Search PubMed⌕ Search

Biomedical subjects

L H Parsons

Publications and source records attributed to L H Parsons.

At least 19 recordsLinked to original sources
PubMed2006

Basis of the gabamimetic profile of ethanol.

This article summarizes the proceedings of a symposium held at the 2005 Research Society on Alcoholism meeting. The initial presentation by Dr. Wallner provided evidence that selected GABA(A) receptors containing the delta subunit display sensitivity to low intoxicating ethanol concentrations and this sensitivity is further increased by a mutation in the cerebellar alpha6 subunit, found in alcohol-hypersensitive rats. Dr. Mameli reported that ethanol affects gamma-aminobutyric acid (GABA) function by affecting neural circuits that influence GABA release. Dr. Parsons presented data from electrophysiological and microdialysis investigations that ethanol is capable of releasing GABA from presynaptic terminals. Dr. Morrow demonstrated that systemic ethanol increases neuroactive steroids in brain, the absence of which alters various functional responses to ethanol. Dr. Criswell presented evidence that the ability of ethanol to increase GABA was apparent in some, but not all, brain regions indicative of regional specificity. Further, Dr. Criswell demonstrated that neurosteroids alone and when synthesized locally by ethanol act postsynaptically to enhance the effect of GABA released by ethanol in a region specific manner. Collectively, this series of reports support the GABAmimetic profile of acutely administered ethanol being dependent on several specific mechanisms distinct from a direct effect on the major synaptic isoforms of GABA(A) receptors.

Alcoholism↗
PubMed2004

Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels.

Previous work has demonstrated that peripheral serotonin(1B) (5-HT(1B)) receptor agonist administration facilitates the behavioral and neurochemical effects of cocaine. This study used dual probe microdialysis to investigate whether activation of serotonin(1B) (5-HT(1B)) receptors in the ventral tegmental area (VTA) alters the ability of peripherally administered cocaine to elevate dopamine (DA) levels in the ipsilateral nucleus accumbens (NAcc) of drug-naive Wistar rats. Intra-VTA administration of the selective 5-HT(1B) agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b]pyridin-5-one dihydrochloride (CP 93,129) by reverse dialysis produced a dose-dependent (30 and 100 microM) potentiation of cocaine-induced (10 mg/kg i.p.) increases in NAcc DA efflux and concurrent cocaine-induced decreases in VTA GABA efflux. There was no effect of either local CP 93,129 or peripheral cocaine on VTA glutamate efflux. Intra-VTA administration of the 5-HT(1A/7) receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT; 100 microM) did not alter cocaine-induced alterations in NAcc DA or VTA GABA, suggesting that the effects of CP 93,129 were not mediated through 5-HT(1A) receptors. Moreover, the effects of intra-VTA CP 93,129 (100 microM) on both cocaine-induced increases in NAcc DA levels and cocaine-induced decreases in VTA GABA levels were reversed by coadministration of the selective 5-HT(1B) receptor antagonist 3-[3-(dimethylamine)propyl]-4-hydroxy-N-[4-(4-pyridinyl] phenyl] benzamide dihydrochloride (GR 55562; 300 microM). In the absence of cocaine, intra-VTA CP 93,139 produced an increase in NAcc DA and decrease in VTA GABA levels. However, intra-VTA GR 55562 alone had no effect on any of our neurochemical measures. These findings indicate that activation of VTA 5-HT(1B) receptors potentiates cocaine-induced increases in NAcc DA levels by enhancing the ability of cocaine to decrease VTA GABA efflux.

Animals↗
PubMed2002

5-HT(6) receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine.

The localization of serotonin 5-HT(6) receptors in limbic and motor brain regions, and the high affinity of these receptors for several antipsychotic agents, suggest that they may be involved in motor activity, reward-related behaviors, and psychotic disorders. The present study characterized the effects of a novel 5-HT(6) receptor antagonist, SB 258510A, on psychostimulant-induced motor activity, self-administration, and increases in extracellular dopamine in the nucleus accumbens and frontal cortex of male Wistar rats. The locomotor-activating effects of amphetamine (1mg/kg) were dose-dependently enhanced by pretreatment with SB 258510A (3, 10mg/kg). Similarly, amphetamine self-administration was dose-dependently altered by SB 258510A in a manner indicative of enhanced reinforcing effects of amphetamine on both fixed and progressive ratio schedules of reinforcement. SB 258510A treatment had no effect on either cocaine-induced locomotor activity or cocaine self-administration. Dual-probe in vivo microdialysis revealed that pretreatment with 3mg/kg SB 258510A potentiated an amphetamine-induced increase in extracellular dopamine more robustly in the frontal cortex than in the nucleus accumbens. These data indicate that activation of 5-HT(6) receptors may regulate behaviors related to amphetamine but not cocaine, and point to the frontal cortex as a possible site of action for these effects.

Amphetamine↗
PubMed2001

Functional consequences of repeated (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys.

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

Animals↗
PubMed2001

5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.

Mutant mice that lack serotonin(1A) receptors exhibit enhanced anxiety-related behaviors, a phenotype that is hypothesized to result from impaired autoinhibitory control of midbrain serotonergic neuronal firing. Here we examined the impact of serotonin(1A) receptor deletion on forebrain serotonin neurotransmission using in vivo microdialysis in the frontal cortex and ventral hippocampus of serotonin(1A) receptor mutant and wild-type mice. Baseline dialysate serotonin levels were significantly elevated in mutant animals as compared with wild-types both in frontal cortex (mutant = 0.44 +/- 0.05 n M; wild-type = 0.28 +/- 0.03 n M) and hippocampus (mutant = 0.46 +/- 0.07 n M; wild-type = 0.27 +/- 0.04 n M). A stressor known to elicit enhanced anxiety-like behaviors in serotonin(1A) receptor mutants increased dialysate 5-HT levels in the frontal cortex of mutant mice by 144% while producing no alteration in cortical 5-HT in wild-type mice. There was no phenotypic difference in the effect of this stressor on serotonin levels in the hippocampus. Fluoxetine produced significantly greater increases in dialysate 5-HT content in serotonin(1A) receptor mutants as compared with wild-types, with two- and three-fold greater responses being observed in the hippocampus and frontal cortex, respectively. This phenotypic effect was mimicked in wild-types by pretreatment with the serotonin(1A) antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (p-MPPI). These results indicate that deletion of central serotonin(1A) receptors results in a tonic disinhibition of central serotonin neurotransmission, with a greater dysregulation of serotonin release in the frontal cortex than ventral hippocampus under conditions of stress or increased interstitial serotonin levels.

Aminopyridines↗
PubMed2001

Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors.

The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5-HT transmission in the nucleus accumbens--neurochemical systems that are activated by cocaine and ethanol self-administration and deficient during withdrawal--as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli. The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug-related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior. Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.

Adaptation, Physiological↗
PubMed2000

Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants: potential mechanism for addiction vulnerability.

Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viral-induced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of d-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity.

Animals↗
PubMed2000

Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.

The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the long-term addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (SDeltas) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective SDeltas were withheld until the animals reached an extinction criterion of </=4 responses over three consecutive sessions. Subsequent re-exposure to the cocaine SDelta, but not the nonreward SDelta, produced strong recovery of responding at the previously active lever in the absence of any further drug availability. The efficacy and behavioral selectivity of the cocaine SDelta remained unaltered throughout an 8-day test period. Exposure to the cocaine SDelta significantly increased dopamine efflux in the NAcc and amygdala as measured by intracranial microdialysis in a separate group of rats. Dopamine levels remained unaltered in the presence of the nonreward SDelta. The results demonstrate that cocaine-predictive stimuli elicit robust and persistent cocaine-seeking behavior, and that this effect may involve activation of dopamine transmission in the NAcc and amygdala.

Amygdala↗
PubMed1999

RU 24969, a 5-HT1A/1B agonist, elevates brain stimulation reward thresholds: an effect reversed by GR 127935, a 5-HT1B/1D antagonist.

Recent studies suggest that serotonergic neurotransmission through the serotonin-1B (5-HT1B) receptor is involved in reward processes. The purpose of the present studies was to investigate the effects of 5-HT(1B) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a current-threshold ICSS task. Male Wistar rats were prepared with bipolar electrodes in the lateral hypothalamus. When stable baseline thresholds were established, the effects of the mixed 5-HT(1A)/1B receptor agonist, RU 24969 (0-1 mg/kg, SC), on ICSS behavior were assessed. Administration of this compound elevated ICSS thresholds without affecting response latencies, a measure of general motoric activity. The 5-HT(1B/1D) receptor antagonist, GR 127935 (0-10 mg/kg, SC), had no significant effect on ICSS behavior. However, pretreatment with an intermediate dose of GR 127935 (3 mg/kg), which was previously without effect on ICSS behavior, reversed the threshold-elevating effects of RU 24969 (1 mg/kg), suggesting the involvement of the 5-HT1B receptor in this effect of RU 24969 administration. Furthermore, pretreatment with RU 24969 (0.3 and 0.6 mg/kg), prior to 10 mg/kg cocaine hydrochloride, dose-dependently attenuated the threshold-reducing effects of cocaine. This result is interpreted as two opposing drug effects canceling each other out rather than a specific pharmacological antagonism. In conclusion, the results suggest that activation of 5-HT(1B) receptors reduces brain stimulation reward.

Animals↗
PubMed1999

Violent maternal deaths in North Carolina.

OBJECTIVE: To describe the frequency of domestic violence and substance abuse among a series of injury-related maternal deaths, determine awareness of the obstetric provider of domestic violence in those deaths by intimate partner homicide or depression in those deaths by suicide, and examine the relative risk of violent maternal death for unmarried status and non-white race. METHODS: A follow-up investigation was carried out for a case series of 41 injury-related maternal deaths identified from 1992 to 1994 in North Carolina. Death certificates, police records, newspapers, and records from medical examiners were used to ascertain mechanism and intent, history of alcohol or drug abuse, and, in cases of homicide, the relationship of the perpetrator to the victim. The obstetric provider was asked about his or her knowledge of domestic violence, depression, and drug or alcohol abuse relevant to the deceased victim. RESULTS: A total of 21 women (51.2%) were known to have or suspected of having been abused by either an intimate partner or an acquaintance. Of the 41 women, 11 (26.8%) were known to have abused drugs and/or alcohol. The obstetric provider was aware or suspicious of abuse in one third of homicides committed by an intimate partner. In three of the five suicide deaths, the obstetric provider was aware of depression. CONCLUSION: Domestic violence and drug and alcohol abuse were common in this series of injury-related maternal deaths. Domestic violence and depression were often unrecognized by the obstetric provider in these severe cases.

Adult↗
PubMed1999

Dopamine activation of endogenous cannabinoid signaling in dorsal striatum.

We measured endogenous cannabinoid release in dorsal striatum of freely moving rats by microdialysis and gas chromatography/mass spectrometry. Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol. Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride. Administration of the D1-like (D1, D5) receptor agonist SKF38393 had no such effect. These results suggest that functional interactions between endocannabinoid and dopaminergic systems may contribute to striatal signaling. In agreement with this hypothesis, pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole. The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice. These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs.

Animals↗
PubMed1998

Serotonin1B receptor stimulation enhances cocaine reinforcement.

The effects of serotonin1B [5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- benzamide (p-MPPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Simple microbore high-performance liquid chromatographic method for the determination of dopamine and cocaine from a single in vivo brain microdialysis sample.

A microbore chromatographic method for the analysis of both dopamine and cocaine from in vivo brain microdialysis samples is described. To eliminate the need for separate chromatographic systems for each analyte, post-column electrochemical and ultraviolet detection systems were arranged in series. The limit of quantitation for dopamine (5 fmol) was well within range for detecting dialysate concentrations of this neurotransmitter in rats which were in a baseline, drug-free state. The limit of quantitation for cocaine (0.5 pmol) was sufficient to detect brain cocaine levels following the peripheral administration of a low dose of this psychostimulant (5 mg/kg, i.p.). Estimates of dialysate dopamine and cocaine concentrations after 5, 10 and 20 mg/kg cocaine (i.p.) were in agreement with reports which utilized separate HPLC analyses for each analyte.

Animals↗
PubMed1998

The prevalence of domestic violence among women seeking abortion.

OBJECTIVE: To determine the prevalence of self-reported abuse in a population of women aged 18 years or older seeking elective pregnancy termination, and to compare abused and nonabused women with respect to the primary reasons for pregnancy termination. METHODS: A self-administered questionnaire was returned by 486 women seeking outpatient abortion. The survey included demographic information, abuse screening, and items regarding partner involvement/awareness of the pregnancy, and abuse as a determinant of the abortion decision. One open-ended item asking the primary reason for pregnancy termination was included. RESULTS: The prevalence of self-reported abuse in this population was 39.5%. White women were significantly more likely to report any history of abuse than nonwhite women. Relationship issues were the only reason for pregnancy termination given more often by women with an abuse history than by nonabused women. Women with abuse histories were significantly less likely than nonabused women to inform the partner of the pregnancy or to have partner support for or involvement in the abortion decision. CONCLUSION: The prevalence of abuse reported by women in this population suggests that many women seeking abortion services may have abuse histories. Abused women may have different reasons for pregnancy termination than nonabused women and may be more likely to make the abortion decision without partner involvement. When routine screening for abuse is included in abortion counseling, health providers have the opportunity for developing a safety plan and initiating appropriate referral.

Abortion Applicants↗
PubMed1998

Substance dependence as a compulsive behavior.

A compulsion to take a drug combined with a loss of control in limiting intake is the defining feature of substance dependence or addiction, and is the conceptual framework for the criteria of substance dependence or addiction outlined by the World Health Organization and the American Psychiatric Association. However, defining exactly what constitutes loss of control and compulsive drug taking at the level of animal models is a daunting task, and it is clear that no validated animal model exists for the whole syndrome of addiction. The present discussion redefines loss of control as a narrowing of the behavioral repertoire toward drug-seeking behavior and suggests that there are many sources of reinforcement that contribute to this behavioral focus on drug seeking. Evidence is presented demonstrating separate animal models for many of these sources of reinforcement as well as for most of the criteria for substance dependence. Evidence is also presented showing that the brain neurochemical systems involved in processing drug reward are altered by chronic drug exposure to contribute additional sources of reinforcement. Challenges for the future involve not only elucidation of the neurobiological substrates of the different behavioral components of addiction, but better animal models of these components with which to effect such studies.

Animals↗
PubMed1998

Neurocircuitry targets in ethanol reward and dependence.

Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol-sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA-A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin-releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.

Alcohol Drinking↗