Effects of monoamine oxidase inhibitors on performance during differential reinforcement of low response rate

The effects of three monoamine oxidase inhibitors (MAOI) on performance under a differential-reinforcement-of-low-rate 72-s schedule (DRL 72-s) for water reinforcement were determined. All three drugs (isocarboxazid, iproniazid, phenelzine) reduced response rate and increased reinforcement rate in rats performing under the DRL schedule. Drugs from other classes (alcohol, chlordiazepoxide, morphine, pentobarbital) did not produce similar effects. The ability of MAOI to increase reinforcement rate under a DRL 72-s schedule is similar to that recently reported for tricyclic antidepressants and the two atypical antidepressants mianserin and iprindole. These findings support the contention that the DRL schedule may be useful as a test for identifying new antidepressants and for elucidating the neurochemical effects of antidepressants that are responsible for their therapeutic actions.     

Effects of the beta-2 adrenergic agonist zinterol on DRL behavior and locomotor activity

The purpose of the present study was to assess the behavioral effects of the beta adrenergic agonist zinterol and to determine whether its actions were mediated by beta adrenergic receptors. Zinterol reduced response rate and increased reinforcement rate of rats under a differential-reinforcement-of-low-rate schedule in a dose-dependent manner; significant decreases in response rate and increases in reinforcement rate were observed at doses of 0.1–1 mg/kg. The effect of 0.3 mg/kg zinterol on this behavior was blocked by pretreatment with the beta adrenergic antagonist propranolol. Zinterol also reduced locomotor activity in a dose-dependent manner; significant reductions were observed at doses of 0.3–10 mg/kg. Similarly, the effect of 1 mg/kg zinterol on locomotor activity was antagonized by propranolol. These effects of zinterol were similar to those of other beta adrenergic agonists as well as those of antidepressant drugs. Although the site of action (central versus peripheral) of zinterol was not determined in the present study, an experiment was carried out to determine if zinterol could act centrally after peripheral administration. The ability of repeated, systemic administration of zinterol to reduce the density of beta adrenergic receptors in cerebral cortex and cerebellum was determined. Repeated treatment with a high dose of zinterol (10 mg/kg, IP) reduced the density of beta adrenergic receptors in these brain regions, suggesting that, at least under certain conditions, systemically administered zinterol did have access to the central nervous system.     

Differential sensitivity to the effects of albuterol on locomotor activity and operant behavior

The purpose of the present study was to determine the effects of the beta-2 selective adrenergic agonist albuterol on three behaviors, locomotor activity, behavior maintained under a differential-reinforcement-of-low-rate (DRL) schedule, and behavior maintained under a multiple fixed-interval, fixed-ratio (FI-FR) schedule of reinforcement. Albuterol reduced response rate under the DRL schedule in a manner that resulted in an increase in reinforcement rate. Similarly, albuterol reduced response rate under both components of the multiple FI-FR schedule in a dose-dependent manner. The ED₅₀ values for the effects of albuterol on these two operant behaviors were calculated to be approximately 1 mg/kg and the minimal effective doses were 0.3–1 mg/kg. In addition to affecting operant behavior, albuterol also reduced locomotor activity; the ED₅₀ values and minimal effective doses were 0.05 and 0.03 mg/kg, respectively. The effects of albuterol on DRL behavior, FI-FR behavior and locomotor activity were antagonized by the beta adrenergic antagonist propranolol; this suggests that the behavioral effects of this agonist were mediated, at least in part, by beta adrenergic receptors. The differential sensitivity of locomotor activity and operant behavior to albuterol suggests that the actions of this drug on locomotor activity may be mediated predominantly by peripheral beta adrenergic receptors and that its effects on operant behavior may be mediated by beta adrenergic receptors in the central nervous system.     

Monoamine oxidase of types A and B in the saphenous vein and mesenteric artery of the dog

Summary Homogenates of dog saphenous vein and mesenteric artery were prepared in phosphate buffer. Monoamine oxidase (MAO) activity was determined with ³H-5-hydroxytryptamine (³H-5-HT) as a preferential substrate for MAO type A, ¹⁴C--phenylethylamine as a preferential substrate for MAO type B, and ³H-tyramine as a substrate for both MAO types. K _m and V _max for the different substrates were determined, and clorgyline and (–)-deprenyl were used as specific inhibitors. The endogenous noradrenaline content was compared with the activity of MAO in both blood vessels. The results show that the enzymatic deamination of tyramine is slightly but significantly higher in the mesenteric artery than in the saphenous vein. MAO A activity was significantly higher in the mesenteric artery than in the saphenous vein, but MAO B activity was the same in both vessels. Hence, the ratio MAO A activity/MAO B activity was greater for the mesenteric artery than for the saphenous vein. This difference may be related to the density of the adrenergic innervation of the two blood vessels.Some of the results were presented to the 10^th Annual Meeting of the Portuguese Pharmacological Society (Oeiras, 1979) and to the 4^th Meeting on Adrenergic Mechanisms (Porto, 1980)On leave from Faculdade de Farmácia, Universidade de Coimbra, with a grant from Instituto Nacional de Investigação Científica     

The relationship between acetylator status and inhibition of monoamine oxidase,excretion of free drug and antidepressant response in depressed patients on phenelzine

This study was designed to examine the hypothesis that phenelzine is metabolized by polymorphic acetylation and that its effects are dependent on acetylator status. 30 depressed inpatients were given a 3-week course of phenelzine 30 mg t.i.d. The antidepressant effect, the degree of inhibition of monoamine oxidase and the amount of free phenelzine excreted in the urine were all significantly greater in slow acetylators than in fast. These findings strongly support the hypothesis.     

Buspirone,gepirone, ipsapirone,and zalospirone have distinct effects on the differential-reinforcement-of-low-rate 72-s schedule when compared with 5-HTP and diazepam

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT_1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT_1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT_1A receptor.     

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amitriptyline, (-) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.     

Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines.Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity).Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels.MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.     

Effects of clorgyline and (−)deprenyl on the deamination of normetanephrine and noradrenaline in strips and homogenates of the canine saphenous vein

Summary The influence of specific inhibitors of MAO A (clorgyline) and MAO B [(–)deprenyl] on the metabolism of normetanephrine (NMN), in strips of canine saphenous vein was studied, both in the absence and in the presence of inhibitors of neuronal (cocaine) and extraneuronal (hydrocortisone) uptake. Moreover, the formation of metabolites of noradrenaline and of NMN by saphenous vein homogenates and the influence of clorgyline or (–)deprenyl on this formation are described.Clorgyline reduced to the same degree (by about 70%) the formation of methoxy-hydroxy-phenylglycol (MOPEG) and of vanillylmandelic acid (VMA) in strips incubated with NMN, whereas (–)deprenyl reduced by about 50% the formation of MOPEG and had no effect on VMA production. Hydrocortisone had effects very similar to those of (–)deprenyl.Saphenous vein, homogenates ()-methylation inhibited), deaminated both noradrenaline and NMN; clorgyline and (–)deprenyl reduced the formation of metabolites of both noradrenaline and NMN.It is concluded that both MAO A and B are able to deaminate noradrenaline and NMN, but that in the intact tissue the former has no access to MAO B. Even in intact tissues MAO B may play a role in the metabolism (but not in the inactivation) of noradrenaline by deaminating the NMN formed from noradrenaline and giving preferentially origin to MOPEG.Supported by Instituto Nacional de Investigação Científica (INIC, FmPl)On leave from Faculdade de Farmácia, Universidade de Coimbra, with a grant from Instituto Nacional de Investigação Científica     

The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat

Rationale: Endogenous opioid systems within the mesencephalic periaqueductal gray matter (PAG) appear to be intricately involved in many affective, defensive, submissive, and reflexive responses, and these systems are activated by aversive stimuli. Objectives: The present experiments evaluated the influence of opioid receptors within the PAG on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Methods: Defeat stress consisted of: (1) an aggressive confrontation with a ”resident” stimulus rat in which the experimental ”intruder” rat exhibited escape, defensive and submissive behaviors [i.e. upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident rat with a wire mesh screen for ca. 25 min. Defeat stress was immediately followed by an experimental session with thermal antinociceptive and tactile startle stimuli (20 psi airpuffs). Results: The μ opioid receptor agonist morphine (0.3, 1, 3 μg IC) attenuated startle-induced USV and the tail-flick reflex in socially inexperienced and defeated rats, with both groups of rats demonstrating equal sensitivity to morphine. Morphine decreased defeat-induced USV and increased the display of the crouch posture in defeated rats; these morphine effects in socially inexperienced and defeated rats were re- versed with the opioid receptor antagonist naltrexone (0.1 mg/kg IP). Conclusions: These results reveal that the ventrolateral PAG is an important site in which μ opioid receptor agonists such as morphine mediate affective vocal and submissive responses, yet this structure is not critical in the display of defeat stress-augmented effects of morphine. Endogenous opioid mechanisms appear to participate in the organization of defensive behavior, namely, to facilitate a shift from active to passive forms of coping. Received: 9 November 1998 / Final version: 29 April 1999     

Antagonism of the Acute and Long–term Biochemical Effects of 4–Chloroamphetamine on the 5–HT Neurones in the Rat Brain by Inhibitors of the 5–Hydroxytryptamine Uptake

Abstract The effects of H 102/09 ((Z)–3–(4–bromophenyl)–N, N–dimethyl–3–(3–pyridyl)allylamine dihydrochloride) and chlorimipramine, two inhibitors of the membrane 5–hydroxytryptamine (5–HT) uptake, on the acute and long–term effects of 4–chloroamphetamine on the 5–HT neurones in rats were examined. The acute effect determined as the decrease in the brain level of 5–HT was antagonized by both compounds. The long–term effects determined as the decreases in 5–hydroxyindoles and the synaptosome accumulation of ¹⁴–C–5–HT were antagonized by a single injection of H 102/09 (20 mg/kg intraperitoneally) immediately before or shortly after the 4–chloroamphetamine administration. Chlorimipramine, 40 mg/kg intraperitoneally, had no antagonizing effect but on repeated injections of 40 mg/kg intraperitoneally before and four times with 3 hours' intervals after 4–chloroamphetamine, a partial antagonism of the longterm decrease in 5–HT was obtained. Combined with proadifen (SK & F 525 A) chlorimipramine partially antagonized the long–term effect. Two monoamine oxidase inhibitors (pheniprazine and clorgyline), pretreatment of the rats with p–chlorophenylalanine (2 × 300 mg/kg intraperitoneally) or proadifen alone (40 mg/kg intraperitoneally injected before and four times with 3 hours' interval) had no antagonistic effect on the long–term decrease in 5–HT. The accumulation of ³H–chloroamphetamine in synaptosomes of the hypothalamus midbrain region was slightly decreased by high concentrations of H 102/09 at 37° and 0°. H 102/09 decreased slightly but significantly the ratio between the ³H–chloramphetamine in the synaptosomal fraction and the supernatant as obtained when the rats were killed 2 hours after the injection. The increased efflux of ³H–5–HT from synaptosomes in vitro produced by 4–chloroamphetamine, ouabain and low external Na⁺ concentrations was in all cases inhibited by H 102/09 at 2.5 × 10^–6 M. Although the antagonism of the acute effect of 4–chloroamphetamine seems to be related to inhibition of the membrane 5–HT transport mechanism the antagonism of the long–term, irreversible effect produced by 4–chloroamphetamine may also involve an additional as yet unknown mechanism.     

Comparative effects of 1α‐hydroxyvitamin D3 and 1,25‐dihydroxyvitamin D3 on transporters and enzymes in fxr(+/+) and fxr(‐/‐) mice

Previous studies have shown that 1α,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P‐gp expression. The present study compared the equimolar efficacies of 1α‐hydroxyvitamin D₃ [1α(OH)D₃] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half‐life that is converted to 1,25(OH)₂D₃, and 1,25(OH)₂D₃ on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)‐directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(‐/‐)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D₃ and 1,25(OH)₂D₃, 1α(OH)D₃ treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(‐/‐) mice compared to 1,25(OH)₂D₃ treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P‐gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D₃ treatment. The higher activity of 1α(OH)D₃ was explained by its rapid conversion to 1,25(OH)₂D₃ in tissue sites, furnishing higher plasma and tissue 1,25(OH)₂D₃ levels compared to following 1,25(OH)₂D₃‐treatment. In conclusion, 1α(OH)D₃ exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)₂D₃ in mice. Copyright © 2013 John Wiley & Sons, Ltd.     

Potential protective effects of a traditional Chinese herb,Litsea coreana Levl., on liver fibrosis in rats

Objectives It was found that total flavonoids from Litsea coreana Levl. (TFLC), which is a traditional Chinese medicine, had a preventive effect against hepatic steatosis in our previous study. This study was designed to evaluate whether TFLC could improve liver fibrosis in rats. Methods The liver fibrosis model rats were treated with composite factors of high‐fat emulsion (10 ml/kg) via gavage accompanied by a subcutaneous injection of low‐dose CCl₄. Thirty rats were given composite factors plus TFLC (100, 200, 400 mg/kg), respectively, for 8 weeks. Key findings The results showed that TFLC (200 and 400 mg/kg) treatment significantly reduced the elevation of liver index (liver weight/body weight) and spleen index (spleen weight/body weight), alanine transaminase, aspartate aminotransferase, hyaluronic acid, laminin, procollagen III N‐terminal peptide, procollagenase IV and hydroxyproline. In addition, TFLC treatment improved the morphologic changes of hepatic fibrosis, suppressed expression of α‐smooth muscle actin, collagen I, transforming growth factor (TGF)‐β1 and TGFβ receptor (TGFβR)1, and increased peroxisome proliferator‐activated receptor‐γ expression in the liver of hepatic fibrosis rats. Conclusions In conclusion, TFLC is able to ameliorate liver injury and protect rats from liver fibrosis. This process may be related to inhibiting the expression of transforming growth factor‐β1 and increasing the expression of peroxisome proliferator‐activated receptor‐γ.     

The NMDA positive modulatord-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat

According to the view that N-methyl-d-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulatord-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D₁ dopamine receptor blocker SCH 23390 or the D₂ antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore, the positive NMDA modulator allowed (–)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.     

The effects of cocaine and denervation on the sensitivity to noradrenaline,its uptake and the termination of its action in isolated venous tissue

Summary The action of staphylococcal alpha toxin (ST) on potential difference (PD) and short-circuit current (SCC) of the isolated frog skin was studied. Ringer solution bathed the corial side and 20 mM NaCl bathed the epidermal side. PD and SCC decreased to about half after the administration of ST to the corial side of the skin. Later, SCC raised considerably. The replacement of 20 mM NaCl by KCl on the epidermal side of the ST-pretreated skin did not cause any substantial decrease of PD, while in the untreated skin the same replacement caused a sharp drop of PD. No secondary increase of SCC was observed after ST administration when the Ringer solution bathing the corial side of the skin contained 1/2 S0₄ ^– instead Cl^–. In contrast to the normal skin, dilution from 120 to 2 mM of the NaCl solution on the epidermal side led to a PD increase in the toxin-treated skin.Na⁺ fluxes across the skin in both directions were measured by means of radioisotopes. The direction of net flux of Na⁺ was reversed after treatment with the toxin. The results demonstrated two phases of ST action. Na⁺ transport is damaged in the first phase; in the second phase an outflux of Cl^– is induced.The changes of water permeability of the frog urinary bladder were determined by weighing bags formed from the bladders. The addition of the toxin to the medium bathing the serosal side resulted in increased weight losses. The transport of water was increased.A preliminary account of some of these results was presented (Kadlec and apek, 1969).     

Differential effects of glibenclamide on responses to thromboxane A2 mimic, U46619, in the pulmonary and hindquarters vascular beds of the cat

The inhibitory effects of the oral sulfonylurea, glibenclamide, on vasoconstrictor responses to the thromboxane A₂ mimic, U46619, were investigated in the pulmonary and hindquarters vascular beds of the cat under constant flow conditions. When lobar arterial tone was at resting conditions (14±2 mm Hg), intralobar injections of U46619, prostaglandin F_2α, prostaglandin D₂, angiotensin II, norepinephrine, and BAY K 8644 caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following an intralobar infusion of glibenclamide (5 mg/kg), vasoconstrictor responses to U46619, prostaglandin F_2α and prostaglandin D₂ were significantly reduced, whereas vasoconstrictor responses to norepinephrine and angiotensin II were not altered and responses to BAY K 8644 were significantly enhanced. When tone in the pulmonary vascular bed was raised to a high steady level (36±3 mm Hg), glibenclamide in a dose of 5 mg/kg i.a. markedly attenuated responses to injections of U46619 and reduced the vasodilator responses to the K⁺-ATP channel opener, levcromakalim, whereas responses to acetylcholine and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide donor, were not changed. In the hindquarters vascular bed of the cat, administration of glibenclamide in a dose of 5 mg/kg i.a. had no significant effect on vasoconstrictor responses to U46619, norepinephrine or angiotensin II. Hindquarters vasodilator responses to levcromakalim, but not to nitric oxide, were decreased significantly following administration of glibenclamide. These data suggest that glibenclamide, in addition to inhibiting K⁺-ATP channels, has thromboxane A₂ receptor blocking activity in the pulmonary vascular bed of the cat. These data also suggest that vasoconstrictor responses to U46619 may be mediated by different thromboxane A₂ receptors with different binding affinities in the pulmonary and in the hindquarters vascular beds of the cat.     

Biphasic effects of δ9-tetrahydrocannabinol on variable interval schedule performance in rats

Four rats were trained to barpress for water reinforcement under a variable interval 60 sec schedule. Nine acute administrations of (–) ⁹-trans-tetrahydrocannabinol, in amounts ranging from 0.25 to 16.0 mg/kg, produced dose-related effects on responding; overall response rate increased at lower doses, while higher doses produced ataxia and a complete suppression of responding. Increased response rates reflected changes both in response spacing and in the lengths of post-reinforcement pauses. It was concluded that marihuana has a biphasic effect on variable interval water-reinforced behavior in rats.The authors thank Reid Vandell for his assistance in collecting the data. Research supported by National Institute of Mental Health Grant MH20363-01 to D. P. Ferraro. Synthetic ⁹-THC obtained by approval of the FDA-NIMH Psychotomimetic Agents Advisory Committee. The animals involved in this study were maintained in accordance with Guide for Laboratory Animal Facilities and Care as published by the National Academy of Sciences-National Research Council.     

Differential effects of acute cannabinoid drug treatment,mediated by CB<Subscript>1</Subscript> receptors,on the in vivo activity of tyrosine and tryptophan hydroxylase in the rat brain

The acute effects of cannabinoid drugs on the synthesis of noradrenaline, dopamine, and serotonin (5-HT) were assessed, simultaneously, using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Treatment (1 h, i.p.) with ⁹-tetrahydrocannabinol (THC, 5, 10, and 20 mg/kg) and the cannabinoid receptor agonist WIN 55,212–2 (WIN, 2 and 4 mg/kg) increased dopa/noradrenaline synthesis (40–70%) in various brain regions enriched in this neurotransmitter (e.g., cerebral cortex, hippocampus, hypothalamus). In most brain regions, the content of noradrenaline was reduced by cannabinoid drugs (27–66%). For the effects of WIN (2 and 4 mg/kg), an inverse correlation (r=–0.61, P=0.036) was obtained between the accumulation of dopa and the content of noradrenaline in the hypothalamus. The stimulatory effect on dopa accumulation induced by THC was antagonized by the selective CB₁ receptor antagonists SR141716A and AM 281 (10 mg/kg). In contrast, THC and WIN decreased the synthesis of dopa/dopamine in the corpus striatum (16–37%) and that of 5-HTP/5-HT (20–35%) in brain regions enriched in 5-HT (e.g., cerebral cortex and hippocampus). These inhibitory effects of THC and WIN were also antagonized by AM 281 and/or SR141716A. THC did not alter the content of 5-HT or dopamine in the brain. The effects may be related to the activation of presynaptic inhibitory cannabinoid CB₁ receptors located on the neurones themselves (serotonin) and on facilitatory (dopamine) and inhibitory interneurones (noradrenaline).