Initiation of maternal behavior in the rat: possible involvement of limbic norepinephrine

The dorsal norepinephrine (NE) fiber system was manipulated in pregnant female rats. Brainstem lesions of the dorsal bundle, depleting NE in cortex and hippocampus, resulted in deficits in maternal-behavior onset in primiparous rats. Similarly, fornix-bundle transections, depleting only hippocampal NE, were associated with an absence of pup care. Hypothalamic NE levels, as well as dopamine and serotonin concentrations in cortex, hippocampus and hypothalamus, were not significantly affected by these manipulations. The data are discussed in terms of behavioral specificity, possible hormonal involvement and interactions with diencephalic mechanisms controlling the onset of maternal behavior in the female rat.     

Tolerance to cannabinoid-induced behaviors in mice treated chronically with ethanol

Rationale  

Chronic ethanol (EtOH) treatment decreases the motor-impairing effects of cannabinoids and downregulates the cannabinoid type 1 (CB1) receptor. However, these studies have been limited to measures of ataxia and analysis of CB1 expression from whole-brain or hippocampal preparations.     

Dopamine, norepinephrine and serotonin transporter gene deletions differentially alter cocaine-induced taste aversion

Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al., 2005b; Grupp, 1997; Roberts and Fibiger, 1997). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, and SERT, respectively) on cocaine's aversive properties has yet to be performed (Uhl et al., 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT.     

Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception.

Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.     

G-protein mediation of cannabinoid-induced phospholipase activation.

The release of arachidonic acid from mouse peritoneal and S49 cells induced by delta 1-tetrahydrocannabinol was found to be altered by prior exposure of the cells to either pertussis toxin or cholera toxin. The stable analogs of GTP and GDP, GTP-gamma-S and GDP-beta-S, were also effective in changing the extent of arachidonate release in saponin-treated cells. GDP-beta-S essentially abolished the THC response, while GTP-gamma-S showed effects mainly on vehicle-treated cells. The cataleptic action of THC in intact mice which is mediated by eicosanoids was also attenuated by pertussis toxin pretreatment. It is suggested that the THC receptor is coupled to phospholipases through one or more G-proteins and that adenylate cyclase probably does not have a role in this mechanism.     

Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin.     

Acquired aversion to amphetamine solutions

Aversion to d-amphetamine solutions in a two-bottle amphetamine vs. water test increased as the concentration of d-amphetamine was increased. Initial exposure to a high concentration (0.5 mg/cc) of d-amphetamine resulted in a subsequent aversion to a low concentration (0.001 mg/cc). An aversion to a 0.1 mg/cc d-amphetamine solution was rapidly acquired even when the alternative solution was a nonpreferred bitter quinine solution. Significantly, the quinine solution continued to be consumed even when the amphetamine solution was replaced with water. The results were discussed in terms of a learned aversion to amphetamine.     

Mechanism of stress-induced subsensitivity to norepinephrine

Chronic footshock stress in rats produces a persistent reduction in the sensitivity of the norepinephrine (NE)-cAMP generating system in the cerebral cortex, an effect similar to that reported after chronic antidepressant treatment. The present studies show that footshock-induced subsensitivity is not related to changes in either beta or alpha-1 adrenergic receptors, phosphodiesterase or total adenylate cyclase activity. The stress does induce a small, selective decrease in binding at high affinity alpha-2 receptor sites but this change does not appear to explain the decreased responsiveness to NE. These data and related findings by others using restraint stress indicate that the mechanism of subsensitivity after chronic stress resembles in part that seen after antidepressants but may also involve additional phenomena which may not occur after the latter agents.     

Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor. In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn. Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation. These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor. Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This "dual", concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.     

Drug-induced conditioned aversion to mouse-killing in rats

Posttrial administration of atropine methylnitrate (MA) to rats that kill mice resulted in a marked inhibition of mouse-killing behavior. This conditioned aversion to mouse-killing after treatment with MA was more readily produced in rats fed ad lib than in those on a restricted food regimen. Food-deprived rats demonstrated a greater incidence of predatory behavior (i.e., consumption of the prey) than did killer rats not deprived of food. Predatory behavior appeared more sensitive to this conditioned aversion procedure than did the act of killing.     

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.     

Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses

Several anatomical, biochemical and pharmacological evidence support the existence of bidirectional interactions between cannabinoid and opioid systems. The present review is focused on the participation of the endogenous opioid system in the antinociceptive and emotional-like responses induced by cannabinoids, and the development of tolerance to cannabinoid pharmacological effects. Cannabinoid and opioid agonists produce antinociception by acting on similar structures within the central nervous system, and a peripheral mechanism has been also proposed for both compounds. Pharmacological studies have suggested that the endogenous opioid system could be involved in cannabinoid antinociception and the development of cannabinoid tolerance. Recent studies using knockout mice have also demonstrated the role of the opioid system in cannabinoid antinociception and tolerance, although some discrepancies with the previous pharmacological results have been reported when using knockout mice. On the other hand, cannabinoid administration can induce anxiolytic-like responses that are mediated at least in part by an endogenous opioid activity on micro- and delta-opioid receptors.     

Conditioned taste aversion to ethanol induced by zimeldine

Conditioned taste aversions (CTA) were induced to both ethanol and saccharin solutions with the serotonin uptake inhibitor Zimeldine. When animals were pretreated with Zimeldine prior to the presentation of a novel flavour a CTA did not result. However, there is evidence that Zimeldine induces an unconditioned suppression of drinking. These results are discussed in terms of their relevance to Zimeldine's effects on voluntary ethanol consumption.     

Conditioned taste aversion to chlorpromazine,but not to haloperidol

Using in rats a Conditioned Taste Aversion (CTA) procedure, chlorpromazine was shown to possess significant US properties at the highest dose tested (8 mg/kg IP repeated four times). In contrast, haloperidol failed to exert a similar effect at a dosage (1.6 mg/kg IP X 4) at least twice as high, in terms of pharmacological activity, as the effective chlorpromazine dosage. These data suggest that the induction of neuroleptic extrapyramidal side effects and the antidopaminergic properties shared by the two drugs may not be responsible for the aversive effect of chlorpromazine. However, it cannot be excluded than haloperidol produces an aversion which is antagonized by some action of the drug not shared by chlorpromazine.     

Conditioned aversion to a preferred solution following methamphetamine injections

Holtzman (Sprague-Dawley) rats which were injected in amounts ranging from 0.50–3.0 mg/kg i.p. of methamphetamine avoided a 0.1% saccharin solution which had been paired temporally with the injection, and drank water in a subsequent two-bottle choice situation under non-drug conditions. The aversion persisted for the duration of the experiment, which lasted and obtained whether the animals were fluid-deprived or fluid-satiated. Saline-injected controls, on the other hand, exhibited a 90% saccharin solution preference. Rats which received 0.25 mg/kg contiguous with the drug, or animals given 3.0 mg/kg paired with water, exhibited as extreme a preference for the saccharin solution as did the saline controls. It was concluded that neither a drugmediated taste quality change nor physiological cues associated with thirst were adequate axplanations for the avoidance behavior exhibited, but that the drug was perceived as a noxious stimulus at levels above 0.50 mg/kg under the conditions described above.This experiment was supported in part by grants HD 00668 and 1 RO 1 MH 18904 from NIH and NIMH, and by a grant the Committee on Tobacco and Health, American Medical Association.     

Supersensitivity to norepinephrine induced by prenatal exposure to ethanol

Pregnant random bred mice were treated with ethanol (ETOH) (0.33 g/kg) for 1 or 2 days prior to parturition. When compared to saline controls, ETOH-treated adult males had vasa deferentia that were supersensitive to norepinephrine (NE). Tissues from mice prenatally treated for 1 day with ETOH showed a decreased response to electrical stimulation whereas vas deferens obtained from 2-day-treated ethanol showed no significant difference in the response compared to that of controls. These findings indicate that prenatal exposure to ETOH can influence the subsequent sensitivity of the vas deferens to adrenergic stimulation. These changes appear to reflect effects of ETOH during critical periods.