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

The contribution of dopaminergic neurons to self-stimulation of the ventral tegmental area, nucleus accumbens and prefrontal cortex was investigated. The ventral tegmental area is the site of non-striatal dopaminergic neurons and their axons project to the nucleus accumbens and prefrontal cortex. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens significantly reduced self-stimulation of the ipsilateral ventral tegmental area but did not influence self-stimulation of the contralateral ventral tegmental area. Injections of spiroperidol into the prefrontal cortex did not reduce self-stimulation of the ipsilateral or contralateral ventral tegmental area. Electrical stimulation of sites in the nucleus accumbens positive for self-stimulation antidromically activated neurons of the ventral tegmental area, and a reduction of discharge of these neurons following administration of apomorphine suggested that they were dopaminergic neurons. These observations provide additional evidence implicating dopaminergic neurons in brain-stimulation reward and suggest that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens but not the prefrontal cortex.     

Intracranial self-stimulation effects along the route of the nigro-striatal bundle

Recent evidence suggesting a possible dopaminergic nigro-striatal substrate of self-stimulation led us to map this route for both self-stimulation and stimulus-bound motor effects. The results of 128 electrode placements show that the route of the nigrostriatal projection supports strong self-stimulation effects from the substantia nigra to the ento-peduncular nucleus. Beyond this level, such effects disappear. Our results indicate that the striatum itself is neutral with regard to reinforcement, and suggest that such apparent neutrality cannot be ascribed to motor or other artifacts. These findings require a reappraisal of the hypothesis of a dopaminergic self-stimulation system, although they are not in conflict with the idea that dopaminergic manipulations may affect self-stimulation through some more general regulatory influence on operant responding.     

The DNA content of cerebral cortex neurons. Determinations by cytophotometry and high performance liquid chromatography

The boundaries and relative sensitivities of the substrates of septal and cortical brain stimulation reward were mapped in relation to the dopamine terminal fields in these regions using a dorsal-ventral moveable electrode. Brain stimulation was rewarding at all levels of the posterior lateral septum and not just in the region of dopamine terminal innervation. Reward thresholds, ease of training, maximum response rates and stability of responding were all unrelated to the proximity of the stimulating electrode to the band of dopamine terminals revealed by glyoxylic acid-induced dopamine fluorescence. Stimulation was also rewarding in the anterior lateral septum; the best sites were in the ventral portions of this region although dopamine terminal fluorescence was uniform throughout. Thus the anatomy of the brain stimulation reward substrate of the lateral septal nucleus does not bear a special relation to the anatomy of dopamine terminals within this region. Stimulation was also rewarding in each of the dopamine terminal fields of the cerebral cortex. The best self-stimulation was obtained with electrodes in the medial frontal cortex; sulcal frontal cortex was next best, entorhinal cortex was next, and pyriform cortex, though reliably positive, supported the weakest self-stimulation. Variations in self-stimulation threshold were seen as electrodes were moved through homogeneous regions of dopamine terminal density in some regions, while stable thresholds were associated with movements through areas of varying dopamine terminal density in others; thus, again, there was no special relation between goodness of self-stimulation and density of dopaminergic innervation. These data suggest that rewarding brain stimulation in these regions is not due to direct activation of either the dopaminergic terminals or the cells that they innervate.     

Brain stimulation reward and dopamine terminal fields. II. Septal and cortical projections

The boundaries and relative sensitivities of the substrates of septal and cortical brain stimulation reward were mapped in relation to the dopamine terminal fields in these regions using a dorsal-ventral moveable electrode. Brain stimulation was rewarding at all levels of the posterior lateral septum and not just in the region of dopamine terminal innervation. Reward thresholds, ease of training, maximum response rates and stability of responding were all unrelated to the proximity of the stimulating electrode to the band of dopamine terminals revealed by glyoxylic acid-induced dopamine fluorescence. Stimulation was also rewarding in the interior lateral septum; the best sites were in the ventral portions of this region although dopamine terminal fluorescence was uniform throughout. Thus the anatomy of the brain stimulation reward substrate of the lateral septal nucleus does not bear a special relation to the anatomy of dopamine terminals within this region. Stimulation was also rewarding in each of the dopamine terminal fields of the cerebral cortex. The best self-stimulation was obtained with electrodes in the medial frontal cortex; sulcal frontal cortex was next best, entorhinal cortex was next, and pyriform cortex, though reliably positive, supported the weakest self-stimulation. Variations in self-stimulation threshold were seen as electrodes were moved through homogenous regions of dopamine terminal density in some regions, while stable thresholds were associated with movements through areas of varying dopamine terminal density in others; thus, again, there was no special relation between goodness of self-stimulation and density of dopaminergic innervation. These data suggest that rewarding brain stimulation in these regions is not due to direct activation of either the dopaminergic terminals or the cells that they innervate.     

Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses

Evidence from ex vivo analyses of dopaminergic function following self-stimulation behavior is reviewed and compared to in vivo analyses of extracellular dopamine measured by chronoamperometry during self-stimulation. Both data bases provide strong support for a dopaminergic substrate for brain-stimulation reward obtained by electrical stimulation of the ventral tegmental area (VTA). Data obtained from in vivo measures of dopamine release are particularly compelling as a positive correlation was observed between the rate/intensity function for self-stimulation and increments in the oxidation current for dopamine. An examination of the effects of the dopamine uptake blockers, cocaine and GBR 12909 on self-stimulation and stimulated release of dopamine revealed a facilitation of both measures. In contrast, the noradrenaline uptake blocker desipramine had no effect on either self-stimulation or extracellular dopamine. These pharmacological experiments also are consistent with a dopaminergic substrate of brain-stimulation reward at electrode sites in the VTA.     

Footshock stress facilitates self-stimulation of the medial prefrontal cortex but not the lateral hypothalamus in the rat

The effects of stress on self-stimulation were investigated by exposing rats to either controllable, uncontrollable or no footshock. Both controllable and uncontrollable footshock increased medial prefrontal cortex self-stimulation rates immediately as well as 24 h following treatment. Controllable footshock produced a greater enhancement than uncontrollable footshock. In contrast, self-stimulation of the lateral hypothalamus was unaffected by either footshock treatment. These results are interpreted with reference to the neurochemical response of the mesocortical dopaminergic system to acute stress.     

The acquisition of self-stimulation of the medical prefrontal cortex following exposure to escapable or inescapable footshock

The effect of acute stress on the acquisition of an instrumental action reinforced by electrical stimulation of the medial prefrontal cortex (MPC) was investigated by exposing rats to either escapable, inescapable or no footshock prior to daily self-stimulation training sessions. Treatment with inescapable footshock did not affect the number of sessions required for acquisition of MPC self-stimulation but did increase the rate of responding over acquisition sessions compared with the no-shock group. When the treatment footshock was escapable, however, both a facilitation in acquisition, as indexed by a reduction in the number of sessions to criterion, and an increase in the rate of MPC self-stimulation was found. These data were interpreted as offering evidence for the operation of a dopaminergic mechanism in the acquisition of MPC self-stimulation. Further, they indicate, contrary to the reported effects of footshock on self-stimulation of other brain areas, that exposure to acute stress has a facilitatory effect on the rate of self stimulation of the MPC.     

Brain-stimulation reward associated with stimulation of the supracallosal bundle

Self-stimulation was observed with electrodes in the supracallosal bundle. Histological verification of the locus of the stimulating electrodes, the antidromic activation of locus ceruleus neurons, the attenuation of self-stimulation of the supracallosal bundle by administering colchicine to the locus ceruleus, and the differential effects of d- and l-amphetamine suggest that during self-stimulation of the bundle there is activation of noradrenergic fibers projecting from the locus ceruleus. The electrodes in the supracallosal bundle are also in close proximity to the cingulate gyrus, a region of dopamine innervation, but electrodes there yielded a low percentage of sites positive for self-stimulation. The results suggest that self-stimulation of the supracallosal bundle is associated with the activation of noradrenergic neurons but involvement of dopaminergic neurons cannot be ruled out.     

Re-evaluation of the role of dopamine in intracranial self-stimulation using in vivo microdialysis.

Rats were implanted with an electrode-microdialysis assembly in order to test the hypothesis that the reward signal elicited by medial forebrain bundle stimulation is relayed by the meso-accumbens dopamine cells. We first obtained the strength-duration function of self-stimulation, that is, a family of behaviorally equivalent stimuli (pulse intensity and pulse duration pairs yielding a constant self-stimulation rate). We then collected the self-stimulation-bound intra-accumbens dopamine for several pairs of intensity and duration, selected from within the strength-duration function. Our reasoning was that if the reward signal travels along the meso-accumbens dopaminergic neurons, the release of dopamine should not depend on the stimulus parameters because behaviorally equivalent stimuli should produce a constant output in all neural stages carrying the reward signal. The results showed that short duration/high intensity pulses induced considerably larger increases in dopamine levels than long duration/low intensity pulses, despite the fact that these stimuli maintained a constant self-stimulation rate. Among the interpretations envisaged, the most parsimonious one seems to be that the MFB rewarding signal is not relayed exclusively by meso-accumbens dopaminergic cells and that the latter may play a permissive-facilitator role at some transmission stage of the reward signal.     

Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation

The ability of chronic treatment with the atypical neuroleptic clozapine to induce functional dopaminergic hypersensitivity in laboratory rats was assessed. The intracranial electrical self-stimulation paradigm, known to be sensitive to changes in functional dopaminergic sensitivity, was used. Animals with electrodes in the ventral tegmental nucleus (mesolimbic dopamine cell body area) showed a marked increase in self-stimulation rate following 3 weeks of chronic clozapine. This increase was similar in magnitude and duration to that shown by animals given 3 weeks of chronic haloperidol. In contrast, animals with electrodes in the substantia nigra (nigrostriatal dopamine cell body area) showed no change in self-stimulation rate following 3 weeks of chronic clozapine. These data are interpreted in the light of previous suggestions that clozapine and other atypical neuroleptics may possess functional selectivity for the mesolimbic dopamine system.     

Self-stimulation in the mesencephalic trajectory of the ventral noradrenergic bundle

The ventral noradrenergic bundle (VB) was mapped for self-stimulation throughout the region of its separation from the dorsal noradrenergic bundle in the mesencephalon of the rat. Eleven positive electrodes were located in the VB at sites clearly caudal to all known dopamine cell groups. Since the activation of dopamine neurons or other noradrenergic systems by current spread could be ruled out, the self-stimulation behavior was attributed to the activation of noradrenergic fibers in the VB itself. The cells of origin of these fibers were not determined, but it is probable from other evidence that noradrenergic cells from groups A6 and A7 were mainly involved. Twenty-nine electrodes in rostral VB sites yielded significantly higher maximum self-stimulation rates than the 11 caudal VB electrodes. The higher rates observed at rostral VB sites were attributed to: (a) the simultaneous activation of dorsal bundle and periventricular noradrenergic reward components that join the VB via the tegmental radiations, (b) the simultaneous activation of dopaminergic systems in the region of the substantia nigra, and (c) reduction of caudal VB rates by the simultaneous activation of directly-demonstrated escape systems.     

Brain reward in the absence of alpha-synuclein

Alpha-synuclein has been implicated in the pathophysiology of Parkinson's disease. Recent studies revealed its role as a negative regulator of dopamine release in the nigrostriatal dopaminergic system. Alpha-synuclein may, however, play a more universal role in dopaminergic neurotransmission. It may represent an endogenous modulator in the mesolimbic dopaminergic system, and be involved in brain reward. We show here that the absence of alpha-synuclein resulting from spontaneous mutation in a subline of C57BL/6J mice greatly increased the rate of operant behavior during intracranial self-stimulation. The present work demonstrates that a lack of alpha-synuclein sensitized the brain reward system, implying that the levels of alpha-synuclein expression may predispose an individual to drug abuse or to a number of psychiatric diseases.     

Increase in mesolimbic electrical self-stimulation after chronic haloperidol: reversal by L-DOPA or lithium

After chronic neuroleptic drug treatment, an increase in electrical intracranial self-stimulation (ICSS) rate is seen from electrodes in the A10 dopaminergic nucleus. This increase, which persists for approximately 3 weeks following drug withdrawal, is believed to represent a behavioral manifestation of drug-induced dopaminergic synaptic supersensitivity. Chronic L-DOPA caused a partial reversal of haloperidol-induced ICSS increase. Lithium carbonate, given concurrently with the haloperidol, partially prevented the development of ICSS supersensitivity. It is concluded that dopaminergic synaptic sensitivity has a two-way modulatory capability.     

Antagonism of footshock stress-induced inhibition of intracranial self-stimulation by naloxone or methamphetamine

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes implanted in the ventral tegmental area (VTA). The effect of inescapable footshock on response rates to ICSS was examined in the present study. Markedly decreased response rates to ICSS were observed 15 min to 24 h following inescapable footshock. Naloxone (10.0 mg/kg) itself was without effect on response rates to ICSS, but completely antagonized the decreased response rates by the stressor treatment. A relatively low dose of methamphetamine (0.5 mg/kg), which showed no effect on ICSS rates in naive rats, also antagonized the decreased response rates to ICSS. The present results suggest that inescapable footshock may release endorphin in the mesolimbic or mesocortical area; the released endorphin may act on dopaminergic nerve endings and interrupt dopaminergic transmission. The decreased activity of dopaminergic neurons may cause the decreased response rates to ICSS.     

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward

Summary Two specific 5-HT_1A agonists, 8-OH-DPAT (0–300 g/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 g/kg produced a sustained enhancement of responding while higher doses (100–300 g/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT_1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.     

Motivated behavior and the estrous cycle in rats

(1) The estrous cycle in the rat may be used to study recurrent changes in motor behaviors and motivation which are strongly related to cyclic hormonal and CNS changes. (2) The peak in motivated behaviors occurs during a sharply defined period on the night between proestrus and estrus and is evident in facilitated wheel-running, lordosis, and intracranial self-stimulation. (3) Behaviors without a clearly motivated character do not show an estrous cyclicity. (4) The estrous cyclic variation in intracranial self-stimulation was observed at a specific locus — the pars campacta of the substantia nigra. (5) A neurochemical link between sexually motivated behavior, wheel running and intracranial self-stimulation is suggested. This link is in part dopaminergic but is probably also activated by many other systems.     

Hippocampus modulates self-stimulation reward from the ventral tegmental area in the rat

Rats with electrodes in the ventral tegmental area were tested for the threshold of intracranial reward using a rate insensitive self-stimulation procedure. It was found that an electrolytic lesion of a part of the dorsal hippocampus induced a marked decrease in the variation of thresholds across rats, while the mean reward level did not change. This indicates that a factor is removed, by the hippocampal lesion, which causes differences in reward between individual rats. It is suggested that the mesolimbic dopaminergic system is involved in this modulatory influence of the hippocampus on reward.     

Differential effect of self-stimulation on dopamine release and metabolism in the rat medial frontal cortex, nucleus accumbens and striatum studied by in vivo microdialysis.

Changes in the extracellular levels of dopamine (DA) and its metabolites in the dopaminergic terminal regions, the medial frontal cortex (MFC), nucleus accumbens (NAC), and striatum (STR), were measured by microdialysis during self-stimulation of the medial forebrain bundle (MFB) in rats pretreated with the DA uptake inhibitor, nomifensine (1 mg/kg, i.p.). Self-stimulation of the MFB in nomifensine-pretreated rats caused an increase in the extracellular DA level in the MFC and NAC but not in the STR. Self-stimulation also increased the extracellular concentrations of the main DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a similar extent in the MFC and NAC and to a lesser extent in the STR. Thus, there was a regional difference in the neurochemical changes following self-stimulation with either the MFC or the NAC showing larger extracellular levels of DA, DOPAC, and HVA than the STR. Furthermore, these changes were observed on both hemispheres ipsilateral and contralateral to the stimulation. The results indicate that self-stimulation of the MFB preferentially activates the mesocorticolimbic DA systems, thereby bilateral increases in the release of DA and its metabolism being produced in their terminal regions, the MFC and NAC.     

The effects of ventral tegmental administration of GABA(A), GABA(B), NMDA and AMPA receptor agonists on ventral pallidum self-stimulation

The ventral pallidum (VP) is a basal forebrain structure that is interconnected with motor and limbic structures and may be considered as an interface between motivational and effector neural signals. Results from a considerable number of studies suggest that this structure is critically involved in reward-related behavior. The VP shares reciprocal connections with other reward-implicated regions, such as the ventral tegmental area (VTA). This anatomy predicts that drug-induced neuronal alterations in the VTA could profoundly alter the function of the VP. Here, using the curve-shift intracranial self-stimulation method, we studied the effects of muscimol (GABA(A) agonist), baclofen (GABA(B) agonist), NMDA and AMPA, microinjected bilaterally into the VTA on the rewarding efficacy of VP self-stimulation. Central injections of the highest dose of muscimol (0.128 microg) resulted in significant elevations in VP self-stimulation thresholds, indicating a reduction in the rewarding efficacy of the stimulation. Elevations in VP self-stimulation thresholds were also evident after intrategmental injections of higher doses of baclofen (0.12, 0.48 microg). By contrast, intrategmental activation of NMDA and AMPA receptors did not affect reward thresholds. These findings suggest that GABAergic and glutamatergic transmission in the VTA activate different circuits that may mediate different functions. Thus, the VTA--VP projection activated by GABA modulates VP stimulation reward, while the projection activated by glutamate may be involved in reward-unrelated effects, rather than in the processing of reward. The decreased rewarding efficacy of VP self-stimulation following intrategmental injections of muscimol and baclofen may be due to GABAergic modulation of ventral tegmental dopaminergic and nondopaminergic neurons projecting to the VP.     

Similar potencies of CCK-8 and its analogue BOC(Nle28;Nle31)CCK27-33 on the self-stimulation behaviour both are antagonized by a newly synthesized cyclic CCK analogue

Neurons with co-localized cholecystokinin (CCK) and dopamine (DA) are present predominantly in the ventral tegmental area (VTA) and project mainly to the caudal part of the medial nucleus accumbens. The activity of this dopaminergic system can be evaluated by means of the intracranial self-stimulation behaviour (ICSS) on male Wistar rats having chronic electrodes implanted into the medial forebrain bundle in the postero-lateral area of the hypothalamus. The direct injection of the CCK analogue BOC(Nle28;Nle31)CCK27-33 (BDNL-CCK7) into a lateral ventricle decreased the electrical self-stimulation of the medial forebrain bundle. Nevertheless, this decrease in self-stimulation was steeper (immediately after the injection vs a delay of +/- 5-10 min.) than the CCK8-induced ICSS depletion. The intracerebroventricular (ICV) injection of 150 pmol and 1000 pmol BC-197 (BOC-D.Asp-Tyr(SO3H)-Nle-D.Lys-Trp-Nle-Asp-Phe-NH2) was ineffective to modify the self-stimulation behaviour when administered alone while a 150 pmol BC-197 dosage was able to antagonize the decreasing effect of 150 pmol CCK-8 on ICSS. Nevertheless, a dosage 6 times as important, i.e. 1000 pmol BC-197, was needed to antagonize the depression induced by 150 pmol BDNL-CCK7 on ICSS behaviour. These results support the equipotence of BDNL-CCK7 to CCK-8 in decreasing the self-stimulation behaviour after their direct administration into the lateral ventricle. They further give evidence of the relevance of BC-197 in antagonizing the respective effects of both compounds on the ICSS.