Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system

We demonstrated involvement of the ventral tegmental area (VTA) dopaminergic system in orexin-induced hyperlocomotion and stereotypy in rats. In double-label immunohistochemical study of rat brain, we found that tyrosine hydroxylase (TH)-immunoreactive cells in the VTA received innervation from orexin immunoreactive-fibers. Orexin-A induced an increase in [Ca(2+)](i) in isolated A10 dopamine neurons in a dose-dependent manner. In behavioral studies, we found that orexin-A induced hyperlocomotion, stereotypy and grooming behavior when administered centrally in rats, and these effects were abolished by dopamine D(2) (haloperidol and sulpiride) or D(1) (SCH23390) antagonists. These results suggest that the orexin-induced hyperlocomotion, stereotypy and grooming behavior are mediated by the dopaminergic system and this pathway might be involved in orexin-induced emotional responses.     

Neurotensin affects hyperactivity but not stereotypy induced by pre and post synaptic dopaminergic stimulation

The effects of intraventricular administration of neurotensin (0.9, 3.75 and 15.0 micrograms) on hyperactivity and stereotypy induced by either amphetamine (1 mg/kg), nomifensine (20 mg/kg), apomorphine (0.5 mg/kg) or N-n-propylnorapomorphine (0.5 mg/kg) were examined. Results indicate that for each drug treatment, the effects of neurotensin were identical: hyperactivity was significantly reduced while stereotypy remained unaffected. Results also revealed that neurotensin significantly increased the hypothermia induced by apomorphine and N-n-propylnorapomorphine. Possible mechanisms which could underly neurotensin's selective inhibitory action on hyperactivity produced by both pre and post synaptic dopaminergic stimulation are discussed.     

Brain mechanisms of amphetamine-induced anorexia,locomotion, and stereotypy: A review

Evidence on the central mechanisms mediating amphetamine-induced anorexia, locomotion, and stereotypy is reviewed, with the findings suggesting the following conclusions. The central mediation of amphetamine's anorexic effect involves both dopaminergic (nigrostriatal system) and noradrenergic (lateral hypothalamus and ascending noradrenergic pathways) processes, with amygdala-hypothalamic connections and cortical sites serving a possible addition role in such an effect of the drug. The central mediation of amphetamine's locomotor-stimulating effect involves both dopaminergic (nigrostriatal and mesolimbic systems) and noradrenergic (ascending noradrenergic pathways as well as their hypothalamic and cortical projections) processes. While the role of amygdala sites in amphetamine-induced locomotion is unclear, additional central processes exert inhibitory influences on the mediation of such an effect of the drug. The central mediation of amphetamine's stereotypical effect involves a rather exclusive role of the dopaminergic nigrostriatal system, although such mediational principles are influenced by additional inhibitory processes. Finally, evidence on the overlap and dissociation of central processes associated with these behavioral effects of the drug is discussed and the importance of such principles to amphetamine studies briefly indicated.     

Effect of sulpiride,an atypical neuroleptic,on apomorphine-induced growth hormone secretion

NAIR, N. P. V., S. LAL, H. I. ISKANDAR, P. ETIENNE, P. L. WOOD AND H. GUYDA. Effect of sulpiride, anatypical neuroleptic, on apomorphine-induced growth hormone secretion. BRAIN RES. BULL. 8(6) 587–591, 1982.—Sulpiride (100 mg IM), an atypical neuroleptic, which does not block dopamine (DA) receptors that are linked to adenylate cyclase, abolished the growth hormone (GH) response to the DA receptor agonist, apomorphine (Apo) HC1 (0.5 mg SC) in seven healthy male subjects. These results suggest that Apo increases GH secretion in man by an effect on DA receptors that are not linked to adenylate cyclase.     

Towards a comprehensive model of stereotypy: integrating operant and neurobiological interpretations

The predominant models on the emergence and maintenance of stereotypy in individuals with developmental disabilities are based on operant and neurobiological interpretations of the behavior. Although the proponents of the two models maintain largely independent lines of research, operant and neurobiological interpretations of stereotypy are not mutually exclusive. The paper reviews the two models of stereotypy and proposes an integrated model using recent findings on the neurobiology of reinforcement. The dopaminergic system and the basal ganglia are both involved in stereotypy and in reinforcement, which provides a potential link between the models. Implications of the integrated model for future research are discussed in terms of improving the assessment and treatment of stereotypy in individuals with developmental disabilities.     

Pre- and postsynaptic neurochemical alterations following estrogen-induced striatal dopamine hypo- and hypersensitivity

The administration of pharmacologic doses of estrogen results in a biphasic response in striatal dopamine sensitivity, as measured by apomorphine-induced stereotypy. At 24 hr after the last dose of estradiol benzoate (EB) there is a suppression of apomorphine-induced stereotypy, which is followed by an increased sensitivity to apomorphine at 48 hr. The dopamine hyposensitivity is reflected postsynaptically by an increased KD (i.e., decreased affinity) for 3H-spiroperidol binding to striatal membranes, while the hypersensitive phase is reflected by an increased Bmax for 3H-spiroperidol binding to striatal membranes. Presynaptically during the hyposensitive phase the tyrosine hydroxylase displayed a decreased KM for the pterine cofactor. The decreased KM for the cofactor was retained in the hypersensitive animals, however the Vmax for tyrosine hydroxylase was decreased during the hypersensitive phase of the EB-induced changes in dopamine sensitivity. The presynaptic or autoreceptor sensitivity of the dopamine neurons projecting to the striatum was assessed by determining the apomorphine IC50 value for the inhibition of synaptosomal tyrosine hydroxylase activity. Utilizing this assay the animals that were hyposensitive to dopamine showed a normal presynaptic sensitivity, while those animals that had developed a hypersensitivity to dopamine following EB were also hypersensitive to dopamine presynaptically.     

Behavioral sensitization to dopaminergic inhibitory and stimulatory effects induced by low vs. high dose apomorphine treatments: An unconventional dose and response reversal sensitization challenge test reveals sensitization mechanisms

Low dose apomorphine treatments preferentially activate dopamine autoreceptors and inhibit dopamine neurons as well as behavior. In contrast, high doses of apomorphine induce locomotor stimulation by activating dopamine postsynaptic receptors. We compared the effects of low (0.05 mg/kg) vs. high (2.0 mg/kg) repeated apomorphine treatments (5) using paired/unpaired protocols upon the development of Pavlovian conditioned drug responses and upon drug sensitization effects. In addition to the conventional challenge test for sensitization, we also conducted a treatment reversal sensitization test in which low dose groups received the high dose treatment and vice versa. The high dose treatment produced the expected Pavlovian conditioned locomotor stimulant response as well as a sensitization effect in the high dose challenge test; but in the low dose challenge test, the effect was desensitization. The low dose apomorphine regimen induced an inhibitory sensitization effect in the low dose challenge test. In the high dose reversal challenge test, there was a sensitization effect to the locomotor stimulant effect. The low dose apomorphine treatments, however, did not produce a Pavlovian conditioned locomotor inhibitory effect. Surprisingly, the dose reversal challenge test revealed context-independent as well as context-specific sensitization/desensitization effects. These findings demonstrate that Pavlovian drug conditioned effects and drug sensitization effects are independent phenomena and that sensitization effects are not response specific. Moreover, context-specific vs. context-independent sensitization effects were protocol dependent but not drug dose dependent.     

Modulation of hypothalamic mu-opioid receptor density by estrogen: A quantitative autoradiographic study of the female

The labelling of hypothalamic binding sites by [¹²⁵I]-FK, a specific mu-opioid receptor ligand, was studied in female C57BL/6J mice to test whether removal of ovarian steroids affected the density of distribution of receptor binding. Labelling densities in the forebrain of normally cycling (intact) females (N = 12), were compared to those in mice that had been ovariectomized (OVX) for 6 weeks (n = 8) and in mice that had been OVX and implanted with an estradiol (E2) capsule (OVX+E₂) for 6 weeks (n = 11). Frozen sections from the rostral forebrain were incubated with 1 nM [I25I]-FK and processed for light microscopic autoradiography. The diagonal band of Broca (DBB), organum vasculosum lamina terminalis (OVLT), preoptic area (POA), septum, parietal cortex, and striatum were analyzed using computerized image analysis. The distribution of labelling was similar in all three experimental groups in all the regions; however, labelling was significantly reduced in the ventrolateral POA of OVX animals compared to intact females. Labelling densities in the OVX animals replaced with the gonadal steroid estradiol were not significantly different from those in normally cycling mice. This study demonstrates a region-specific loss of mu-opiate receptor labelling following long-term deprivation of gonadal steroids, and supports the hypothesis that estrogen directly or indirectly influences the density of mu-opioid receptors in the rostral forebrain of female mice.     

Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist

Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0 mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03 mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.     

Genotype-dependent effects of chronic stress on apomorphine-induced alterations of striatal and mesolimbic dopamine metabolism

After 10 daily consecutive restraint experiences, DBA/2 (DBA) mice showed an increase of climbing behavior after injection of 0.25 mg/kg of the dopamine (DA) agonist apomorphine (APO), while no changes were observed following vehicle or 1 mg/kg of APO. By contrast, chronically stressed C57BL/6 (C57) mice showed a clear-cut decrease of climbing behavior at the dose of 0.25 mg/kg of APO and a similar, although less pronounced, effect of stress on the behavior of mice injected either with vehicle or with 1 mg/kg APO. The DA agonist at these same doses decreased 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) concentrations in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of both strains. Higher DOPAC, HVA and 3-MT concentrations were evident in stressed DBA mice receiving 0.25 mg/kg but not 1 mg/kg of APO, in both CP and NAS. Concerning C57 mice, lower concentrations of the 3 metabolites were present at both doses of APO in the NAS of stressed mice in comparison with non-stressed animals, while no significant stress-related effects were evident in the CP. Non-significant differences between control and stressed mice of both strains were evident as regards DA concentrations in CP and NAS. These results suggest that repeated stressful experiences lead to a hyposensitivity of DA presynaptic receptors in DBA mice while they produce a sensitization of mesolimbic DA presynaptic receptors possibly accompanied by down-regulation of postsynaptic DA receptors in the C57 strain.     

Functional alterations of the nigrostriatal dopamine system in estrogen receptor-alpha knockout (ERKO) mice

Estrogen represents an important factor for the development and function of the nigrostriatal dopamine system. Estrogen also controls sex-specific differentiation and activity of the nigrostriatal dopaminergic system. We used an estrogen receptor-alpha knockout (-/-) model (ERKO) to study the influence of this particular receptor subtype on the regulation of functional characteristics of the male and female nigrostriatal dopamine system. On the striatal level, we found a sex-specific regulation of dopamine D1 receptors (D1) and dopamine receptor-interacting protein 78 (Drip78). In female (-/-) mice D1 receptor expression levels were increased compared to wild type (wt) animals, whereas in male (-/-) mice Drip78 mRNA levels were decreased compared to wt. In the midbrain, expression of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) was reduced in (-/-) mice of both sexes. Glial cell line-derived neurotrophic factor (GDNF) expression was not affected. These data demonstrate that the integrity of estrogen receptor-alpha (ERalpha) signalling is necessary for the regulation of gene expression of proteins known to be important for the function of the nigrostriatal system at the postsynaptic striatal and presynaptic midbrain level.     

The effect of delta sleep-inducing peptide (DSIP) and phosphorylated DSIP (P-DSIP) on the apomorphine-induced hypothermia in rats

Delta sleep-inducing peptide (DSIP) and P-DSIP, phosphorylated analogue, were found to have enhancing effects on hypothermia induced by i.p. injection of apomorphine (2 mg/kg), a dopamine agonist. Further, the action of P-DSIP appeared and diminished more quickly than that of DSIP. A minimal effective dose of these peptides was 10 ng and the dose-response relationship exhibited an inverted bell-shape with a maximal effective dose of 1 μg. By the pretreatment of anti-DSIP the enhancing effect of DSIP but not P-DSIP, was totally abolished and the action of both peptides was antagonized by haloperidol. These findings suggest that DSIP and P-SIP have a close relation to the dopaminergic system on the thermoregulatory mechanisms.     

Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women--a preliminary study

Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinson’s disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic system by sex hormones, as there is preliminary evidence that estrogen modulates treatment response in these disorders. Furthermore, sex differences in dopamine-mediated cognitive decline suggest estrogen may also play a role in healthy aging. However, the effects of estrogen on the dopaminergic system are poorly understood, and nobody has examined the effect of long-term estrogen therapy (ET) on this system. We compared dopaminergic responsivity (growth hormone (GH) response to apomorphine) in post-menopausal women on ET to women who were ET-naïve. GH response to subcutaneous apomorphine (0.005 mg/kg) was measured in two groups of healthy post-menopausal women aged between 55 and 70 years: those taking ET (n=13) and those who had never taken ET (n=13). Neither group was taking any other medication. GH was measured at 15 min intervals from −30 min before administration of apomorphine to 90 min post-administration. GH response was measured in two ways: area under the curve (AUC) and maximum response over baseline (GH). There were no between-group differences in demographic or baseline variables. The ET treated women had a significantly greater (p=0.03) AUC than ET naïve women (mean±S.D.; 5.3±4.7 vs. 2.6±2.3). However, (GH) did not differ significantly between groups (6.1 mU/l±6.2 vs. 2.7 mU/l±S.D.=4.1). Also, analysis of GH response over time revealed a significant main effect of time (p<0.0005), and a group by time interaction (p=0.004), but no significant main effect of group. Our results suggest that ET may enhance dopaminergic responsivity in post-menopausal women. Estrogen deficiency following menopause may partly explain age and gender differences in late-onset neuropsychiatric disorders.     

Rett syndrome: A preliminary analysis of stereotypy,stress, and negative affect

Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting females. It is characterized by apparently normative development of motor and communicative abilities followed by deterioration in these domains. Stereotypic hand movements are one of the core diagnostic criteria for RTT. There is some anecdotal but limited scientific evidence that changes in hand stereotypy may be a sign of increased anxiety or arousal (i.e., a ‘stress response’) in RTT. Understanding stress responsivity is difficult in RTT because almost all individuals are nonverbal or otherwise severely communicatively impaired. This study used direct behavioral observation to quantify and compare the frequency of hand stereotypy and signs of negative affect during presumed periods of high and low stress associated with functional analysis conditions (negative reinforcement [‘escape’] and control [‘free play’], respectively) for 5 females with RTT (mean age = 17.8; range 4–47). Negative affect was more likely to occur during negative reinforcement (‘stress’) conditions for each participant whereas hand stereotypies did not differ across conditions for any of the participants. Although preliminary, the results suggest that hand stereotypy may not be a valid behavioral ‘stress-response’ indicator in females with RTT. Alternatively, the approach we used may have been limited and not sufficient to evoke a stress response. Either way, more work with direct relevance to improving our understanding of hand stereotypy and anxiety in RTT in relation to social context appears warranted.     

Effects of reducing stereotypy on other behaviors: A systematic review

Researchers have shown that high levels of stereotypy in individuals diagnosed with autism spectrum disorders were correlated with more significant impairments in social and adaptive functioning. Reducing stereotypy may thus potentially occasion an increase in appropriate social and adaptive behaviors. Hence, the purpose of this systematic review was to examine the effects of reducing stereotypy on engagement in other behaviors. Following a thorough literature search, we identified 60 studies that both reduced engagement in stereotypy and measured engagement in at least one other behavior. We divided the studies into six broad categories: noncontingent reinforcement, differential reinforcement, punishment-based interventions, multiple contingencies, physical exercise, and other antecedent-based interventions. The results of our analyses suggest that reducing stereotypy produces reallocation toward other behaviors, albeit not necessarily appropriate. As such, clinicians and researchers targeting stereotypy should plan to strengthen an appropriate alternative behavior while targeting all response forms of stereotypy for reduction. Moreover, our review suggests that measuring untargeted behaviors when implementing interventions designed to reduce stereotypy may be essential in clinical and research settings.     

Effects of septal lesions and chronic estrogen treatment on dopamine,GABA and lordosis behavior in male rats

GORDON, J. H., D. M. NANCE, C. J. WALLIS AND R. A. GORSKI. Effects of septal lesions and chronic estrogentreatment on dopamine, GABA and lordosis behavior in male rats. BRAIN RES. BULL. 4(1) 85–89, 1979.—Septal lesions (SL) in female rats result in an increased sensitivity to the behavioral effects of acute estradiol benzoate (ACUTE-EB; 2 μg/day × 3) treatment as measured by the lordosis quotient (LQ; number of lordotic responses × 100/number of mounts). Male rats, intact or castrated, do not show this enhanced behavioral response to ACUTE-EB unless they are treated with EB (2 μg/day) for 2–4 weeks immediately following the production of SL. The present study was undertaken to examine possible neurochemical alterations which could account for the enhanced behavioral sensitivity to ACUTE-EB seen in the SL male rat treated chronically with EB during the postlesion period (SL-EB). Three groups, normal males, SL-EB and SL males chronically treated with oil (SL-oil), were subdivided and treated with ACUTE-EB or oil and decapitated. The brains were removed, frozen and stored at ?50°C prior to dissection and assay. Tyrosine hydroxylase (TH) activity was assayed in the dopamine (DA) rich areas of the forebrain (striatum, STR; nucleus accumbens septi, ACB; and olfactory tubercle). The TH activity was significantly suppressed in both the STR and ACB of the SL-EB males treated with ACUTE-EB. The glutamic acid decarboxylase (GAD) activity in both the substantia nigra and ventral tegmentum was significantly increased in the SL-EB males given ACUTE-EB relative to that of all other groups. In summary, SL-EB males given ACUTE-EB show (1) an enhanced LQ, (2) decreased TH activity in the region of DA terminals, and (3) increased GAD activity in the region of DA cell bodies. The increase in GAD activity is suggested to be a result of an altered neuronal feedback because of plastic changes that occur during chronic EB treatment following production of SL. This probable increase in inhibitory tone in the region of the DA cell bodies may explain the observation that the SL-EB male exhibits decreased DA turnover following ACUTE-EB treatment. Moreover, since DA may be inhibitory to the display of lordosis behavior, the SL-EB males may show an enhanced LQ, at least partially, because of this reduction in DA activity.     

Effects of multiple interventions for reducing vocal stereotypy: Developing a sequential intervention model

Despite the availability of several interventions designed to reduce engagement in vocal stereotypy, few studies have compared two or more interventions together. Consequently, practitioners have limited amount of data to make informed decisions on whether an intervention may be more suitable than another to begin treating vocal stereotypy. The purpose of the study was to address this limitation by examining the direct and collateral effects of multiple interventions in 12 individuals with autism and other developmental disabilities in order to guide the development of a sequential intervention model. Using single-case experimental designs, we conducted a series of four experiments which showed that (a) noncontingent music generally produced more desirable outcomes than differential reinforcement of alternative behavior, (b) differential reinforcement of other behavior reduced vocal stereotypy in two participants for whom noncontingent music had failed to do so, (c) the addition of simple prompting procedures may enhance the effects of the interventions, and (d) the effects of noncontingent music may persist during sessions with extended durations. Based on these results, we propose a sequential intervention model to facilitate the initial and subsequent selection of an intervention most likely to reduce vocal stereotypy while producing desired collateral outcomes.     

Neuroprotection by estrogen against MPP+-induced dopamine neuron death is mediated by ERalpha in primary cultures of mouse mesencephalon

Estrogen involvement in neuroprotection is now widely accepted, although the specific molecular and cellular mechanisms of estrogen action in neuroprotection remain unclear. This study examines estrogenic effects in a mixed population of cells in attempts to identify the contributing cells that result in estrogen-mediated neuroprotection. Utilizing primary mesencephalic neurons, we found expression of both estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) with a predominance of ERalpha on both dopamine neurons and astrocytes. We also found that 17beta-estradiol protects dopamine neurons from injury induced by the complex I inhibitor, 1-methyl-4-phenyl pyridinium (MPP(+)) in a time- and ER-dependent manner. At least 4 h of estrogen pre-treatment was required to elicit protection, an effect that was blocked by the ER antagonist, ICI 182,780. Moreover, ERalpha mediated the protection afforded by estrogen since only the ERalpha agonist, HPTE, but not the ERbeta agonist, DPN, protected against dopamine cell loss. Since glial cells were shown to express significant levels of ERalpha, we investigated a possible indirect mechanism of estrogen-mediated neuroprotection through glial cell interaction. Removal of glial cells from the cultures by application of the mitotic inhibitor, 5-fluoro-2'-deoxyuridine, significantly reduced the neuroprotective effects of estrogen. These data indicate that neuroprotection provided by estrogen against MPP(+) toxicity is mediated by ERalpha and involves an interplay among at least two cell types.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D1 and D2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D₁ and D₂ dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D₁ and D₂ dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (‘priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D₁ and D₂ receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D₁/D₂ agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D₁ and D₂ dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.     

Prefrontal cortex and neostriatum self-stimulation in the rat: Differential effects produced by apomorphine

In a dose-response experiment, the effects of intraperitoneal injections of the dopamine receptor agonist, apomorphine (0.075, 0.15, 0.3, 0.6 and 1.2 mg/kg) were studied on self-stimulation elicited from electrodes implanted in the medial and sulcal prefrontal cortex and caudate-putamen in the rat. From the medial and sulcal prefrontal cortex electrodes, apomorphine produced a dose-related decrease of self-stimulation rate which was consistent across animals. From the caudate-putamen electrodes, on the contrary, apomorphine produced a facilitatory effect in the majority of the animals at one or more doses, however, at other doses a decreased self-stimulation rate was observed. The clear and consistent effects of apomorphine on self-stimulation of the prefrontal cortex, together with other experimental evidence in the same line, suggest that dopamine is mediating self-stimulation of this cortical area.