Stimulation of D2-receptors in rat nucleus accumbens slices inhibits dopamine and acetylcholine release but not cyclic AMP formation

We compared some functional responses of D1- and D2-receptor stimulation in tissue slices of rat neostriatum with those in slices of the nucleus accumbens. In both brain regions D2-receptor stimulation inhibited the electrically evoked release of radiolabeled dopamine and acetylcholine. In both brain regions D1-receptor stimulation and forskolin increased the cyclic AMP formation. Only in the neostriatum, stimulation of D2-receptors inhibited the formation of cyclic AMP, brought about by forskolin or by D1-receptor stimulation. It is concluded from these experiments that, although functional responses of D2-receptor stimulation can be demonstrated in the nucleus accumbens, D2-receptors in this brain region are apparently uncoupled to adenylate cyclase.     

Sexual experience sensitizes mating-related nucleus accumbens dopamine responses of female Syrian hamsters.

We examined the effects of prior sexual experience on extracellular concentrations of dopamine in the nucleus accumbens of female hamsters. Nucleus accumbens dopamine was measured by in vivo microdialysis during mating in female Syrian hamsters that had previously been given six prior sexual encounters with a male, three prior encounters, or were sexually naive. High levels of sexual behavior were observed in all three groups, which were accompanied by increases in dialysate dopamine during periods when the male was present. However, females that received six prior sexual encounters had significantly elevated and prolonged increases in dialysate dopamine compared with those of the sexually naive females or females with only three prior sexual encounters with a male. The data indicate that the mesolimbic system can be sensitized by repeated experiences associated with a motivated behavior.     

Studies on the pharmacology of neurones in the nucleus accumbens of the rat.

A study was made of the effects of iontophoretically applied drugs on single neurones in the nucleus accumgens and caudate nucleus of rats anaesthetized with urethane. Neurones in the caudate nucleus were inhibited by dopamine, dibutyryl cyclic AMP, ADTN and ergometrine. Acetylcholine and homocysteic acid caused excitation of striatal neurones. In the nucleus accumbens neurones were inhibited by dopamine, ADTN, ergometrine, dibutyryl cyclic AMP, glycine and gamma-aminobutyric acid. The responses of glycine and gamma-aminobutyric acid were antagonised by strychnine and picrotoxin, respectively. Acetylcholine and homocysteic acid caused excitation of neurones in the nucleus acumbens; the effects of acetylcholine were blocked by atropine. The results are consistent with the suggestion that dopamine is an inhibitory transmitter in the nucleus accumbens and in the caudate nucleus and support the hypothesis that the effects of dopamine are mediated by cyclic AMP. The locomotor stimulants ADTN and ergometrine mimicked the inhibitory actions of dopamine in both the striatum and in the nucleus accumbens. These results support the suggestion that dopamine receptors in the nucleus accumbens are involved in the actions of locomotor stimulant drugs.     

Comparison of dopamine binding sites in the rat superior cervical ganglion and caudate nucleus

A comparison of morphological and biochemical characteristics of the D1-type dopamine receptor has been assessed in two experimental tissues, the superior cervical ganglion (SCG) and caudate nucleus of the rat. Correlation of the distribution of this dopaminergic binding site using in vitro autoradiographic localization of [3H]SCH 23390, a selective D1-binding antagonist, demonstrated no specific association of this receptor subtype with cyclic AMP immunoreactive structures in the superior cervical ganglion. In contrast, the caudate nucleus demonstrated specific D1-binding sites associated with cyclic AMP immunoreactive elements. Biochemical analyses of the D1-dopamine binding sites showed only 20% of the amount of radioligand bound in SCG homogenates as compared to the quantity bound in homogenates of the caudate nucleus. The non-cyclase linked dopaminergic receptor, assessed using D2-type radioligand binding, was much less prevalent than the binding of the D1-subtype in either experimental tissue. Only a small amount of [3H]sulpiride binding, indicative of the D2-receptor subtype, could be measured in the SCG as compared to the caudate nucleus. This work has demonstrated differences in the amount, and the cellular association of dopamine binding sites in peripheral versus central nervous system areas with dopamine sensitive adenylate cyclase mechanisms.     

Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain: Regional differences

The influence of D-lysergic acid diethylamide (LSD) and mescaline on adenylate cyclase activity was studied in homogenates of Cebus and rhesus monkey anterior limbic cortex (ALC), frontal cortex (FC), caudate nucleus and retina. Previous studies have shown these tissues to contain dopamine-stimulated adenylate cyclase (AC). In addition, we are now reporting the presence of a dopamine-sensitive adenylate cyclase in the auditory cortex. AC of ALC and auditory cortex was stimulated by LSD and mescaline, whereas activity of FC, caudate nucleus and retina was not stimulated by the same agents. In contrast to regional specificity for stimulation, LSD was capable of antagonizing dopamine-stimulated activity in all brain regions examined. LSD and mescaline produced similar maximal stimulation (about 70%) of AC of ALC homogenates, but the EC50 for LSD (0.43 micrometer) was about one-tenth that for mescaline (4.5 micrometer). Similar relative potencies were also observed for the auditory cortex enzyme. Although much weaker than LSD, methamphetamine also produced a dose-dependent stimulation of ALC AC. Both agonist and antagonist effects of the hallucinogens appear to involve interaction with dopamine receptors; LSD- or methamphetamine-stimulated activity in ALC was blocked by haloperidol and fluphenazine, which are dopamine antagonists, but not by phentolamine, an alpha-receptor blocker. Antagonism of dopamine by LSD in both ALC and FC was found to be competitive and mescaline was an effective but weaker antagonist than was LSD. In addition, neither histamine--nor Gpp(NH)p--stimulated activity of FC was inhibited by LSD. It is proposed that the occurrence of dopamine agonistic action of hallucinogens in only certain regions of primate brain may provide a basis for at least some of the behavioral effects of LSD, mescaline and methamphetamine in primates.     

Effects of adenosine on cAMP production during early development in the optic tectum of chicks

Accumulation of cyclic adenosine monophosphate (cAMP) elicited by adenosine was studied in slices and membrane preparations of optic tectum from chicks aged 1–13days post-hatch. Accumulation of cAMP promoted by adenosine declined with age, chicks and the lowest in 11-day-old chicks. However, when the slices were incubated with adenosine and the phosphodiesterase inhibitor-Ro 20-1724 the differences between teh two ages were abolished, suggesting a higher phosphodiesterase activity in 11-day-old chicks. In membrane preparations, although basal adenylate cyclase activity was lower in three-day-old chicks, the guanylyl-imidodiphosphate (Gpp(NH)p) concentration curves for stimulation of adenylate cyclase activity indicated a higher sensitivity of G protein to Gpp(NH)p at this age. This hypothesis was reinforced by the observation that the binding of [³H]Gpp(NH)p to the membrane preparation was greater in three-day-old animals. In spite of these differences, the percentage of adenylate cyclase activity stimulation by 2-chloroadenosine (2CADO) + Gpp(NH)p was the same at both ages. These findings suggest that the decreased response evoked by adenosine during development is probably due to increased phosphodiesterase activity and a lower sensitivity of adenylate cyclase activity to Gpp(NH)p.     

Pertussis toxin lesioning of the nucleus caudate-putamen attenuates adenylate cyclase inhibition and alters neuronal electrophysiological activity

Receptor-mediated inhibition of brain adenylate cyclase activity has been well characterized at the biochemical level. However, less understood is how these, typically modest, inhibitory effects on cyclase activity correlate with the electrophysiological activity of brain preparations. In addressing this question, we injected pertussis toxin (PT) into the nucleus caudate-putamen of intact rats, and observed a subsequent attenuated inhibition of adenylate cyclase activity in caudate membranes, which correlated with altered electrophysiological activity in this nucleus. PT completely abolished and electrophysiological activity in this nucleus. PT completely abolished and significantly reduced, respectively, dopamine D2 and opioid receptor-mediated inhibition of adenylate cyclase. In addition, pretreatment of rat caudate nuclei with PT attenuated the amount of in vitro ADP-ribosylation of 41,000 and 39,000 Da PT substrates measured in caudate membranes. Extracellular recording of the spontaneous activity of caudate neurons revealed that PT pretreatment significantly increased firing rates above those of cells recorded from sham-operated and unoperated controls. Furthermore, a significantly greater number of cells pretreated with PT displayed interspike intervals less than 50 ms, reflecting 'burst-like' activity. In short, the inactivation of G-proteins serving as PT substrates in rat caudate-putamen renders caudate cells more likely to fire spontaneously, and to fire in bursting, rather than uniform, patterns of activity. These observations suggest that PT substrates identical or similar to those which regulate adenylate cyclase, play a significant role in governing the electrophysiological behavior of intact caudate neurons.     

A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function.

Previous studies have shown that chronic morphine increases levels of the G-protein subunits Gia and Goa, adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Gia and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of Gia seen in the NAc, increased levels of Gia and Goa in amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region.     

Stimulated limbic and striatal dopamine release measured by fast cyclic voltammetry: anatomical, electrochemical and pharmacological characterisation

Fast cyclic voltammetry at carbon fibre microelectrodes was used to monitor stimulated release of electroactive species simultaneously in both caudate and nucleus accumbens. The released species was identified as dopamine in both nuclei on the basis of anatomical, electrochemical and pharmacological criteria. Dopamine release in the nucleus accumbens was consistently evoked at more ventromedial stimulation sites than for caudate. In both nuclei, release was reduced or abolished by α-methyl-p-tyrosine and Ro 41284. Pargyline, cocaine and GBR 12909 potentiated release while desipramine had no effect. In conjunction with the electrochemical data, the results indicate that dopamine is the sole species detected in caudate and accumbens following stimulation of the median forebrain bundle.     

Isolated neuronal growth cones from developing rat forebrain possess adenylate cyclase activity which can be augmented by various receptor agonists

Isolated neuronal growth cones from neonatal rat forebrain were found to contain a high specific activity of adenylate cyclase (61 pmol cyclic AMP/min/mg protein) compared to the pelleted starting homogenate (5 pmol cyclic AMP/min/mg protein). Forskolin at 10(-4) M increased adenylate cyclase activity in both the pelleted homogenate and growth cone fraction by 70 and 217 pmol cyclic AMP/min/mg protein, respectively, over basal levels. The incremental effect of forskolin was 3-fold greater in the growth cone fraction than in the pelleted homogenate. However, relative to basal levels in each of the two fractions, forskolin increased adenylate cyclase activity in the growth cone fraction by only approx. 5-fold compared to 15-fold in the pelleted homogenate. Dopamine (10(-4) M), vasoactive intestinal polypeptide (10(-6) M) and isoproterenol (10(-5) M) also augmented adenylate cyclase activity in the two fractions. In the growth cone fraction, dopamine and vasoactive intestinal polypeptide produced a stimulation over basal levels by approx. 20 pmol cyclic AMP/min/mg protein while isoproterenol produced a stimulation of approx. 10 pmol cAMP/min/mg protein. The incremental effects of these receptor agonists in the growth cone fraction are approx. 5-fold greater than in the pelleted homogenate. The dopamine-sensitive adenylate cyclase activity in the growth cone fraction could be blocked by the compound SCH23390, a selective D1 receptor antagonist. At saturating concentrations, all combinations of dopamine, vasoactive intestinal polypeptide and isoproterenol were found to be completely additive on adenylate cyclase activity in the growth cone fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

beta-adrenergic receptor-adenylate cyclase of denervated sarcolemmal membrane.

Five days after motor denervation, mammalian skeletal muscle sarcolemma undergoes a 50% decline in basal and catecholamine-stimulated adenylate cyclase activity. Sodium fluoride- and 5′-guanylyl imidophosphate [Gpp(NH)p)]-stimulated activities also are depressed. However, properties of the β-adrenergic receptor in the plasma membrane preparation of denervated muscle are similar to those of normal innervated muscle. The number and affinity of specific (?)-[³H]dihydroalprenolol binding sites, the effects of catecholaminergic ligands on binding (isoproterenol > epinephrine > norepinephrine), the stimulatory effects of Gpp(NH)p on adenylate cyclase activity, and the shift in concentration of catecholamines required to activate adenylate cyclase in the presence of Gpp(NH)p were similar in normal and denervated membranes. Thus denervation appears to uncouple the adenylate cyclase response from β-adrenergic stimulation primarily by a loss of adenylate cyclase activity with no change in receptor properties.     

Alterations of catecholamine-sensitive adenylate cyclase in gerbil cerebral cortex after bilateral ischemia

Alterations in central concentrations of cyclic nucleotides occur in mammalian brain during ischemic episodes. Our aim was to evaluate the catecholamine sensitivity of adenylate cyclase using homogenates of the gerbil cerebral cortex during periods of bilateral ischemia and recirculation. After 15-min ischemia without recirculation, the sensitivity of adenylate cyclase was usually enhanced to norepinephrine (NE) and dopamine (DA) alone or in the presence of guanosine triphosphate (GTP) but not 5′-guanylyl imidodiphosphate [Gpp(NH)p]. After 60-min ischemia (no recirculation), the sensitivity of the enzyme to NE and DA showed either no change from sham controls or a slight decrease. Responses, however, in the presence of GTP remained elevated. When the animals were subjected to 15-min ischemia followed by 15-min recirculation, enzyme activation by NE and DA with or without GTP and Gpp(NH)p was usually greater than controls. After 60-min ischemia plus 15-min recirculation, however, enzyme responsiveness to catecholamines and NaF was attenuated. No changes in either high and low K_m cyclic AMP phosphodiesterase or in guanylate cyclase were observed during ischemic episodes. The results indicate that the catecholamine-elicited activity of adenylate cyclase became elevated as a consequence of a short duration of ischemia. Longer periods of ischemia thought to be irreversible showed deficits in adenylate-cyclase sensitivity to catecholamines unless GTP was present. In the presence of GTP, enzyme sensitivity was restored as long as recirculation was prevented. Thus adverse consequences of recirculation on neuronal membranes or receptors could be evaluated by their state of GTP sensitivity.     

β-Adrenergic receptor-adenylate cyclase of denervated sarcolemmal membrane

Five days after motor denervation, mammalian skeletal muscle sarcolemma undergoes a 50% decline in basal and catecholamine-stimulated adenylate cyclase activity. Sodium fluoride- and 5′-guanylyl imidophosphate [Gpp(NH)p)]-stimulated activities also are depressed. However, properties of the β-adrenergic receptor in the plasma membrane preparation of denervated muscle are similar to those of normal innervated muscle. The number and affinity of specific (−)-[³H]dihydroalprenolol binding sites, the effects of catecholaminergic ligands on binding (isoproterenol > epinephrine > norepinephrine), the stimulatory effects of Gpp(NH)p on adenylate cyclase activity, and the shift in concentration of catecholamines required to activate adenylate cyclase in the presence of Gpp(NH)p were similar in normal and denervated membranes. Thus denervation appears to uncouple the adenylate cyclase response from β-adrenergic stimulation primarily by a loss of adenylate cyclase activity with no change in receptor properties.     

Brain forskolin binding in mice dependent on and tolerant to ethanol

Chronic ethanol ingestion by mice was previously shown to result in decreased activation of adenylate cyclase by guanine nucleotides and beta-adrenergic agonists, and in the loss of the high affinity beta-adrenergic agonist binding site in frontal cortex and hippocampus but not in cerebellum. These results indicate a regional specificity of ethanol's actions on beta-adrenergic receptors, the guanine nucleotide binding protein (Gs) and/or adenylate cyclase. To further detail the anatomical specificity of the effects of ethanol ingestion on receptor-coupled adenylate cyclase (AC) systems we have quantified the binding of [3H]forskolin to brain sections of control and ethanol-fed mice. High-affinity forskolin binding, thought to represent the complex of the alpha-subunit of Gs (as) and AC, was decreased in several brain areas including frontal cortex and hippocampus, but not in cerebellum, nucleus accumbens and certain other brain areas of ethanol-fed mice. Guanine nucleotides, such as Gpp(NH)p, generally enhanced forskolin binding in control animals. In ethanol-fed mice, however, Gpp(NH)p failed to enhance forskolin binding in most brain regions. These findings suggest that chronic ethanol ingestion may decrease the amount or function of as-AC in certain brain regions. Moreover, the regulation of the formation of this complex in different brain regions may affect responses to ethanol ingestion in mice.     

Serotonin- and dopamine-sensitive adenylate cyclase in molluscan nervous system. Biochemical and electrophysiological analysis of the pharmacological properties and the GTP-dependence

Helix aspersa neuronal cell membranes contain distinct serotonin (5-HT) and dopamine (DA) sensitive adenylate cyclases. We have taken advantage of the fact that in this system, both in vitro (enzymatic assays) and in vivo (electrophysiological measurements) experiments can be used to explore the GTP dependence and the pharmacological properties of this neurotransmitter-sensitive enzyme system. The first property was studied using non-hydrolysable GTP analogs (guanosine 5'-O-(3-thio-triphosphate) or GTP gamma S, and guanosine 5'-imido diphosphate or Gpp(NH)p). In vitro, these two components stimulate the enzyme activity but with different potencies (Kapparent = 10(-8) to 5 X 10(-8) M for GTP gamma S, and 10(-5) M for Gpp(NH)p). Intracellular injections of GTP gamma S, but not of Gpp(NH)p, produced an electrophysiological response similar to the one elicited by 5-HT and DA. These results imply that, even in the presence of the high endogenous GTP concentration normally present in the cell (10(-3) M), GTP gamma S may bind to the GTP-binding protein. Such an interpretation is consistent with the in vitro competition experiments between GTP and GTP gamma S for adenylate cyclase activation. The pharmacology of 5-HT and DA receptors involved in adenylate cyclase stimulation and electrophysiological responses was studied. Serotoninergic antagonists and neuroleptics inhibited the 5-HT-sensitive adenylate cyclase in a stereospecific manner. However, their inhibition was not simply competitive. Our results suggest that they irreversibly bind a component localized on the cytoplasmic side of the membrane. Unexpectedly, the DA receptor coupled with adenylate cyclase was insensitive to any of the several antagonists tested.     

Desensitization of the dopaminergic system in bovine retina following incubation with high potassium.

The effect of potassium depolarization on dopamine D1 receptor activity in bovine retina was investigated. Preincubation of bovine retinas in buffer containing high KCl (56 mM) as compared to a low KCl control buffer resulted in a significant decrease in dopamine-stimulated adenylate cyclase activity with no change in basal or GTP-stimulated adenylate cyclase activity. The apparent Vmax for dopamine was decreased from 102 +/- 15 pmol/min/mg protein in retinas preincubated in high KCl to 71 +/- 11 pmol/min/mg protein in control retinas (n = 5). The apparent Ka for dopamine stimulation of the enzyme did not change. The potassium-induced desensitization could be blocked by preincubation with the dopamine antagonist cis-flupenthixol suggesting that the desensitization was caused by the release of dopamine. The rapid desensitization was not accompanied by a change in D1 receptor density as assessed by binding of [3H]SCH23390 nor in agonist binding as assessed by competition of the selective D1 agonist, SKF38393, for [3H]SCH23390 binding. The potassium-induced desensitization was mimicked by preincubation of retinas in control medium containing isobutylmethylxanthine or dibutyryl cyclic AMP. Incubation of retinas in 56 mM KCl also led to a decrease in activation of adenylate cyclase by vasoactive intestinal polypeptide. These results strongly suggest that potassium depolarization leads to a very rapid heterologous desensitization of adenylate cyclase in bovine retinas.     

Functional Fast Scan Cyclic Voltammetry Assay to Characterize Dopamine D2 and D3 Autoreceptors in the Mouse Striatum

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Interaction of morphine, etorphine and enkephalins with dopamine-stimulated adenylate cyclase of monkey amygdala

Adenylate cyclase activity (AC) of homogenates of monkey amygdaloid nucleus was approximately doubled in the presence of dopamine (10 micrometer). Morphine, etorphine, and several enkephalin analogs (met-enkephalin, D-ala2-met-enkephalin, and D-met2, pro5-enkephalinamide) were capable of inhibiting the stimulation of AC produced by dopamine (90-100% with etorphine or D-ala2-met-enkephalin). Unlike morphine and etorphine, the peptides exhibited bell-shaped dose-response curves for this inhibition with maximal effects at approximately 1 X 10(-7) M, but negligible effects at 1 X 10(-5) M. Under the conditions studied, only etorphine inhibited basal AC. Naloxone antagonized the inhibitory effects of each of the opioids tested, and dextrorphan, an inactive L-(+)-opiate, failed to inhibit the dopamine response. Together these data indicate that the effects were mediated via the classically described stereospecific opiate receptor. The relative order of potency (etorphine greater than enkephalins greater than morphine) was similar to that previously reported for the binding affinities of these drugs in rat brain homogenates. The influence of narcotic agents on dopamine stimulated AC was eliminated by either freezing the amygdaloid tissue or preincubating the homogenate at 4 degrees C; the dopamine responses, however, could still be elicited. The narcotic receptor interaction with the adenylate cyclase thus appears to be distinct from and more labile than that of the dopamine receptor. Gpp(NH)p-stimulated AC was not inhibited by morphine. It is postulated that the inhibition involves interaction of opiate receptors with catalytic units of dopamine-stimulated AC, but not with other cyclase species which may provide the major component of Gpp(NH)p-stimulated activity in amygdala.     

Opioid modulation and sensitization of dopamine release elicited by sexually relevant stimuli: a high speed chronoamperometric study in freely behaving rats

High speed chronoamperometry was used to measure oxidation and reduction currents associated with monoamine release in the caudate putamen and nucleus accumbens of freely moving rats exposed to bedding from cages that housed other male, ovariectomized female, or estradiol-progesterone-primed female rats. Estrus female, but not male or ovariectomized female bedding potently increased the electrochemical signal from electrodes implanted within the nucleus accumbens, and less effectively from more dorsal sites. Naloxone pretreatment attenuated the increase in the electrochemical signal. Repeated exposure to estrus female bedding led to an increased, or sensitized, response within the nucleus accumbens that was also sensitive to naloxone pretreatment. The ratios of the reduction to oxidation currents indicated that dopamine was the principal contributor to the increase in the electrochemical signal, suggesting that activation of the mesolimbic dopamine system accompanies exposure to sexually relevant stimuli. These results suggest that the facilitation of sexual behaviors by dopamine may be due, at least in part, to the processing of incentive motivational cues, and not necessarily to effects on copulation, itself. The results of the present study also suggest that opioid peptides contribute to the activation of mesolimbic dopamine by sexually relevant olfactory stimuli.     

Dopamine receptors and learned helplessness in the rat: an autoradiographic study

(1) Disturbances of mesolimbic and mesocortical dopamine (DA) function have been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder. (2) Utilizing the learned helplessness (LH) animal model of clinical depression and quantitative autoradiography, the authors studied the densities of D1 and dopamine-2-like receptors (D2-like receptors) in medial prefrontal cortex, septum, nucleus accumbens and caudate nucleus in rats that received inescapable stress and were subsequently tested for LH behavior. (3) Dopamine-1 receptor (D1 receptor) densities were significantly higher in the core and shell of the nucleus accumbens and in the medial caudate nucleus of rats that did not become helpless after stress, compared to rats that developed LH. (4) Densities of D2-like receptors were significantly lower in the core of the nucleus accumbens in both the LH and the nonhelpless (NH) rats compared to controls. Densities of D2-like receptors were also lower in the medial and lateral caudate nuclei in LH rats compared to the other groups. (5) Increased D1 receptor densities in NH rats in the nucleus accumbens may be associated with an adaptive or protective role of this brain region in the prevention of escape deficits after exposure to inescapable stress. (6) Decreased D2-like receptor densities in the caudate nucleus in helpless rats may reflect a motor deficit associated with LH behavior, while decreases of D2-like receptor densities in the core of the nucleus accumbens may reflect a generalized effect of exposure to inescapable stress. (7) This study highlights the importance of the mesolimbic/nigrostriatal dopaminergic systems in mediating behavioral responses to inescapable stress.