Effects of dopamine supersensitivity on lateral hypothalamic self-stimulation in rats

Dopamine (DA) receptor supersensitivity was demonstrated by potentiated d-amphetamine stereotypy after a three-day treatment regimen in which the DA receptor blocker pimozide (4.0 mg/kg) was administered twice daily. Similarly-induced DA supersensitivity produced a significant increase in the rate of lever-pressing for lateral hypothalamic (LH) intracranial self-stimulation (ICSS) and a significant decrease in ICSS thresholds. No change from pretreatment baselines was observed in vehicle-treated control animals. Following three-day treatment with the noradrenaline-(NA) and DA-receptor blocker, haloperidol (4.0 mg/kg twice daily), a single injection of the alpha-adrenergic agonist clonidine (0.15 mg/kg) caused increased running behavior. In contrast clonidine decreased running in rats pretreated with chronic pimozide or vehicle. These results indicate an increase in the sensitivity of central NA receptors following chronic haloperidol but not chronic pimozide. Taken together, these findings were interpreted as a potentiation in the reinforcing properties of LH-ICSS after chronic pimozide treatments due to increases in the sensitivity of DA and not NA receptors.     

Catecholamines and self-stimulation: evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine.

Investigation of the role of noradrenaline (NA) and dopamine (DA) in self-stimulation showed that d-amphetamine (which releases more DA than does l-amphetamine, but not more NA) was much more effective than l-amphetamine in enhancing self-stimulation of NA sites in the locus coeruleus and near-lateral hypothalamus. In DA sites in the substantia nigra and far-lateral hypothalamus the effects of the 2 isomers were confirmed to be more nearly equal. Thymoxamine HCl (10 mg/kg IP), a specific alpha-adrenergic receptor blocker, depressed self-stimulation at all sites, but significantly more severely at DA sites. Thus the drugs most effective in influencing self-stimulation at a particular site were those acting predominantly on the unstimulated system. These findings were interpreted in terms of a hypothesis that DA and NA play complementary roles in self-stimulation and that both are essential; or, more specifically, that DA pathways, implicated in other motivational activites, contribute to a state of drive or arousal necessary for self-stimulation; while response-contingent noradrenergic activity (elicited by the electrodes directly via a transsynaptic route) mediates reinforcement. Further predictions from this hypothesis were tested as follows: (1) Direct pharmacological stimulants of adrenergic alpha-receptors should disrupt self-stimulation by acting randomly on the reinforcement system and disrupting response-reward contingencies; this was confirmed by the finding that the alpha-receptor stimulant clonidine HCl (0.05 mg/kg) depressed self-stimulation at all sites tested. (2) Drect stimulants of DA receptors should enhance self-stimulation of NA sites by augmenting dopaminergic motivational activity; but in rats with DA electrodes, noncontingent stimulation of DA receptors would also impose similar noncontingent activity on the transsynaptic noradrenergic reinforcement pathways and thus depress self-stimulation; this was confirmed by the finding that apomorphine (0.3-1.0 mg/kg) was strongly stimulant for NA electrodes but strongly depressant for DA electrodes, and that the degree and direction of these effects was highly correlated with the differential effects of d- l-amphetamine (rho = .65, p less than 0.01). Neither effect of apomorphine depended on the occurrence of motor stereotypy. These results can be interpreted in terms of 2-component models for self-stimulation, with the predominant transmitter of the drive component being identified as DA and that g the reinforcing component as NA.     

Dopamine mediates ipsi- and contraversive circling elicited from the substantia nigra

It was found that ipsiversive and contraversive circling could be induced by imposed stimulation of the lateral and medial portions of the substantia nigra pars compacta (SNC), respectively. Stimulation of more ventral sites in the substantia nigra (SN) did not elicit circling. Pimozide, a dopamine (DA) antagonist, dose dependently blocked both ipsiversive and contraversive circling induced by imposed stimulation of the SN, but did not alter circling elicited from the non-dopaminergic cerebral peduncle. However, amphetamine, a catecholamine agonist, did not facilitate stimulation-induced circling elicited from the SN possibly because it releases DA on both sides of the brain and thus fails to exaggerate the imbalance of activity produced by stimulation. Taken together these results suggest that DA is involved in SN mechanisms mediating both ipsiversive and contraversive stimulation induced circling and provide further evidence that the lateral SN may be functionally antagonistic to the medial SN.     

Effects of apomorphine on self-stimulation behaviour in dorsal and ventral area of lateral hypothalamus in mice

Intraperitoneal injections of low doses of apomorphine, a dopaminergic receptor agonist, depressed briefly, and then enhanced self-stimulation behaviour in the dorsal area of lateral hypothalamus. In contrast, only depressant effects were observed in the ventral area. These differential effects suggests the presence of a dopaminergic componant in the dorsal hypothalamic self-stimulation system.     

Effects of [Des-Tyr 1]-gamma-endorphin and alpha-endorphin on substantia nigra self-stimulation.

The β-lipotropin fragments, [des-Tyr¹]-γ-endorphin (DTγE, β-LPH_62–77) and α-endorphin (β-LPH_61–76) affect self-stimulating behavior associated with electrical stimulation of neurons of the ventral tegmentum area of rats in an opposite way. Subcutaneous administration of DTγE (5 and 25 μg) attenuated and that of α-endorphin (5 and 25 μg) facilitated this behavior. Similar opposite effects were observed after subcutaneous treatment with respectively the neuroleptic haloperidol (5 μg) and the psychostimulant amphetamine (100 μg). By using a biphasic testparadigm of decreasing and subsequent increasing the stimulating current intensity it was noted that the neuropeptides predominantly exerted their effect on responding at current intensities in the neighbourhood of the threshold for eliciting the behavior, whereas the neuroleptic and psychostimulant drug appeared to affect responding at currents associated with maximal performance as well. In contrast to haloperidol, the effectiveness of DTγE was of a long term nature, in that performance of the rat was still affected 24 hr after peptide treatment. The results support the hypothesis that DTγE in some aspects interacts with brain substrates in a way comparable to that of neuroleptics. The data further suggest that closely related fragments of β-lipotropin modulate on-going activity of in particular dopaminergic neuronal systems.     

A role of the polysynaptic system of substantia nigra in the cholinergic-dopaminergic equilibrium in the central nervous system

Summary Unilateral intranigral injections of apomorphine (APO, 2 g) depressed locomotor activity and increased relax EEG pattern in the rabbit, while carbachol (Carb, 2 g) increased the locomotor activity, elevated the alert index, and produced episodes of epileptoidal discharges, usually beginning in the substantia nigra (SN). They were most intensive in the VL thalamic and weaker in the caudate nucleus. Carb also produced sniffing, head turning and rotations ipsilateral to the injection side. APO given into the same site 15 min before Carb abolished or decreased the intensity of EEG epileptoidal discharges, antagonized sniffing and prevented rotations. Given into SN, APO depressed the homovanillic acid (HVA) level in both striata, the effect being highly significant only in the ipsilateral structure. Carb also depressed weakly the striatal HVA level. The HVA level in rabbits receiving a combined treatment (APO 15 min before Carb) did not differ from that in solvent-injected animals.The results suggest that (i) dopamine-sensitive receptors in SN exert an inhibitory influence on the activity of dopamine nerve endings in the striatum, (ii) cholinergic stimulation of SN produces a complex effect on the striatal dopamine nerve ending activity, as it is most probably mediated through two different cholinoceptive outputs from SN: through the nigrostriatal pathway and the nigrothalamic pathway, (iii) simultaneous stimulation of dopamine and acetylocholine receptors in SN shows that the final effects of these two systems are mutually antagonistic and that, (iv) SN may play an important role in balancing the activity of bilateral striata.Preliminary data were presented to the German Pharmacological Society Meeting at Hannover, September 1976     

A within-subject comparison of the effects of morphine on lateral hypothalamic and central gray self-stimulation

The effects of chronic administration of morphine (20 mg/kg) on self-stimulation (SS) of the central gray and lateral hypothalamus were investigated in a within-subject design. The magnitude and time course of the drug-produced changes in SS at the two placements were similar within subjects but varied substantially across subjects. These results are interpreted in the light of evidence pertaining to the anatomical linkage of the substrates for the rewarding effects of central gray and lateral hypothalamic stimulation. The facilitation of SS may be due to a drug-produced sensitization of reward-related neurons. If so, morphine acts either beyond the point of convergence of the two substrates or at an earier stage in each substrate. The across-subject variability is attributed to individual differences in sensitivity to the effects of the drug. The importance of controlling for this subject variable is stressed.     

Apomorphine and amphetamine stereotypy after 6-hydroxydopamine lesions of the substantia nigra

Bilateral lesions of the substantia nigra with 6-hydroxydopamine abolished amphetamine-induced stereotypy but potentiated the stereotypic effects of apomorphine. The lesions reduced neostriatal dopamine to less than 2% of the control value. These observations are at variance with a recent report by Costall et al. (1972) in which it was found that bilateral electrolytic lesions of the substantia nigra abolished apomorphine-induced stereotypy but did not affect amphetamine stereotypy. The present data point to the questionable value of attempting to interpret the behavioral consequences of lesions to central catecholamine neurons in the absence of either biochemical or histochemical verification. The data support the view that amphetamine acts indirectly by increasing the release of catecholamines while apomorphine directly stimulates central dopamine receptors.     

Amphetamine,chlorpromazine and clonidine effects on self-stimulation in caudate or hypothalamus of the squirrel monkey

In 2 separate groups of squirrel monkeys and within 3 animals low rates of intracranial self-stimulation (ICSS) elicited from caudate or lateral hypothalamic brain sites were increased by as much as 200% above control levels by amphetamine (0.5 mg/kg). Thresholds for responding were decreased by 50%. Increasing the drug dose from 2 to 10mg/kg produced response inhibition at both brain sites. The duration of inhibitory action of amphetamine (2.0 mg/kg) on ICSS from the medial forebrain bundle (MFB) area of the lateral hypothalamus was 6 hr. At caudate sites ICSS did not occur until 48 hr had elapsed. A 10 mg/kg dose of amphetamine produced a duration of action of 36 hr in the MFB and 84 hr in the caudate. Chlorpromazine (CPZ) doses of 0.5 and 1.0 mg/kg decreased caudate ICSS significantly more than lateral hypothalamic ICSS. At 1.0 mg/kg the duration of action of CPZ was 6 hr at lateral hypothalamic brain sites and 24 hr at caudate sites. At a 2.0 mg/kg CPZ dose the duration of action was 12 hr in the MFB and 36 hr in the caudate. A dose of 0.10 mg/kg of clonidine blocked high rates of MFB ICSS while within the same animal caudate ICSS was much less affected. Higher doses (0.25 mg/kg) sedated the animal and ICSS was equally inhibited at both sites. These findings, using ICSS as a behavioral measure, suggest that the effects of amphetamine and CPZ involve not only hypothalamic structures but more anterior telencephalic sites as well. The prolonged actions of amphetamine and CPZ on caudate ICSS suggest that drugs acting, in part, on dopamine containing neurons will interfere with certain caudate mediated behavior. Further, since hypothalamic but not caudate ICSS sites are more dose sensitive to drugs that selectively act on NE containing neurons, other amines in addition to NE may play a role in the support of ICSS.     

Self-stimulation of the subfornical organ and lateral hypothalamus: Differential effects of atropine and methysergide

The effects of cholinergic blockade of neurons by atropine or serotonergic blockade by methysergide was investigated in rats responding for brain-stimulation reward. Bipolar stimulating electrodes were placed either in the subfornical organ (SFO) or the lateral hypothalamus (LH). Atropine sulphate and methysergide significantly suppressed self-stimulation of the SFO but not of the LH, suggesting that cholinergic and serotonergic neurons are involved in brain-stimulation reward associated with this site.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Role of pars compacta of the substantia nigra in circling behavior

The significance of pars compacta of the substantia nigra in the mediation of ci circling behavior was assessed by placing unilateral radio-frequency lesions in that neural region, in adjoining tegmental areas, or in the median raphe and adjacent reticular formation; additional ablations were made by infusing 8 μg/4 μl 6-hydroxydopamine (6-OHDA) into the ventral mesencephalon. Rotational behavior was recorded in a photocell apparatus during 15 min sessions. Precise and virtually complete lesions of pars compacta, as evidenced by histological and histochemical analyses, resulted in spontaneous contralateral circling for a postoperative period of 5 days. More vigorous and sustained contralateral rotations were observed in animals with lesions in the region of the median raphe. Other thermal or 6-OHDA mesencephalic lesions did not produce spontaneous circling. On postoperative days 9–23, the animals were administered in random sequence d-amphetamine (1.5 and 5.0 mg/kg) and apomorphine (1.0 mg/kg). At least 48 hr separated each drug test. Amphetamine (1) facilitated contralateral turning in animals with damage to the median raphe and adjacent regions but induced ipsilateral circling in animals sustaining variable degrees of pars compacta damage as a result of midbrain 6-OHDA injections, (2) produced ipsilateral turning in rats with lesions involving portions of pars compacta in addition to the medial lemniscus (at 1.5 but not 5.0 mg/kg drug), pars reticulata (at 5.0 but not 1.5 mg/kg drug), or the ventromedial tegmentum and, in some cases, subthalamic regions (at 5.0 but not 1.5 mg/kg drug), and (3) had no effect upon circling in animals with discrete pars compacta lesions in a dose of 1.5 mg/kg but produced ipsiversive circling after 5.0 mg/kg. Apomorphine did not elicit turning in animals with relatively precise lesions of pars compacta but did produce turning in experimental groups that sustained simultaneous damage to pars compacta and additional systems including portions of the ventromedial tegmentum, pars reticulata of the substantia nigra, or medial lemniscus. The contralateral turning induced by apomorphine in rats with 6-OHDA or radio-frequency lesions of the ventral mesencephalon suggests that mechanisms mediating this drug-induced behavior, although previously attributed almost exclusively to dysfunctions in nigral function, probably include systems involving extra-nigral regions as well. Coupling this consideration with the finding that lesions in the median raphe and contiguous areas elicited more intense circling than nigral ablations suggests that the role of pars compacta in rotational behavior may be less significant than previously believed.     

Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats

Norepinephrine (NE) and dopamine (DA) receptor blockade differentially affected amphetamine self-administration. DA blockade (pimozide, 0.0625 to 0.5 mg/kg, or (+)-butaclamol, 0.0125 to 0.1 mg/kg) caused periods of increased rate of responding for amphetamine which were followed, in the case of higher doses, by response cessation. The response cessation produced by 0.5 mg/kg pimozide was not reversed by non-contingent amphetamine injections until well after the peak effect of the pimozide was over. When access to amphetamine injections was delayed until 4 h after animals received 0.5 mg/kg pimozide, rate of responding was elevated. Thus DA seems to be critically involved in mediation of the reinforcing effects of amphetamine. Alpha-NE blockade with phentolamine (2.5–10 mg/kg) produced dose-related decreases in responding; blockade with phenoxybenzamine (1.25–10 mg/kg) had no effect. Beta-NE blockade with l-propranolol (2.5–10 mg/kg) decreased responding, although probably not through a beta-blocking action. The effects of phentolamine and propranolol do not appear to result from attenuation of the reinforcing effects of amphetamine.     

Effects of agonists and antagonists of D1 and D2 dopamine receptors on self-stimulation of the medial prefrontal cortex in the rat

The possible participation of D1 versus D2 dopamine receptors in mediating dopaminergic neurotransmission of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was studied neuropharmacologically. Intracerebral as well as intraperitoneal injections of agonists and antagonists of dopamine receptors were used in this study. In all experiments performed with systemic injections, spontaneous motor activity (SM) was measured parallel to self-stimulation behavior as control for non specific effects of the drugs. Intracranial injections were done unilaterally serving SS of the contralateral side (not injected or injected with 0.9% NaCl) as control in the same animals. Spiroperidol and pimozide were used as D1-D2 dopamine antagonists, while sulpiride was used as a specific D2 antagonist. Apomorphine was used as D1-D2 agonist, while bromocriptine and lergotrile were used at doses in which these ergot drugs are considered predominantly D2 agonists. Sulpiride, intraperitoneally or intracerebrally injected at the same locus at which the stimulating electrode was located produced no effect on SS. On the contrary, the D1-D2 antagonists, spiroperidol and pimozide intraperitoneally or intracerebrally injected produced a dose-dependent decrease on SS. On the basis of these data it is suggested, that the dopamine neurotransmission involved in SS of the MPC is mediated via D1 dopamine receptors. This suggestion is further emphasized by the results obtained with the agonists, apomorphine, bromocriptine and lergotrile. Apomorphine produced a dose-related decrease on SS and a decrease at lower doses and an increase at higher doses on SM. Bromocriptine and lergotrile had, on the contrary, no effect on SS and a dose-related decrease on SM.     

Effets de lésions du septum,de l'amygdale,du striatum,de la substantia nigra et de l'ablation des bulbes olfactifs sur le comportement d'agressivité intraspécifique induit par l'apomorphine chez le rat

Lesions of the septal region have been found to enhance apomorphine-induced aggressive behavior, without however facilitating its appearance in non-aggressive rats. This effect has been observed following bulbectomy or destruction of the anterior part of the striatum. Conversely, lesions of the amygdala or substantia nigra have been shown to produce an inhibitory effect on this behavior. It has also been observed that the septal syndrome was the most clear-cut one in those rats which were the most sensitive to the aggresion inducing effect of apomorphine. These results have been compared with those related to other aggressive behaviors, and the site of action of apomorphine has been discussed.

L'auteur remercie vivement le Docteur J. Jacob pour les précieux conseils qu'il lui a apporté au cours de ce travail et de la rédaction de ce manuscrit. Il remercie également le Professeur D. Albe-Fessard pour son aimable acceuil à l'Institut Marey et le Docteur J. Delacour qui l'a si obligeamment initié aux techniques stéréotaxiques.     

Effects of peripheral and central dopamine blockade on lateral hypothalamic self-stimulation: Evidence for both reward and motor deficits

The effects of dopamine receptor antagonists on lateral hypothalamic self-stimulation were analyzed using a reward summation function (RSF) technique. This paradigm relates running speed in a runway to the number of stimulation pulses received as a reward, and it is able to separately characterize changes in reward pulse effectiveness and motor performance. Pimozide, administered peripherally (0.125, 0.25, 0.5 mg/kg, IP), dose-dependently shifted the RSF toward higher values of number of pulses indicating reduced reward. Pimozide also reduced the asymptotic running speed of the RSF, indicating a deficit in motor performance. In a second experiment, α-flupenthixol infused directly into the nucleus accumbens (0.5 μg-0.5 μg, bilaterally) induced changes in the RSF similar to those obtained with peripheral neuroleptic treatment. These findings are discussed from the perspective that dopamine is involved both in the perception of reward value and in the performance of the response to obtain reward.     

Movement induced in cataleptic rats: Differential effects produced by electrical stimulation of the lateral hypothalamus,substantia nigra,and reticular formation

Haloperidol catalepsy can be countered by electrical stimulation of the lateral hypothalamus (LH) and, to a lesser extent, the reticular formation (RF). Substantia nigra (SN) stimulation proved to be least effective in this regard. Dissociation between behavioral arousal and cortical EEG during stimulation of the RF in cataleptic rats was observed.     

Oleoylethanolamide exerts partial and dose-dependent neuroprotection of substantia nigra dopamine neurons

Oleoylethanolamide (OEA), agonist of nuclear PPAR-α receptors and antagonist of vanilloid TRPV1 receptors, has been reported to show cytoprotective properties. In this study, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. First, PPAR-α receptors were confirmed to be located in the nigrostriatal circuit, these receptors being expressed by dopamine neurons of the substantia nigra, and intrinsic neurons and fibers bundles of the dorsal striatum. In the substantia nigra, their location was confined to the ventral tier. The in vitro study showed that 1 μM OEA exerted a significantly neuroprotective effect on cultured nigral dopamine neurons, effects following U-shaped dose-response curves. Regarding the in vivo study, rats were locally injected with OEA into the right striatum and vehicle into the left striatum 30 min before 6-OHDA-induced striatal lesion. In the short term, signals of heme oxygenase-1 (oxidation marker, 24 and 48 h post-lesion) and OX6 (reactive microglia marker, 96 h post-lesion) were found to be significantly less intense in the striatum pretreated with 5 μM OEA. In the long term (1 month), reduction in striatal TH and synaptophysin was less intense whether the right striatum was pretreated with 5 μM OEA, and nigral TH+ neuron death was significantly reduced after pretreatment with 1 and 5 μM OEA. In vivo effects also followed U-shaped dose-response curves. In conclusion, OEA shows U-shaped partial and dose-dependent neuroprotective properties both in vitro and in vivo models of substantia nigra dopamine neuron degeneration. The occurrence of U-shaped dose-response relationships normally suggests toxicity due to high drug concentration or that opposing intracellular pathways are activated by different OEA doses.     

Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats

Rationale We have recently found that blockade of dopamine D1-type receptors in the ventral tegmental area reduces the rewarding effects of intravenous cocaine; here, we explored the possibility that blockade of D1 receptors in the adjacent substantia nigra (SN)—not usually considered part of reward circuitry—might have similar effects.Objective To test the hypothesis that blockade of dopamine D1 receptors in the SN reduces the rewarding effects of cocaine.Methods Twenty one rats were prepared with intravenous catheters and with bilateral guide cannulae implanted such that injections could be made directly into the SN or just dorsal to the SN. The rats were trained to self-administer intravenous cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR1) schedule of reinforcement. After stable responding developed, 13 of the animals were tested following pretreatment with bilateral microinjections of SCH 23390 at doses of 0, 1, 2 or 4 g/0.5 l into the SN and 8 were tested with injections of 0 g or 4 g/0.5 l into a site 2 mm dorsal to the SN site.Results Microinjections of SCH 23390 in the SN significantly increased rates of cocaine self-administration, while injections dorsal to SN had no significant effect on responding.Conclusions These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drugs ability to elevate dopamine levels in the nucleus accumbens.