Effects of adenosine A<Subscript>2A</Subscript> receptor stimulation on cocaine-seeking behavior in rats

Rationale  

Dopamine (DA) receptor stimulation in the nucleus accumbens (NAc) plays an important role in regulating cocaine-seeking behavior. Adenosine receptors antagonize the effects of DA receptor stimulation on intracellular signaling, neuronal output, and behavior.     

HQSAR and molecular docking studies of furanyl derivatives as adenosine A<Subscript>2A</Subscript> receptor antagonists

Structure- and ligand-based computational design strategies were used to understand the molecular requirements of furanyl derivatives 2-(furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines (TfPAs), 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (TaPAs), and 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amines (TTAs) as adenosine A_2A receptor (A_2AR) antagonists. First, we studied the structure–activity relationship of the selected compounds using hologram quantitative structure–activity relationship (HQSAR) methodology. The best model (training set included 67 compounds) included fragment parameters such as atoms (A), bonds (B), connections (C), and donors/acceptors groups (DA) and had a good q ² value of 0.776 including size fragments of 7–10 and the hologram length of 199. It also predicted adequately the compounds contained in the test set (10 compounds). In addition, we studied the binding orientations of the higher and less active compounds using flexible molecular docking. We found orientations that are in agreement with previous reports.     

Cytotoxic purine nucleoside analogues bind to A<Subscript>1</Subscript>, A<Subscript>2A</Subscript>, and A<Subscript>3</Subscript> adenosine receptors

Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A₁, A_2A, or A₃ receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A_2B receptors. Clofarabine and cladribine both bound to the A_2A receptor with a K _i of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A₃ receptor with a K _i of 10 μM, and none of these compounds bound to the A_2B receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A₁ receptor. In addition, clofarabine, cladribine, and fludarabine were A₁ agonists (IC₅₀ 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K _i > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.     

Intra-accumbens injections of the adenosine A<Subscript>2A</Subscript> agonist CGS 21680 affect effort-related choice behavior in rats

RATIONALE: Nucleus accumbens dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired accumbens DA transmission reallocate their behavior away from food-reinforced activities that have high response requirements and instead select less-effortful types of food-seeking behavior. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related processes, emerging evidence also implicates adenosine A(2A) receptors. OBJECTIVE: The present work was undertaken to test the hypothesis that accumbens A(2A) receptor stimulation would produce effects similar to those produced by DA depletion or antagonism. MATERIALS AND METHODS: Three experiments assessed the effects of the adenosine A(2A) agonist CGS 21680 on performance of a concurrent choice task (lever pressing for preferred food vs. intake of less preferred chow) that is known to be sensitive to DA antagonists and accumbens DA depletions. RESULTS: Systemic injections of CGS 21680 reduced lever pressing but did not increase feeding. In contrast, bilateral infusions of the adenosine A(2A) receptor agonist CGS 21680 (6.0-24.0 ng) into the nucleus accumbens decreased lever pressing for the preferred food but substantially increased consumption of the less preferred chow. Injections of CGS 21680 into a control site dorsal to the accumbens were ineffective. CONCLUSIONS: Taken together, these results are consistent with the hypothesis that local stimulation of adenosine A(2A) receptors in nucleus accumbens produces behavioral effects similar to those induced by accumbens DA depletions. Accumbens adenosine A(2A) receptors appear to be a component of the brain circuitry regulating effort-related choice behavior.     

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A<Subscript>2A</Subscript> and A<Subscript>1</Subscript> antagonists

Rationale  

Adenosine A_2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone.     

Adenosine A<Subscript>2A</Subscript> receptor deficient mice are partially resistant to limbic seizures

The neuromodulator adenosine, acting through activation of four defined metabotropic receptors called A₁, A_2A, A_2B and A_3, has been proposed as an endogenous anticonvulsant. Here, the consequences of deleting the adenosine A_2A receptor have been examined in different experimental models of epilepsy. A_2AR KO mice were not protected against seizures originating from brainstem structures, namely electroshock-induced seizures. The intensities of seizures induced by pentylenetetrazol or pilocarpine, as well as the percentages of convulsing mice, were significantly reduced in A_2A receptor knockout (A_2AR KO) animals. A_2AR KO mice exhibited reduced pentylenetetrazol-induced kindled seizures, demonstrating an important role of the A_2A receptor in the acquisition of kindling. These data suggest that adenosine stimulating A_2A receptors modulates excitatory neurotransmission and exacerbates limbic seizures. It is therefore suggested that adenosine A_2A receptor antagonists might offer protection from some epileptic syndromes.     

NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D<Subscript>2/3</Subscript> dopamine receptor stimulation in rats

Rationale Recent experiments from this laboratory demonstrated synergistic effects of AMPA/kainate receptor blockade and D_2/3 dopamine (DA) receptor stimulation on brain stimulation reward and locomotor activity.Objectives Using place conditioning, this study explored further the interaction between DA and glutamate (Glu) using the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801, the AMPA/kainate receptor antagonist NBQX, and the D_2/3 DA receptor agonist 7-OH-DPAT.Methods Effects of these compounds, alone and combined, were measured in male Sprague–Dawley rats using an unbiased two-compartment place conditioning procedure.Results 7-OH-DPAT (0.03–5.0 mg kg^–1, s.c.) administered immediately prior to conditioning was ineffective; when administered 15 min prior to conditioning, only the highest dose (5.0 mg kg^–1, s.c.) induced conditioned place preference (CPP). Acquisition of 7-OH-DPAT-induced CPP was blocked by MK-801 (0.06 or 0.13 mg kg^–1, i.p.) or NBQX (0.5 g) microinjected into the nucleus accumbens (NAS) shell subregion. Intra-NAS shell administration of 7-OH-DPAT (5.0 g) or NBQX (0.5 g), alone or combined, failed to induce place conditioning, and this lack of effect was not due to state dependency. Administration of MK-801 or 7-OH-DPAT (5.0 mg kg^–1) during the conditioning phase acutely increased horizontal activity, but neither compound, alone or combined, induced conditioned locomotor effects.Conclusions Acquisition of place conditioning induced by systemic administration of 7-OH-DPAT is blocked by systemic NMDA receptor antagonism by MK-801 or by the AMPA/kainate receptor antagonist NBQX microinjected into the NAS shell subregion.Anna-Maria Biondo and Robert L.H. Clements contributed equally to this work.     

Enhanced adenosine A<Subscript>2B</Subscript> mediated coronary response in reserpinised rat heart

In this study, we investigated the effect of noradrenaline depletion on contractile recovery in rat isolated heart following myocardial ischaemia. Groups tested included control tissues and hearts from reserpinised rats. Reserpine 1 mg/kg s.c. was injected into rats 18 to 24 h prior to experiments. Hearts underwent 15 min global normothermic ischaemia followed by 30 min reperfusion.Functional data (end diastolic pressure (EDP), heart rate (HR), left ventricular developed pressure (LVDP), dP/dt(max), dP/dt(min)) showed that contractile function following ischaemia-reperfusion is unaffected by reserpinisation. However, pre- and post-ischaemic coronary flow rates (CFR) were increased by 16 to 38% in hearts from reserpinised rats versus control hearts. Pre-ischaemic CFRs in control hearts (11.17+/-0.67 ml/in(-1) x g tissue(-1), n=9) were significantly lower then CFRs derived from reserpinised rat hearts (14.57+/-0.72 ml/min(-1)/g tissue(-1), n=10). Post-ischaemic reactive hyperaemia was evident in all groups. CFRs in reserpinised hearts remained elevated when compared to pre-ischaemic values through reperfusion (P<0.05). Reserpine treatment did not significantly alter pre- or post-ischaemic adenosine efflux. The A(2B) adenosine receptor antagonist alloxazine (10 microM) attenuated pre- and post-ischaemic CFRs in both control and reserpinised hearts (P<0.05) without altering the hyperaemic response while the A(2A) adenosine receptor antagonist 8-(3-chlorostyryl) caffeine (1 microM) did not alter CFRs in both groups. The A(3) adenosine receptor antagonist MRS1191 (0.1 microM) increased CFR in control and reserpinised hearts (P<0.05).Catecholamine depletion with reserpinisation enhances the responsiveness of the coronary resistance vessels to endogenous adenosine through activation of the A(2B) adenosine receptor.     

A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A<Subscript>1</Subscript> and A<Subscript>2A</Subscript> receptors

Rationale There is no consensus on the contribution of adenosine A₁ and A_2A receptor blockade to motor-activating effects of caffeine.Objective Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A₁ and A_2A receptor antagonists.Methods The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A₁ receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A_2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A₁ receptor agonist N ⁶-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A_2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined.Results The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3.Conclusions The results indicate a predominant role for A₁ receptors in the motor-activating effects of acutely administered caffeine.     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

5-HT<Subscript>1A</Subscript> agonists: alcohol drinking in rats and squirrel monkeys

Rationale. Increased alcohol intake after administration of low doses of 5-HT_1A agonists is thought to be due to a reduction in 5-HT impulse flow due to activation of 5-HT_1A somatodendritic receptors, whereas decreased alcohol drinking found after administration of higher doses of 5-HT_1A agonists may be mediated by action at postsynaptic 5-HT_1A receptors. Objective. This study compares Long-Evans rats and squirrel monkeys to examine the hypothesis that low doses of the 5-HT_1A selective agonists, 8-OH-DPAT and alnespirone, will preferentially increase, and at higher doses decrease alcohol drinking, and whether these effects can be antagonized by WAY 100635. Methods. Male Long-Evans rats were induced to drink from two bottles, one containing a solution of 10% ethanol and 1% sucrose (w/v), the other containing an equally preferred concentration of sucrose. Squirrel monkeys also drank from two bottles, one containing a solution of 2% ethanol and 15% sucrose (w/v), the other, water. Results. In rats, low doses of both 8-OH-DPAT (0.018–0.03 mg/kg) and alnespirone (0.3–3.0 mg/kg) increased alcohol drinking by ca. 100% without altering sucrose intake. The highest dose of 8-OH-DPAT (0.1 mg/kg) suppressed intake of both solutions without significant motor impairment. Pretreatment with WAY 100635 (0.1 mg/kg), shifted the entire dose-effect curve of 8-OH-DPAT to the right, and antagonized the effects of the 0.56 mg/kg dose of alnespirone. In the monkeys, administration of both agonists dose-dependently decreased alcohol intake and were behaviorally sedative. Conclusions. These results support the hypothesis that in rats, 5-HT_1A receptor stimulation activates somatodendritic receptors at lower doses and postsynaptic receptors at higher doses, each with opposite effects on alcohol intake. The absence of such biphasic dose-effect curves in monkeys suggests a different function of 5-HT_1A somatodendritic receptors in rats and monkeys, at least with regard to alcohol drinking. Electronic Publication     

The adenosine A<Subscript>2A</Subscript> antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists

Rationale  Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A_2A receptors. Objective  Adenosine A_2A receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. Materials and methods  The adenosine A_2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure. Results  MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses. Conclusions  The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A_2A receptors on the same population of striatal neurons.     

Caffeine and a selective adenosine A<Subscript>2A</Subscript> receptor antagonist induce reward and sensitization behavior associated with increased phospho-Thr75-DARPP-32 in mice

Rationale  Caffeine, an antagonist of adenosine A₁ and A_2A receptor, is the most widely used psychoactive substance in the world. Evidence indicates that caffeine interacts with the neuronal systems involved in drug reinforcing. Although adenosine A₁ and/or A_2A receptor have been found to play important roles in the locomotor stimulation and probably reinforcing effect of caffeine, the relative contribution of the A₁ and/or A_2A receptors to the acute and chronic motor activation and reinforcing effects of caffeine has not been completely investigated. Objective  The roles of adenosine A₁ and/or A_2A receptor and the association of phospho-Thr75-dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) in the motor activation and reinforcing effects of caffeine, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A₁ antagonist, and 5-amino-7-(β-phenylethyl)-2-(8-furyl) pyrazolol [4,3-e]-1,2,4-triazolol [1,5-c] pyrimidine (SCH58261), a selective A_2A receptor antagonist were examined. Methods  Locomotor stimulation and behavioral sensitization of caffeine, DPCPX, and SCH58261 were studied in C57BL/6 male mice following acute and chronic administration. Conditioned place preference (CPP) paradigm was used to evaluate the drug-seeking potential of these compounds. Furthermore, the expression of phospho-Thr75-DARPP-32 in striatal membrane from behaviorally sensitized mice was analyzed by Western blot. Results  Caffeine and SCH58261 but not DPCPX induced CPP and locomotor sensitization in C57BL/6 mice. The locomotor sensitization after chronic treatment was associated with increased DARPP-32 phosphorylation at Thr75 in the striatum. Conclusion  Caffeine-induced reinforcing effect and behavioral sensitization are mediated by antagonism at adenosine A_2A receptor. These effects are associated with phosphorylation of DARPP-32 at Thr75 in the striatum.     

Effect of the adenosine A<Subscript>2A</Subscript> receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat

Rationale  

Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A_2A receptors in striatal areas, including the nucleus accumbens.     

The tachykinin NH2-senktide inhibits alcohol intake in alcohol-preferring rats.

The present study evaluated the effect of the intracerebroventricular injection of the tachykinins, substance P, neurokinin A and [Asp5.6,MePhe8]substance P(5-11) (also referred to as NH2-senktide), on the alcohol intake of genetically selected, alcohol-preferring rats. Animals were offered both water and 8% ethanol 2 h/day; tachykinins were administered just before access to fluids. Neurokinin A and substance P did not modify alcohol intake at doses up to 1000 and 2000 ng/rat, respectively. On the other hand, NH2-senktide potently suppressed alcohol intake at doses of 31.2-500 ng/rat. At the same doses, however, it did not significantly affect water intake. This finding suggests that its effect on alcohol intake might be rather selective and not due to general impairment of the behavior. Activation of tachykinin NK-3 receptors, for which NH2-senktide is a highly selective agonist, produces angiotensin II release in the brain; however, the effect of NH2-senktide on alcohol intake is probably not mediated by angiotensin II, as suggested by the fact that it is not modified by captopril pretreatment.     

Loss of adenosine A<Subscript>2B</Subscript> receptor mediated relaxant responses in the aged female rat bladder; effects of dietary phytoestrogens

This study examined the effect of age, ovariectomy and dietary phytoestrogen ingestion on adenosine A_2B receptor mediated relaxant responses and mRNA expression of adenosine receptor subtypes in the rat isolated bladder. Female Wistar rats (8 weeks) were anaesthetised and the ovaries were removed (ovx) or left intact (sham). Rats were fed either normal rat chow (soy, phytoestrogens) or a non-soy (phytoestrogen free) diet. Isolated bladder from rats aged 12, 24 or 52 weeks were pre-contracted with 3 μM carbachol prior to a concentration response curve to 5′-(N-ethylcarboxamido) adenosine (NECA) being obtained. In 12-week-old rats, the bladder exhibited enhanced relaxant responses to NECA in soy-fed rats (P < 0.05), whilst at 24 weeks of age, the relaxant responses to NECA were attenuated in all the groups studied except soy-treated sham rat bladders in which the relaxant responses were enhanced. At 52 weeks of age, no relaxant effects were observed in any of the treatment groups and NECA-induced contractile responses occurred. In all bladders, the adenosine A_2B receptor was the most abundantly expressed. In bladders from young and mature female rats, the mRNA expression of adenosine receptors (A₁, A_2A and A_2B) was lowest in the bladder from non-soy-fed ovariectomised animals and the use of phytoestrogens in the diet increased the mRNA expression of these receptors (P < 0.05). While a soy diet improves the relaxant effects to the adenosine analogue via adenosine A_2B receptors in bladders from younger rats, the benefits are lost with advancing age.     

Combined discriminative stimulus effects of midazolam with other positive GABA<Subscript>A</Subscript> modulators and GABA<Subscript>A</Subscript> receptor agonists in rhesus monkeys

Rationale Interactions among compounds at GABA_A receptors might have important implications for the therapeutic and other effects of positive GABA_A modulators (e.g. benzodiazepines).Objectives This study examined whether a midazolam discriminative stimulus is modified by GABA_A agonists that act at sites other than benzodiazepine sites.Methods Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA_A receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA_A receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam.Results When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1–3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32–1 mg/kg), gaboxadol (3.2–10 mg/kg) and progabide (10–32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive.Conclusions Direct-acting GABA_A receptor agonists are qualitatively different from positive GABA_A modulators in rhesus monkeys trained to discriminate midazolam. Although GABA_A receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA_A receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl^– flux at the GABA_A receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.     

5-HT<Subscript>1A</Subscript> receptor expression during memory formation

Rationale It has been reported that 5-HT_1A receptors modulate learning and memory and diverse pharmacological and genetic evidence supports this notion. Nevertheless, there are few works about expression of these receptors during memory formation. Objective We aimed to determine 5-HT_1A receptor expression in brain areas of untrained, passive, and autoshaping trained groups of rats. Methods Ex vivo receptor autoradiography using the ligand agonist [³H]8-hydroxy-2-[di-n-propylamino]tetralin] (8-OH-DPAT) was used. Results The trained group relative to untrained animals showed increases of 5-HT_1A receptor expression in 14 brain areas, decrements in 7, and no changes in 12. Thus, in contrast to untrained rats, 5-HT_1A receptor expression of autoshaping trained rats was augmented in the tubercule olfactory, septal nucleus, nucleus accumbens, caudate putamen, globus pallidus, striate, and parietal (1 and 2), temporal cortex (1 and 3), granular retrosplenial cortex (1), amygdala, and median and dorsal raphe nuclei. In contrast, in the latter group, receptors were decreased in the CA1 area, hypothalamus dorsal, frontal cortex (1 and 3), occipital cortex, cingulate cortex (1 and 2), and cuneiform nucleus. There were significant differences between passive vs trained groups, but not regarding untrained rats, in the lateral olfactory tract, dentate gyrus, CA3 area, ventromedial hypothalamic, lateral hypothalamus, preoptic medial, frontal cortex (2), granular retrosplenial cortex (2), entorhinal cortex (1 and 2), piriform cortex, and substantia nigra. Conclusions These data suggest that upregulated, downregulated, and “silence” of 5-HT_1A receptors in brain areas form part of neural circuits engaged in memory formation by demonstrating a high degree of specificity and memory mapping.