendocrinology
Citation Excerpt :
As the most studied and tied to reward-relevant functions are the mesocorticolimbic and nigrostriatal DA pathways that originate in the midbrain VTA and substantia nigra (SN), respectively, and project to various limbic and cortical sites including the NAc, amygdala (AMY), ventral pallidum (VP), dorsal striatum (DS), hippocampus (HIP) and prefrontal cortex (PFC). Early on it was shown that DA receptor antagonists [105] and lesioning of DA neurons via 6-hydroxydopamine (6-OHDA) [204] inhibit BSR whereas drugs that directly or indirectly increase DA tone, including amphetamine [115], cocaine [89], heroine/morphine [88,286] and nicotine [174] enhance the rewarding effects of MFB stimulation. Despite the potent impact on BSR produced by modulation of DA signalling, the traversing of DA fibers along portions of the MFB and the facilitatory action of MFB self-stimulation on DA release [139,256], the results of several studies suggest that the neurons directly activated by MFB stimulation are not dopaminergic [40,116,364].
The tendency to engage in or maintain feeding behaviour is potently influenced by the rewarding properties of food. Affective and goal-directed behavioural responses for food have been assessed in response to various physiological, pharmacological and genetic manipulations to provide much insight into the neural mechanisms regulating motivation for food. In addition, several lines of evidence tie the actions of metabolic signals, neuropeptides and neurotransmitters to the modulation of the reward-relevant circuitry including midbrain dopamine neurons and corticolimbic nuclei that encode emotional and cognitive aspects of feeding. Along these lines, this review pulls together research describing the peripheral and central signalling molecules that modulate the rewarding effects of food and the underlying neural pathways.
Repeated exposure to rewarding brain stimulation downregulates GluR1 expression in the ventral tegmental area
2001, Neuropsychopharmacology
There is considerable evidence that drug reward and brain stimulation reward (BSR) share common neural substrates. Although it is known that exposure to drugs of abuse causes a variety of molecular changes in brain reward systems, little is known about the molecular consequences of BSR. We report that repeated exposure to rewarding stimulation of the medial forebrain bundle (MFB) selectively decreases expression of GluR1 (an AMPA receptor subunit) in the VTA, without effect on expression of several other proteins (GluR2, NMDAR1, tyrosine hydroxylase). This effect of BSR on GluR1 expression is opposite of that caused by intermittent exposure to cocaine and morphine, which are known to elevate GluR1 expression in the VTA. Considering that elevated GluR1 expression in the VTA has been associated with increased sensitivity to drug reward, the finding that BSR and drugs of abuse have opposite effects on GluR1 expression in this region may provide an explanation for why the reward-related effects of many drugs (cocaine, morphine, amphetamine, PCP, nicotine) do not sensitize with repeated testing in BSR procedures that quantify reward strength.
Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currents in the dorsal raphe nucleus of the rat in vitro
1997, Brain Research
Recently, local injection of morphine in the dorsal raphe nucleus (DRN) has been shown to increase serotonin release in the forebrain of unanesthetized rats. This study investigated the site of action of opioids in rat brain slices containing the DRN. Postsynaptic currents (PSCs), measured intracellularly under voltage clamp, were induced in serotonergic neurons with bath and microiontophoretic applications of NMDA to activate local neurons. Met-enkephalin (ENK) suppressed spontaneous and NMDA-induced GABAergic inhibitory PSCs. This effect, which was mimicked by the μ agonist DAMGO but not the κ-agonist U50488 or the δ-agonist DPDPE, was reversed by the μ antagonist CTOP. ENK also suppressed spontaneous and NMDA-induced glutamatergic excitatory PSCs. By searching with focal microiontophoretic NMDA applications, GABAergic and glutamatergic cells projecting on serotonergic neurons were found in the DRN and the adjacent periaqueductal gray. Consistent with the reduction in PSCs, ENK inhibited/hyperpolarized the great majority (81%) of non-serotonergic neurons recorded extra- and intracellularly in the DRN; the ENK effect reversed polarity at −99±9 mV, close to the potassium reversal potential. In contrast, ENK inhibited/hyperpolarized only 28% of serotonergic neurons; in the affected cells, the ENK effect, blocked by CTOP, had its reversal potential shifted with change of extracellular potassium in agreement with the value predicted by the Nernst equation for a potassium conductance; serotonin occluded the ENK inhibition. Taken together, these results indicate that opioids inhibit both local GABAergic and glutamatergic cells projecting onto DRN serotonergic neurons.
Low-dose apomorphine attenuates morphine-induced enhancement of brain stimulation reward
1996, Pharmacology Biochemistry and Behavior
Thresholds for brain stimulation reward (BSR) delivered to the medial forebrain bundle-lateral hypothalamus were determined by means of a rate free psychophysical method. Lower doses of apomorphine (0.5 to 0.2 mg/kg) produced modest elevations in BSR thresholds. A 0.4 mg/kg dose of apomorphine resulted in emergence of Stereotypic behaviors and the loss of stimulus control. Morphine's BSR threshold lowering effects were significantly blocked by the concurrent administration of a 0.1 mg/kg dose of apomorphine. These results support the hypothesis that presynaptic dopamine neurons are involved in the mediation of morphine's reinforcing effects and that dopamine autoreceptor agonists may be of some use in the pharmacotherapy of opiate abuse.

View all citing articles on Scopus

View full text

Research reportOpioid-neuroleptic interaction in brainstem self-stimulation

Abstract

Pharmacol. Biochem. Behav.

Brain Research

Brain Research

Life Sci.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Brain Research

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Research

Brain Research

Brain Res. Bull.

Brain Research

Brain Research

Brain Research

Neurosci. Lett.

Behav. Brain Res.

Brain Res. Bull.

Physiol. Behav.

Brain Research

Pharmacol. Biochem. Behav.

Brain Research Reviews

Life Sci.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Brain Research

Brain Research

Research report
Opioid-neuroleptic interaction in brainstem self-stimulation